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Psychopharmacology Jul 2024Medications are urgently needed to treat symptoms of drug withdrawal and mitigate dysphoria and psychiatric comorbidities that drive opioid abuse and relapse. ITI-333 is...
RATIONALE
Medications are urgently needed to treat symptoms of drug withdrawal and mitigate dysphoria and psychiatric comorbidities that drive opioid abuse and relapse. ITI-333 is a novel molecule in development for treatment of substance use disorders, psychiatric comorbidities, and pain.
OBJECTIVE
Characterize the preclinical profile of ITI-333 using pharmacological, behavioral, and physiological assays.
METHODS
Cell-based assays were used to measure receptor binding and intrinsic efficacy of ITI-333; animal models were employed to assess effects on opioid reinstatement, precipitated oxycodone withdrawal, and drug abuse liability.
RESULTS
In vitro, ITI-333 is a potent 5-HT receptor antagonist (K = 8 nM) and a biased, partial agonist at μ-opioid (MOP) receptors (K = 11 nM; lacking β-arrestin agonism) with lesser antagonist activity at adrenergic α (K = 28 nM) and dopamine D (K = 50 nM) receptors. In vivo, ITI-333 blocks 5-HT receptor-mediated head twitch and MOP receptor-mediated effects on motor hyperactivity in mice. ITI-333 alone is a naloxone-sensitive analgesic (mice) which suppresses somatic signs of naloxone-precipitated oxycodone withdrawal (mice) and heroin cue-induced reinstatement responding without apparent tolerance or physical dependence after chronic dosing (rats). ITI-333 did not acutely impair gastrointestinal or pulmonary function (rats) and was not intravenously self-administered by heroin-maintained rats or rhesus monkeys.
CONCLUSIONS
ITI-333 acts as a potent 5-HT receptor antagonist, as well a biased MOP receptor partial agonist with low intrinsic efficacy. ITI-333 mitigates opioid withdrawal/reinstatement, supporting its potential utility as a treatment for OUD.
Topics: Animals; Mice; Male; Substance Withdrawal Syndrome; Rats; Humans; Rats, Sprague-Dawley; Receptors, Opioid, mu; Serotonin 5-HT2 Receptor Antagonists; Substance-Related Disorders; Opioid-Related Disorders; Dose-Response Relationship, Drug; Oxycodone; Analgesics, Opioid; Self Administration; Cricetulus; CHO Cells
PubMed: 38710856
DOI: 10.1007/s00213-024-06578-w -
Pharmacopsychiatry May 2024Cariprazine is an atypical dopamine receptor partial agonist antipsychotic available in the form of capsules. Although capsules are one of the most desirable routes of...
INTRODUCTION
Cariprazine is an atypical dopamine receptor partial agonist antipsychotic available in the form of capsules. Although capsules are one of the most desirable routes of administration, there are certain situations (e. g., in an acute psychiatric setting, or when swallowing difficulties, or liquid shortages are present) when they cannot be administered. Therefore, alternative solutions like orodispersible tablets are needed. This study aimed to investigate the bioequivalence of a newly developed orodispersible tablet to the commercially available hard gelatine capsule of cariprazine 1.5 mg.
METHODS
This was a phase I, open-label, randomized, single-dose bioequivalence study. It had a 2-period, 2-sequence, cross-over design, where each subject received one test and one reference product in a randomized sequence, separated by a wash-out period of 55 days. Blood sampling was performed over 72 h after dosing. Cariprazine concentrations were analyzed by a validated HPLC-MS/MS method. Standard bioequivalence statistics was applied to PK parameters calculated by non-compartmental analysis. Safety measures were analyzed descriptively.
RESULT
Pharmacokinetic data of 43 healthy volunteers and safety data of 54 subjects was analyzed. Cariprazine AUC and C geometric mean ratios were 117.76% and 100.88%, respectively. The 90% confidence intervals were within the pre-defined bioequivalence acceptance limits of 80.00% - 125.00%. Safety data was in line with the Summary of Product Characteristics of Cariprazine.
DISCUSSION
The result of this clinical trial proved the bioequivalence of the new orodispersible tablet formulation when compared to hard gelatine capsules, enabling an alternative option for treatment of those suffering from schizophrenia.
