-
Biomolecules Sep 2023The high structural similarity, especially in transmembrane regions, of dopamine, norepinephrine, and serotonin transporters, as well as the lack of all crystal...
The high structural similarity, especially in transmembrane regions, of dopamine, norepinephrine, and serotonin transporters, as well as the lack of all crystal structures of human isoforms, make the specific targeting of individual transporters rather challenging. Ligand design itself is also rather limited, as many chemists, fully aware of the synthetic and analytical challenges, tend to modify lead compounds in a way that reduces the number of chiral centers and hence limits the potential chemical space of synthetic ligands. We have previously shown that increasing molecular complexity by introducing additional chiral centers ultimately leads to more selective and potent dopamine reuptake inhibitors. Herein, we significantly extend our structure-activity relationship of dopamine transporter-selective ligands and further demonstrate how stereoisomers of defined absolute configuration may fine-tune and direct the activity towards distinct targets. From the pool of active compounds, using the examples of stereoisomers and , we further showcase how in vitro activity significantly differs in in vivo drug efficacy experiments, calling for proper validation of individual stereoisomers in animal studies. Furthermore, by generating a large library of compounds with defined absolute configurations, we lay the groundwork for computational chemists to further optimize and rationally design specific monoamine transporter reuptake inhibitors.
Topics: Animals; Humans; Norepinephrine Plasma Membrane Transport Proteins; Serotonin Plasma Membrane Transport Proteins; Biological Transport; Structure-Activity Relationship; Norepinephrine; Ligands
PubMed: 37759815
DOI: 10.3390/biom13091415 -
Frontiers in Psychiatry 2023Despite advances in the treatment of bipolar disorder (BD), most patients do not achieve complete inter-episode recovery and functional disability is common. During...
INTRODUCTION
Despite advances in the treatment of bipolar disorder (BD), most patients do not achieve complete inter-episode recovery and functional disability is common. During periods of relative remission, many patients continue to experience neurocognitive dysfunction, reduced daytime activity levels, and sleep disturbances. This 8-week, randomized, placebo-controlled pilot study evaluated the feasibility, safety and preliminary efficacy of the wake-promoting drug, modafinil (Provigil), on neurocognitive functioning, daytime sleepiness, and sleep quality in affectively-stable BD patients.
METHODS
Twelve individuals with affectively-stable BD were recruited and randomized to a flexible dose of modafinil (100 to 200 mg/day) or placebo, adjunctive to a therapeutic dose of a mood stabilizer. Weekly in-person visits tracked sleep quality and daytime sleepiness as well as side effects and mood symptoms. Neurocognitive functioning was assessed at baseline, week 4, and week 8.
RESULTS
No serious adverse events were reported. Newly emergent side effects in the modafinil group included heart palpitations, itching, fatigue, and decreased energy. Two patients discontinued modafinil owing to side effects and one of these patients withdrew from the study. One patient discontinued placebo and was withdrawn from the study. Preliminary evaluations of clinical efficacy showed a marginally significant interaction between treatment group and time in two cognitive domains (speed of processing and verbal learning), indicating greater improvement in the modafinil group versus placebo. Additionally, there was a marginally significant effect of treatment group on daytime sleepiness, suggesting lower daytime sleepiness in the modafinil group versus placebo. Counterintuitively, we found a significant treatment group by time interaction effect on sleep quality, suggesting greater improvement in sleep quality in the placebo group versus the modafinil group.
DISCUSSION
Results suggest that modafinil is a relatively safe medication for affectively-stable BD patients when given with adjunctive mood stabilizers. Results are suggestive of cognitive benefit and improved daytime sleepiness, but worse sleep quality in those patients prescribed modafinil. A fully powered clinical trial is warranted with specific attention to the characteristics of patients who are most likely to benefit from treatment with modafinil and other methodological lessons learned from this pilot.
CLINICAL TRIAL REGISTRATION
ClinicalTrials.gov, identifier NCT01965925.
PubMed: 37732080
DOI: 10.3389/fpsyt.2023.1246149 -
Journal of Advanced Pharmaceutical... 2023Fatigue is a prevalent symptom experienced by individuals diagnosed with multiple sclerosis (MS), which greatly affects their daily activities and causes frustration and...
