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Current Opinion in Chemical Biology Oct 2023In the review, current status of sulfoxides on the pharmaceutical market is discussed. In the first part of the article, natural sulfoxides will be described with a... (Review)
Review
In the review, current status of sulfoxides on the pharmaceutical market is discussed. In the first part of the article, natural sulfoxides will be described with a special focus on sulforaphane and amanitin, a mushroom toxin which has been developed as payload in antibody drug conjugates in the possible cancer treatment. Controversies associated with the medical use of dimethylsulfoxide are briefly described in the next section. In the part devoted to PPIs, the benefits of using pure enantiomers (chiral switch) are discussed. An interesting approach, repositioning of drugs is exemplified by new possible applications of modafinil and sulindac. The review is concluded by presentation of cenicriviroc and adezmapimod, both with the status of promising drug candidates.
Topics: Sulfoxides; Dimethyl Sulfoxide; Stereoisomerism
PubMed: 37307682
DOI: 10.1016/j.cbpa.2023.102340 -
Frontiers in Pharmacology 2024Mounting evidence from animal models and human studies indicates that psychostimulants can significantly affect social behaviors. This is not surprising considering that... (Review)
Review
Mounting evidence from animal models and human studies indicates that psychostimulants can significantly affect social behaviors. This is not surprising considering that the neural circuits underlying the regulation and expression of social behaviors are highly overlapped with those targeted by psychostimulants, which in most cases have strong rewarding and, consequently, addictive properties. In the present work, we provide an overview regarding the effects of illicit and prescription psychostimulants, such as cocaine, amphetamine-type stimulants, methylphenidate or modafinil, upon social behaviors such as social play, maternal behavior, aggression, pair bonding and social cognition and how psychostimulants in both animals and humans alter them. Finally, we discuss why these effects can vary depending on numerous variables such as the type of drug considered, acute long-term use, clinical recreational consumption, or the presence or absence of concomitant risk factors.
PubMed: 38725665
DOI: 10.3389/fphar.2024.1364630 -
Molecules (Basel, Switzerland) Jul 2023Psychostimulant use disorders (PSUD) affect a growing number of men and women and exert sizable public health and economic burdens on our global society. Notably, there... (Review)
Review
Psychostimulant use disorders (PSUD) affect a growing number of men and women and exert sizable public health and economic burdens on our global society. Notably, there are some sex differences in the onset of dependence, relapse rates, and treatment success with PSUD observed in preclinical and clinical studies. The subtle sex differences observed in the behavioral aspects of PSUD may be associated with differences in the neurochemistry of the dopaminergic system between sexes. Preclinically, psychostimulants have been shown to increase synaptic dopamine (DA) levels and may downregulate the dopamine transporter (DAT). This effect is greatest in females during the high estradiol phase of the estrous cycle. Interestingly, women have been shown to be more likely to begin drug use at younger ages and report higher levels of desire to use cocaine than males. Even though there is currently no FDA-approved medication, modafinil, a DAT inhibitor approved for use in the treatment of narcolepsy and sleep disorders, has shown promise in the treatment of PSUD among specific populations of affected individuals. In this review, we highlight the therapeutic potential of modafinil and other atypical DAT inhibitors focusing on the lack of sex differences in the actions of these agents.
Topics: Female; Humans; Male; Dopamine Uptake Inhibitors; Modafinil; Sex Characteristics; Benzhydryl Compounds; Central Nervous System Stimulants; Cocaine; Dopamine
PubMed: 37446929
DOI: 10.3390/molecules28135270 -
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 -
PloS One 2023Methamphetamine use and related harms have risen at alarming rates. While several psychosocial and pharmacologic interventions have been described in the literature,... (Review)
Review
RATIONALE
Methamphetamine use and related harms have risen at alarming rates. While several psychosocial and pharmacologic interventions have been described in the literature, there is uncertainty regarding the best approach for the management of methamphetamine use disorder (MUD) and problematic methamphetamine use (PMU). We conducted a scoping review of recent systematic reviews (SR), clinical practice guidelines (CPG), and primary controlled studies of psychosocial and pharmacologic treatments for MUD/PMU.