PubMed: 38710207
DOI: 10.1055/a-2291-7130 -
CNS Neuroscience & Therapeutics May 2024The hippocampus has been reported to be morphologically and neurochemically altered in schizophrenia (SZ). Hyperlocomotion is a characteristic SZ-associated behavioral...
AIMS
The hippocampus has been reported to be morphologically and neurochemically altered in schizophrenia (SZ). Hyperlocomotion is a characteristic SZ-associated behavioral phenotype, which is associated with dysregulated dopamine system function induced by hippocampal hyperactivity. However, the neural mechanism of hippocampus underlying hyperlocomotion remains largely unclear.
METHODS
Mouse pups were injected with N-methyl-D-aspartate receptor antagonist (MK-801) or vehicle twice daily on postnatal days (PND) 7-11. In the adulthood phase, one cohort of mice underwent electrode implantation in field CA1 of the hippocampus for the recording local field potentials and spike activity. A separate cohort of mice underwent surgery to allow for calcium imaging of the hippocampus while monitoring the locomotion. Lastly, the effects of atypical antipsychotic (aripiprazole, ARI) were evaluated on hippocampal neural activity.
RESULTS
We found that the hippocampal theta oscillations were enhanced in MK-801-treated mice, but the correlation coefficient between the hippocampal spiking activity and theta oscillation was reduced. Consistently, although the rate and amplitude of calcium transients of hippocampal neurons were increased, their synchrony and correlation to locomotion speed were disrupted. ARI ameliorated perturbations produced by the postnatal MK-801 treatment.
CONCLUSIONS
These results suggest that the disruption of neural coordination may underly the neuropathological mechanism for hyperlocomotion of SZ.
Topics: Animals; Aripiprazole; Schizophrenia; Hippocampus; Antipsychotic Agents; Dizocilpine Maleate; Mice; Disease Models, Animal; Hyperkinesis; Male; Locomotion; Excitatory Amino Acid Antagonists; Mice, Inbred C57BL; Animals, Newborn; Neurons; Theta Rhythm
PubMed: 38702935
DOI: 10.1111/cns.14739 -
Medicine May 2024Glucagon-like peptide-1 receptor agonists (GLP-1RAs) like liraglutide are primarily used for managing blood sugar levels in type 2 diabetes and aiding weight loss....
BACKGROUND
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) like liraglutide are primarily used for managing blood sugar levels in type 2 diabetes and aiding weight loss. Typically, their adverse effects are gastrointestinal, with limited exploration into their impact on mental health.
CASE PRESENTATION
This report examines a 39-year-old male with type 2 diabetes who developed depressive symptoms after starting liraglutide for glycemic control and weight reduction. Symptoms included poor mood, irritability, decreased interest and energy, progressing to sadness, low self-esteem, and physical discomfort. A clinical diagnosis of a depressive episode was made, coinciding with the initiation of liraglutide.
INTERVENTION AND OUTCOME
The patient depressive symptoms significantly improved within a week after discontinuing liraglutide and starting antidepressant therapy. This suggests a possible link between liraglutide and depression, despite considering other factors like diabetes-related stress.
DISCUSSION
The report explores potential mechanisms, such as GLP-1RA effects on glucose fluctuations and dopamine modulation, which might contribute to depressive symptoms. The influence on the brain reward system and the reduction in cravings for addictive substances after GLP-1RA use is also discussed as a factor in mood regulation.
CONCLUSION
This case highlights the necessity of being vigilant about potential psychiatric side effects, particularly depression, associated with GLP-1RAs. The rarity of such reports calls for more research to investigate and understand these implications further.
Topics: Humans; Liraglutide; Male; Diabetes Mellitus, Type 2; Adult; Depression; Hypoglycemic Agents
PubMed: 38701264
DOI: 10.1097/MD.0000000000037928 -
Journal of the Endocrine Society Apr 2024The Roche prolactin immunoassay is used throughout the world. It reports higher values than the Siemens immunoassay but the manufacturer-defined reference intervals are...
CONTEXT
The Roche prolactin immunoassay is used throughout the world. It reports higher values than the Siemens immunoassay but the manufacturer-defined reference intervals are similar. Patient results are often above the Roche upper limit but within the Siemens interval, causing diagnostic confusion.