Fatigue is a prevalent symptom experienced by individuals diagnosed with multiple sclerosis (MS), which greatly affects their daily activities and causes frustration and depression, thus affecting their lives and society. This can be prevented through the use of medicines such as L-carnitine and modafinil. The study aimed to examine the effect of L-carnitine and modafinil on fatigue and which one is better for MS patients. This was a clinical trial. This clinical trial was conducted in cooperation between Al-Kut University College and an MS consultant at Al-Zahraa Teaching Hospital in addition to the private neurological clinic from October 1, 2022, to March 15, 2023. Forty participants were split into two groups; both of which were almost identical characteristics regarding age, disease duration, and degree of fatigue. Group I ( = 20): relapsing-remitting MS patients with fatigue received modafinil. Group II ( = 20): relapsing-remitting MS patients with fatigue received L-carnitine. Fatigue was evaluated according to the Modified Fatigue Impact Scale (MFIS). The statistical work was done in SPSS (IBM Corp., Chicago, IL, USA, version 24). values were calculated by the -test. Significant data have = 0.05. After 2 months of treatment, the results show a significant decrease in MFIS in both groups with a higher reduction in patients who use L-carnitine. Both modafinil and L-carnitine show a significant influence on fatigue in MS patients, and these effects are more in L-carnitine.
PubMed: 37692018
DOI: 10.4103/JAPTR.JAPTR_225_23 -
Revue Neurologique Oct 2023Idiopathic hypersomnia (IH) and Kleine-Levin syndrome (KLS) are rare disorders of central hypersomnolence of unknown cause, affecting young people. However, increased... (Review)
Review
Idiopathic hypersomnia (IH) and Kleine-Levin syndrome (KLS) are rare disorders of central hypersomnolence of unknown cause, affecting young people. However, increased sleep time and excessive daytime sleepiness (EDS) occur daily for years in IH, whereas they occur as relapsing/remitting episodes associated with cognitive and behavioural disturbances in KLS. Idiopathic hypersomnia is characterized by EDS, prolonged, unrefreshing sleep at night and during naps, and frequent morning sleep inertia, but rare sleep attacks, no cataplexy and sleep onset in REM periods as in narcolepsy. The diagnosis requires: (i) ruling out common causes of hypersomnolence, including mostly sleep apnea, insufficient sleep syndrome, psychiatric hypersomnia and narcolepsy; and (ii) obtaining objective EDS measures (mean latency at the multiple sleep latency test≤8min) or increased sleep time (sleep time>11h during a 18-24h bed rest). Treatment is similar to narcolepsy (except for preventive naps), including adapted work schedules, and off label use (after agreement from reference/competence centres) of modafinil, sodium oxybate, pitolisant, methylphenidate and solriamfetol. The diagnosis of KLS requires: (i) a reliable history of distinct episodes of one to several weeks; (ii) episodes contain severe hypersomnia (sleep>15h/d) associated with cognitive impairment (mental confusion and slowness, amnesia), derealisation, major apathy or disinhibited behaviour (hypersexuality, megaphagia, rudeness); and (iii) return to baseline sleep, cognition, behaviour and mood after episodes. EEG may contain slow rhythms during episodes, and rules out epilepsy. Functional brain imaging indicates hypoactivity of posterior associative cortex and hippocampus during symptomatic and asymptomatic periods. KLS attenuates with time when starting during teenage, including less frequent and less severe episodes. Adequate sleep habits, avoidance of alcohol and infections, as well as lithium and sometimes valproate (off label, after agreement from reference centres) help reducing the frequency and severity of episodes, and IV methylprednisolone helps reducing long (>30d) episode duration.
Topics: Adolescent; Humans; Kleine-Levin Syndrome; Idiopathic Hypersomnia; Disorders of Excessive Somnolence; Sleep; Narcolepsy
PubMed: 37684104
DOI: 10.1016/j.neurol.2023.08.010 -
Pharmacology, Biochemistry, and Behavior Sep 2023Substance dependence is a disorder that alters the functioning of the nervous system due to frequent abuse of drugs. The role of dopamine in the addictive effect of...