METHODS
Guided by an a priori protocol, electronic database search updates (e.g., MEDLINE, Embase) were performed in February 2022. Screening was performed following a two-stage process, leveraging artificial intelligence to increase efficiency of title and abstract screening. Studies involving individuals who use methamphetamine, including key subgroups (e.g. those with mental health comorbidities; adolescents/youths; gay, bisexual, and other men who have sex with men) were sought. We examined evidence related to methamphetamine use, relapse, use of other substances, risk behaviors, mental health, harms, and retention. Figures, tables and descriptive synthesis were used to present findings from the identified literature.
RESULTS
We identified 2 SRs, one CPG, and 54 primary studies reported in 69 publications that met our eligibility criteria. Amongst SRs, one concluded that psychostimulants had no effect on methamphetamine abstinence or treatment retention while the other reported no effect of topiramate on cravings. The CPG strongly recommended psychosocial interventions as well as self-help and family support groups for post-acute management of methamphetamine-related disorders. Amongst primary studies, many interventions were assessed by only single studies; contingency management was the therapy most commonly associated with evidence of potential effectiveness, while bupropion and modafinil were analogously the most common pharmacologic interventions. Nearly all interventions showed signs of potential benefit on at least one methamphetamine-related outcome measure.
DISCUSSION
This scoping review provides an overview of available interventions for the treatment of MUD/PMU. As most interventions were reported by a single study, the effectiveness of available interventions remains uncertain. Primary studies with longer durations of treatment and follow-up, larger sample sizes, and of special populations are required for conclusive recommendations of best approaches for the treatment of MUD/PMU.
Topics: Male; Adolescent; Humans; Methamphetamine; Homosexuality, Male; Sexual and Gender Minorities; Artificial Intelligence; Central Nervous System Stimulants
PubMed: 37819931
DOI: 10.1371/journal.pone.0292745 -
Sleep Medicine Dec 2023Modafinil is a common treatment for excessive daytime sleepiness (EDS) in narcolepsy. The long-term use of modafinil can lead to tolerance with the loss of efficacy and...
STUDY OBJECTIVES
Modafinil is a common treatment for excessive daytime sleepiness (EDS) in narcolepsy. The long-term use of modafinil can lead to tolerance with the loss of efficacy and the continuous increase of its dose. Pharmacological strategies to deal with the tolerance to modafinil are lacking. We investigated the efficacy and safety of pitolisant-supported bridging during drug holidays in patients with tolerance to modafinil.
METHODS
Narcolepsy patients on monotherapy with modafinil who developed symptoms of tolerance were eligible. The following alternating therapy regimen was established: Monday to Friday patients continued on modafinil whereas Saturday and Sunday they switched to pitolisant to "bridge" the EDS symptoms. Patients were assessed at baseline and after three months with the Epworth Sleepiness Scale (ESS) and the Ullanlinna Narcolepsy Scale (UNS). Health-related quality of life (HrQol) was evaluated by EuroQol5D. Adverse events were documented in the patients' diaries.
RESULTS
41 patients aged 30.9 ± 5.6 years were included. After three months of the alternating therapy regimen, the symptoms of tolerance decreased and the modafinil dose could be reduced by 41% (p < 0.01) resulting in better safety. The EDS improved on ESS (baseline: 18.2 ± 4.2, follow-up: 12.6 ± 4.0, p < 0.0001) and UNS (baseline: 25.8 ± 7.9, follow-up: 18.9 ± 5.9, p < 0.0001). The HrQol increased significantly.
CONCLUSION
Patients with tolerance to modafinil could benefit from pitolisant-supported bridging during drug holidays. This alternating pharmacological strategy proved to be safe and helped to reduce EDS and to decrease the modafinil dose. Further randomized controlled studies are required to evaluate the different strategies to deal with the tolerance to modafinil.
CLINICAL TRIAL REGISTRATION NUMBER
Clinical Trials.gov Identifier NCT05321355.