OBJECTIVE
Establish new reference intervals for the Roche and Siemens prolactin immunoassays.
METHODS
We established new reference intervals for the Roche and Siemens immunoassays using 374 specimens from healthy outpatients. We performed chart review for unnecessary testing and treatment for 298 patients in a 6-month period with at least 1 Roche prolactin value above the manufacturer-defined upper limit and below our new upper limit.
RESULTS
The new upper limit for the Roche assay was 37.8 ng/mL (females) and 22.8 ng/mL (males). The manufacturer-defined limits were 23.3 ng/mL and 15.2 ng/mL, respectively. New intervals for the Siemens assay matched the manufacturer. No cases of clinically significant pathophysiologic prolactin excess were identified in patients with values between the manufacturer-defined upper reference limit and our new Roche upper limit. Unnecessary further evaluation in these patients included 459 repeat prolactin measurements, 57 macroprolactin measurements, 39 magnetic resonance imaging studies, and 28 endocrine referrals. Eleven patients received dopamine agonists. The minimum cost of excess care using Medicare reimbursement rates was $34 134, with substantially higher amounts billed to patients and their insurance providers.
CONCLUSION
Adoption of new upper reference limits for the Roche prolactin assay of 37.8 ng/mL (females) and 22.8 ng/mL (males) would not delay diagnosis or necessary intervention in patients with clinically significant pituitary tumors but would reduce unnecessary evaluation in patients without pathophysiologic prolactin excess.
PubMed: 38698869
DOI: 10.1210/jendso/bvae069 -
European Journal of Pharmaceutical... Jul 2024Both biphasic dissolution and simultaneous dissolution-permeation (D-P) systems have great potential to improve the in vitro-in vivo correlation compared to simple...
Both biphasic dissolution and simultaneous dissolution-permeation (D-P) systems have great potential to improve the in vitro-in vivo correlation compared to simple dissolution assays, but the assay conditions, and the evaluation methods still need to be refined in order to effectively use these apparatuses in drug development. Therefore, this comprehensive study aimed to compare the predictive accuracy of small-volume (16-20 mL) D-P system and small-volume (40-80 mL) biphasic dissolution apparatus in bioequivalence prediction of five aripiprazole (ARP) containing marketed drug products. Assay conditions, specifically dose dependence were studied to overcome the limitations of both small-scale systems. In case of biphasic dissolution the in vivo maximum plasma concentration (C) prediction greatly improved with the dose reduction of ARP, while in case of the D-P setup the use of whole tablet gave just as accurate prediction as the scaled dose. With the dose reduction strategy both equipment was able to reach 100 % accuracy in bioequivalence prediction for C ratio. In case of the in vivo area under the curve (AUC) prediction the predictive accuracy for the AUC ratio was not dependent on the dose, and both apparatus had a 100 % accuracy predicting bioequivalence based on AUC results. This paper presents for the first time that not only selected parameters of flux assays (like permeability, initial flux, AUC value) were used as an input parameter of a mechanistic model (gastrointestinal unified theory) to predict absorption rate but the whole in vitro flux profile was used. All fraction absorbed values estimated by Predictor Software fell within the ±15 % acceptance range during the comparison with the in vivo data.
Topics: Aripiprazole; Therapeutic Equivalency; Solubility; Antipsychotic Agents; Permeability; Drug Liberation; Humans; Area Under Curve; Tablets
PubMed: 38697313
DOI: 10.1016/j.ejps.2024.106782 -
JAMA Psychiatry May 2024A significant need exists for new antipsychotic medications with different mechanisms of action, greater efficacy, and better tolerability than existing agents....
IMPORTANCE
A significant need exists for new antipsychotic medications with different mechanisms of action, greater efficacy, and better tolerability than existing agents. Xanomeline is a dual M1/M4 preferring muscarinic receptor agonist with no direct D2 dopamine receptor blocking activity. KarXT combines xanomeline with the peripheral muscarinic receptor antagonist trospium chloride with the goal of reducing adverse events due to xanomeline-related peripheral muscarinic receptor activation. In prior trials, xanomeline-trospium chloride was effective in reducing symptoms of psychosis and generally well tolerated in people with schizophrenia.
OBJECTIVE
To evaluate the efficacy and safety of xanomeline-trospium vs placebo in adults with schizophrenia.