Substance dependence is a disorder that alters the functioning of the nervous system due to frequent abuse of drugs. The role of dopamine in the addictive effect of psychostimulants is well known; however, the involvement of the noradrenergic system is still unclear and poorly understood, though drugs like cocaine and amphetamines are known to exert significant activity on this system. The drug modafinil (MOD) has no proven addictive effect. It promotes wakefulness by acting mainly on the dopaminergic system and, to a lesser degree, the noradrenergic (NOR) system. Atomoxetine (ATX) is a non-stimulant drug that acts only on the NOR system, enhancing its activity. The aims of the present study were to analyze the effect of co-activating the DA and NOR systems (with MOD and ATX, respectively) on motor activity and exploratory behavior, and to examine the possible emergence of rewarding properties of MOD and an MOD+ATX mixture. Male Wistar rats at postnatal day 60 were treated chronically (16 days) with either monotherapy with 2ATX, 4ATX, or 60MOD mg/kg, two combinations of these substances -60MOD + 2ATX and 60MOD + 4ATX- or a vehicle. The rats co-administered with 60MOD + 4ATX reduced the rearing behavior frequency induced by MOD, but this behavior was sensitized by self-administration of the MOD+ATX mixture after chronic treatment. The rats pre-treated with 60MOD + 4ATX showed higher self-administration of MOD and greater activity on an operant task to obtain the MOD+ATX mixture. In addition, the 60MOD, 2ATX, and 60MOD + 2ATX groups showed sensitization of exploratory behavior after ingesting the mixture. Results suggest that the noradrenergic system enhances the incentive value of MOD and a MOD+ATX mixture, while also playing an important role in the sensitization of exploratory behavior.
Topics: Male; Animals; Rats; Rats, Wistar; Exploratory Behavior; Motivation; Modafinil; Atomoxetine Hydrochloride; Dopamine
PubMed: 37595803
DOI: 10.1016/j.pbb.2023.173618 -
The Journal of Physiology Sep 2023The secretion of insulin from β-cells in the islet of Langerhans is governed by a series of metabolic and electrical events, which can fail during the progression of...
The secretion of insulin from β-cells in the islet of Langerhans is governed by a series of metabolic and electrical events, which can fail during the progression of type 2 diabetes (T2D). β-cells are electrically coupled via connexin-36 (Cx36) gap junction channels, which coordinates the pulsatile dynamics of [Ca ] and insulin release across the islet. Factors such as pro-inflammatory cytokines and free fatty acids disrupt gap junction coupling under in vitro conditions. Here we test whether gap junction coupling and coordinated [Ca ] dynamics are disrupted in T2D, and whether recovery of gap junction coupling can recover islet function. We examine islets from donors with T2D, from db/db mice, and islets treated with pro-inflammatory cytokines (TNF-α, IL-1β, IFN-ɣ) or free fatty acids (palmitate). We modulate gap junction coupling using Cx36 over-expression or pharmacological activation via modafinil. We also develop a peptide mimetic (S293) of the c-terminal regulatory site of Cx36 designed to compete against its phosphorylation. Cx36 gap junction permeability and [Ca ] dynamics were disrupted in islets from both human donors with T2D and db/db mice, and in islets treated with pro-inflammatory cytokines or palmitate. Cx36 over-expression, modafinil treatment and S293 peptide all enhanced Cx36 gap junction coupling and protected against declines in coordinated [Ca ] dynamics. Cx36 over-expression and S293 peptide also reduced apoptosis induced by pro-inflammatory cytokines. Critically, S293 peptide rescued gap junction coupling and [Ca ] dynamics in islets from both db/db mice and a sub-set of T2D donors. Thus, recovering or enhancing Cx36 gap junction coupling can improve islet function in diabetes. KEY POINTS: Connexin-36 (Cx36) gap junction permeability and associated coordination of [Ca ] dynamics is diminished in human type 2 diabetes (T2D) and mouse models of T2D. Enhancing Cx36 gap junction permeability protects against disruptions to the coordination of [Ca ] dynamics. A novel peptide mimetic of the Cx36 c-terminal regulatory region protects against declines in Cx36 gap junction permeability. Pharmacological elevation in Cx36 or Cx36 peptide mimetic recovers [Ca ] dynamics and glucose-stimulated insulin secretion in human T2D and mouse models of T2D.
Topics: Humans; Mice; Animals; Islets of Langerhans; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Modafinil; Connexins; Insulin; Gap Junctions; Insulin-Secreting Cells; Cytokines
PubMed: 37578890
DOI: 10.1113/JP282114 -
Frontiers in Pharmacology 2023Drug-induced Behavioral Signature Analysis (DBSA), is a machine learning (ML) method for screening of compounds, inspired by analytical methods quantifying gene...