Topics: Humans; Modafinil; Quality of Life; Narcolepsy; Piperidines; Disorders of Excessive Somnolence; Benzhydryl Compounds
PubMed: 37839272
DOI: 10.1016/j.sleep.2023.10.005 -
Attention-Deficit/Hyperactivity Disorder Medications and Work Disability and Mental Health Outcomes.JAMA Network Open Mar 2024Individuals with attention-deficit/hyperactivity disorder (ADHD) often have comorbid psychiatric conditions. Relatively little is known about how specific ADHD...
IMPORTANCE
Individuals with attention-deficit/hyperactivity disorder (ADHD) often have comorbid psychiatric conditions. Relatively little is known about how specific ADHD medications are associated with overall treatment outcomes among these patients.
OBJECTIVE
To investigate the association of the use of specific ADHD medications with hospitalization outcomes and work disability among adolescents and adults with ADHD.
DESIGN, SETTING, AND PARTICIPANTS
This nationwide register-based cohort study identified individuals (aged 16-65 years) with ADHD from Swedish nationwide registers of inpatient health care, specialized outpatient health care, sickness absence, and disability pension during the years 2006 to 2021. Data analysis was performed from November 2022 to August 2023.
EXPOSURE
Use of specific ADHD medications.
MAIN OUTCOMES AND MEASURES
The main outcome measure was psychiatric hospitalization, and secondary outcomes were suicide attempt and/or death by suicide, nonpsychiatric hospitalization, and work disability (ie, sickness absence or disability pension). The risk of outcomes between use vs nonuse periods of ADHD medications was compared in a within-individual design, where a person acts as their own control, and was analyzed with stratified Cox models.
RESULTS
A total of 221 714 persons with ADHD were included in the study cohort (mean [SD] age, 25.0 [11.2] years; 120 968 male individuals [54.6%]). Methylphenidate was the most commonly used ADHD medication (151 837 individuals [68.5%]), followed by lisdexamphetamine (78 106 individuals [35.2%]) during the follow-up (mean [SD], 7.0 [4.7] years). The following medications were associated with a decreased risk of psychiatric hospitalization: amphetamine (adjusted hazard ratio [aHR], 0.74; 95% CI, 0.61-0.90), lisdexamphetamine (aHR, 0.80; 95% CI, 0.78-0.82), ADHD drug polytherapy (aHR, 0.85; 95% CI, 0.82-0.88), dexamphetamine (aHR, 0.88; 95% CI, 0.83-0.94), and methylphenidate (aHR, 0.93; 95% CI, 0.92-0.95). No associations were found for modafinil, atomoxetine, clonidine, and guanfacine. Decreased risk of suicidal behavior was associated with the use of dexamphetamine (aHR, 0.69; 95% CI, 0.53-0.89), lisdexamphetamine (aHR, 0.76; 95% CI, 0.68-0.84), and methylphenidate (aHR, 0.92; 95% CI, 0.86-0.98). None of the medications was associated with increased risk of nonpsychiatric hospitalization; instead, use of amphetamine, lisdexamphetamine, polytherapy, dexamphetamine, methylphenidate, and atomoxetine were associated with decreased risk of nonpsychiatric hospitalization. The results regarding work disability were significant only for the use of atomoxetine (aHR, 0.89; 95% CI, 0.82-0.97), especially among adolescents and young adults aged 16 to 29 years, (aHR, 0.82; 95% CI, 0.73-0.92).
CONCLUSIONS AND RELEVANCE
In this nationwide cohort study of adolescents and adults with ADHD, the use of ADHD medication was associated with fewer hospitalizations for both psychiatric and nonpsychiatric morbidity and lower suicidal behavior.
Topics: Adolescent; Young Adult; Humans; Male; Adult; Attention Deficit Disorder with Hyperactivity; Atomoxetine Hydrochloride; Cohort Studies; Lisdexamfetamine Dimesylate; Methylphenidate; Amphetamine
PubMed: 38506810
DOI: 10.1001/jamanetworkopen.2024.2859 -
Diabetes Aug 2023
Topics: Mice; Male; Animals; Modafinil; Orexins; Hypoglycemia; Glucose; Neurons
PubMed: 37471600
DOI: 10.2337/dbi22-0038