DESIGN, SETTING, AND PARTICIPANTS
EMERGENT-3 (NCT04738123) was a phase 3, multicenter, randomized, double-blind, placebo-controlled, 5-week trial of xanomeline-trospium in people with schizophrenia experiencing acute psychosis, conducted between April 1, 2021, and December 7, 2022, at 30 inpatient sites in the US and Ukraine. Data were analyzed from February to June 2023.
INTERVENTIONS
Participants were randomized 1:1 to receive xanomeline-trospium chloride (maximum dose xanomeline 125 mg/trospium 30 mg) or placebo for 5 weeks.
MAIN OUTCOMES AND MEASURES
The prespecified primary end point was change from baseline to week 5 in Positive and Negative Syndrome Scale (PANSS) total score. Secondary outcome measures were change from baseline to week 5 in PANSS positive subscale score, PANSS negative subscale score, PANSS Marder negative factor score, Clinical Global Impression-Severity score, and proportion of participants with at least a 30% reduction in PANSS total score. Safety and tolerability were also evaluated.
RESULTS
A total of 256 participants (mean [SD] age, 43.1 [11.8] years; 191 men [74.6%]; 156 of 256 participants [60.9%] were Black or African American, 98 [38.3%] were White, and 1 [0.4%] was Asian) were randomized (125 in xanomeline-trospium group and 131 in placebo group). At week 5, xanomeline-trospium significantly reduced PANSS total score compared with placebo (xanomeline-trospium , -20.6; placebo, -12.2; least squares mean difference, -8.4; 95% CI, -12.4 to -4.3; P < .001; Cohen d effect size, 0.60). Discontinuation rates due to treatment-emergent adverse events (TEAEs) were similar between the xanomeline-trospium (8 participants [6.4%]) and placebo (7 participants [5.5%]) groups. The most common TEAEs in the xanomeline-trospium vs placebo group were nausea (24 participants [19.2%] vs 2 participants [1.6%]), dyspepsia (20 participants [16.0%] vs 2 participants [1.6%]), vomiting (20 participants [16.0%] vs 1 participant [0.8%]), and constipation (16 participants [12.8%] vs 5 participants [3.9%]). Measures of extrapyramidal symptoms, weight gain, and somnolence were similar between treatment groups.
CONCLUSIONS AND RELEVANCE
Xanomeline-trospium was efficacious and well tolerated in people with schizophrenia experiencing acute psychosis. These findings, together with the previously reported and consistent results from the EMERGENT-1 and EMERGENT-2 trials, support the potential of xanomeline-trospium to be the first in a putative new class of antipsychotic medications without D2 dopamine receptor blocking activity.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT04738123.
PubMed: 38691387
DOI: 10.1001/jamapsychiatry.2024.0785 -
Frontiers in Pharmacology 2024There is growing evidence that the treatment of several mental disorders can potentially benefit from activation of delta-opioid receptors. In the future,...
There is growing evidence that the treatment of several mental disorders can potentially benefit from activation of delta-opioid receptors. In the future, delta-agonists with a safe pharmacological profile can be used for the treatment of mood disorders in pregnant women. However, the data on prenatal exposure to delta-opioid agonists are missing. The present study is aimed to test the hypothesis that the activation of delta-opioid receptors during gravidity has positive effects on the behaviour accompanied by changes in glutamate and monoamine neurotransmission. Gestating Wistar rats were chronically treated with a selective delta-agonist SNC80 or vehicle. Adult male and female offspring underwent novel object recognition (for the assessment of cognition) and open field (for the assessment of anxiety and habituation) tests, followed by electrophysiological examination of the activity of hippocampal glutamate and midbrain serotonin (5-HT) and dopamine neurons. We found that the maternal treatment with SNC80 did not affect the offspring's anxiety, habituation, and 5-HT neuronal firing activity. Female offspring of SNC80-treated dams exhibited improved novelty recognition associated with decreased firing rate and burst activity of glutamate and dopamine neurons. Maternal treatment with delta-opioid agonists during gestation may have a pro-cognitive effect on offspring without any negative effects on anxiety and habituation. The putative pro-cognitive effect might be mediated via mechanism(s) involving the firing activity of hippocampal glutamate and mesolimbic dopamine neurons.