Drug-induced Behavioral Signature Analysis (DBSA), is a machine learning (ML) method for screening of compounds, inspired by analytical methods quantifying gene enrichment in genomic analyses. When applied to behavioral data it can identify drugs that can potentially reverse behavioral symptoms in animal models of human disease and suggest new hypotheses for drug discovery and repurposing. We present a proof-of-concept study aiming to assess Drug-induced Behavioral Signature Analysis (DBSA) as a systematic approach for drug discovery for rare disorders. We applied Drug-induced Behavioral Signature Analysis to high-content behavioral data obtained with SmartCube, an automated phenotyping platform. The therapeutic potential of several dozen approved drugs was assessed for phenotypic reversal of the behavioral profile of a Huntington's Disease (HD) murine model, the Q175 heterozygous knock-in mice. The Drug-induced Behavioral Signature Analysis predictions were enriched for drugs known to be effective in the symptomatic treatment of Huntington's Disease, including bupropion, modafinil, methylphenidate, and several SSRIs, as well as the atypical antidepressant tianeptine. To validate the method, we tested acute and chronic effects of tianeptine (20 mg/kg) , using Q175 mice and wild type controls. In both experiments, tianeptine significantly rescued the behavioral phenotype assessed with the SmartCube platform. Our target-agnostic method thus showed promise for identification of symptomatic relief treatments for rare disorders, providing an alternative method for hypothesis generation and drug discovery for disorders with huge disease burden and unmet medical needs.
PubMed: 37560472
DOI: 10.3389/fphar.2023.1128562 -
Advances in Experimental Medicine and... 2023Antipsychotic drugs constitute the basis of schizophrenia therapy; however, available pharmaceutical agents lack efficacy for treating the cognitive deficits caused by... (Review)
Review
OBJECTIVE
Antipsychotic drugs constitute the basis of schizophrenia therapy; however, available pharmaceutical agents lack efficacy for treating the cognitive deficits caused by the illness. The aim of the present work is to present current data regarding cognitive rehabilitation of schizophrenia, providing information and guidance to health professionals.
METHOD
A literature search was conducted in the PubMed and Google Scholar Databases from inception up to 1/9/2022. Relevant articles were explored for factors affecting cognitive function, including genetics, psychopathology, time in the course of the illness, and drug therapy. Characteristics and outcome of cognitive rehabilitation programs are briefly presented.
RESULTS
A total of 562 relevant articles were retrieved, 39 of which were selected for the review. Factors contributing to a favorable outcome are young age, early phase of disease, symptomatic control of hostility and conceptual disorganization, lack of negative symptoms, management of drug side effects, and cognitive and cortical reserve. Some evidence for a procognitive effect seems to exist for atypical antipsychotics, clozapine, aripiprazole, memantine, modafinil, d-serine, and cycloserine. The Val/Val polymorphism of the COMT gene seems to be associated with worse outcome. Specific remediation strategies include programs such as Cognitive Enhancement Therapy (CET), Cognitive Adaptation Training (CAT), and RehaCom Cognitive Therapy Software, among others, all employing a range of techniques, from paper-and-pencil to computer-assisted, bottom-up, or top-down approaches, and varying neurocognitive targets.
CONCLUSION
Cognitive symptoms, closely related to functional impairment, still remain a therapeutic challenge. Cognitive rehabilitation strategies are as yet the only treatment modality offering cognitive improvement to patients who struggle to recover.
Topics: Humans; Schizophrenia; Cognitive Training; Antipsychotic Agents; Cognition; Modafinil
PubMed: 37525044
DOI: 10.1007/978-3-031-31978-5_17 -
Psychiatria Danubina 2023
Topics: Humans; Modafinil; Paraphilic Disorders; Sexual Behavior; Compulsive Behavior; Central Nervous System Stimulants
PubMed: 37480319
DOI: 10.24869/psyd.2023.272 -
Diabetes Aug 2023
Topics: Mice; Male; Animals; Modafinil; Orexins; Hypoglycemia; Glucose; Neurons
PubMed: 37471600
DOI: 10.2337/dbi22-0038