PubMed: 38689666
DOI: 10.3389/fphar.2024.1357575 -
BMC Oral Health Apr 2024Periodontitis is a chronic osteolytic inflammatory disease, where anti-inflammatory intervention is critical for restricting periodontal damage and regenerating alveolar...
BACKGROUND
Periodontitis is a chronic osteolytic inflammatory disease, where anti-inflammatory intervention is critical for restricting periodontal damage and regenerating alveolar bone. Ropinirole, a dopamine D2 receptor agonist, has previously shown therapeutic potential for periodontitis but the underlying mechanism is still unclear.
METHODS
Human gingival fibroblasts (HGFs) treated with LPS were considered to mimic periodontitis in vitro. The dosage of Ropinirole was selected through the cell viability of HGFs evaluation. The protective effects of Ropinirole on HGFs were evaluated by detecting cell viability, cell apoptosis, and pro-inflammatory factor levels. The molecular docking between NAT10 and Ropinirole was performed. The interaction relationship between NAT10 and KLF6 was verified by ac4C Acetylated RNA Immunoprecipitation followed by qPCR (acRIP-qPCR) and dual-luciferase reporter assay.
RESULTS
Ropinirole alleviates LPS-induced damage of HGFs by promoting cell viability, inhibiting cell apoptosis and the levels of IL-1β, IL-18, and TNF-α. Overexpression of NAT10 weakens the effects of Ropinirole on protecting HGFs. Meanwhile, NAT10-mediated ac4C RNA acetylation promotes KLF6 mRNA stability. Upregulation of KLF6 reversed the effects of NAT10 inhibition on HGFs.
CONCLUSIONS
Taken together, Ropinirole protected HGFs through inhibiting the NAT10 ac4C RNA acetylation to decrease the KLF6 mRNA stability from LPS injury. The discovery of this pharmacological and molecular mechanism of Ropinirole further strengthens its therapeutic potential for periodontitis.
Topics: Humans; Acetylation; Apoptosis; Cell Survival; Cells, Cultured; Fibroblasts; Gingiva; Indoles; Kruppel-Like Factor 6; Lipopolysaccharides; Molecular Docking Simulation; Periodontitis; N-Terminal Acetyltransferases
PubMed: 38689229
DOI: 10.1186/s12903-024-04250-5 -
Journal of Integrative Neuroscience Apr 2024Parkinson's disease is a progressive neurodegenerative disorder characterized by motor and non-motor symptoms, including hallucinations. The use of antipsychotic... (Review)
Review
Parkinson's disease is a progressive neurodegenerative disorder characterized by motor and non-motor symptoms, including hallucinations. The use of antipsychotic medications is a common strategy to manage hallucinations associated with Parkinson's disease psychosis (PDP). However, careful consideration is necessary when selecting the most appropriate drug due to the potential risks associated with the available treatment options. Atypical antipsychotics (AAPs), such as Pimavanserin and Clozapine, have effectively controlled PDP symptoms. On the contrary, the support for utilizing quetiapine is not as substantial as other antipsychotics because research studies specifically investigating its application are still emerging and relatively recent. The broad mechanisms of action of AAPs, involving dopamine and serotonin receptors, provide improved outcomes and fewer side effects than typical antipsychotics. Conversely, other antipsychotics, including risperidone, olanzapine, aripiprazole, ziprasidone, and lurasidone, have been found to worsen motor symptoms and are generally not recommended for PDP. While AAPs offer favorable benefits, they are associated with specific adverse effects. Extrapyramidal symptoms, somnolence, hypotension, constipation, and cognitive impairment are commonly observed with AAP use. Clozapine, in particular, carries a risk of agranulocytosis, necessitating close monitoring of blood counts. Pimavanserin, a selective serotonin inverse agonist, avoids receptor-related side effects but has been linked to corrected QT (QTc) interval prolongation, while quetiapine has been reported to be associated with an increased risk of mortality. This review aims to analyze the benefits, risks, and mechanisms of action of antipsychotic medications to assist clinicians in making informed decisions and enhance patient care.
Topics: Humans; Antipsychotic Agents; Clozapine; Hallucinations; Parkinson Disease; Piperidines; Quetiapine Fumarate; Urea
PubMed: 38682215
DOI: 10.31083/j.jin2304080