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Advances in Pharmacology (San Diego,... 2024In this review, we critically evaluate the contribution of prodrugs to treating two related psychiatric disorders, attention-deficit hyperactivity disorder (ADHD) and... (Review)
Review
In this review, we critically evaluate the contribution of prodrugs to treating two related psychiatric disorders, attention-deficit hyperactivity disorder (ADHD) and binge-eating disorder (BED). ADHD is characterized by inattentiveness, distractibility, impulsiveness, and hyperactivity. BED is also an impulse-control disorder which leads to frequent, compulsive episodes of excessive eating (binges). Lisdexamfetamine (LDX; prodrug of d-amphetamine) is approved to treat both ADHD and BED. Serdexmethylphenidate (SDX; prodrug of d-threo-methylphenidate) is not clinically approved as monotherapy but, in a fixed-dose combination with immediate release d-threo-methylphenidate (Azstarys™), SDX is approved for managing ADHD in children/adolescents. The pharmacological actions of a stimulant mediate both its efficacy and side-effects. Therefore, daily management of ADHD or BED to maintain optimum efficacy and tolerability places highly restrictive requirements on the pharmacokinetic/pharmacodynamic (PK/PD) characteristics of stimulant medications, especially prodrugs. Prodrugs must have good bioavailability and rapid metabolism to provide therapeutic efficacy soon after morning dosing combined with providing stimulant coverage throughout the day/evening. A wide selection of dosages and linear PK for the prodrug and its active metabolite are essential requirements for treatment of these conditions. The proposed neurobiological causes of ADHD and BED are described. The chemical, pharmacological and PK/PD properties responsible for the therapeutic actions of the prodrugs, LDX and SDX, are compared and contrasted. Finally, we critically assess their contribution as ADHD and BED medications, including advantages over their respective active metabolites, d-amphetamine and d-threo-methylphenidate, and also their potential for misuse and abuse.
Topics: Adolescent; Child; Humans; Attention Deficit Disorder with Hyperactivity; Binge-Eating Disorder; Central Nervous System Stimulants; Dextroamphetamine; Methylphenidate; Prodrugs
PubMed: 38467483
DOI: 10.1016/bs.apha.2023.10.002 -
American Journal of Obstetrics and... Jul 2024Attention-deficit/hyperactivity disorder is a childhood-onset neurodevelopmental disorder that frequently persists into adulthood with 3% of adult women having a... (Review)
Review
Attention-deficit/hyperactivity disorder is a childhood-onset neurodevelopmental disorder that frequently persists into adulthood with 3% of adult women having a diagnosis of attention-deficit/hyperactivity disorder. Many women are diagnosed and treated during their reproductive years, which leads to management implications during pregnancy and the postpartum period. We know from clinical practice that attention-deficit/hyperactivity disorder symptoms frequently become challenging to manage during the perinatal period and require additional support and attention. There is often uncertainty among healthcare providers about the management of attention-deficit/hyperactivity disorder in the perinatal period, particularly the safety of pharmacotherapy for the developing fetus. This guideline is focused on best practices in managing attention-deficit/hyperactivity disorder in the perinatal period. We recommend (1) mitigating the risks associated with attention-deficit/hyperactivity disorder that worsen during the perinatal period via individualized treatment planning; (2) providing psychoeducation, self-management strategies or coaching, and psychotherapies; and, for those with moderate or severe attention-deficit/hyperactivity disorder, (3) considering pharmacotherapy for attention-deficit/hyperactivity disorder, which largely has reassuring safety data. Specifically, providers should work collaboratively with patients and their support networks to balance the risks of perinatal attention-deficit/hyperactivity disorder medication with the risks of inadequately treated attention-deficit/hyperactivity disorder during pregnancy. The risks and impacts of attention-deficit/hyperactivity disorder in pregnancy can be successfully managed through preconception counselling and appropriate perinatal planning, management, and support.
Topics: Humans; Female; Attention Deficit Disorder with Hyperactivity; Pregnancy; Pregnancy Complications; Postpartum Period; Central Nervous System Stimulants; Methylphenidate; Psychotherapy; Atomoxetine Hydrochloride
PubMed: 38432409
DOI: 10.1016/j.ajog.2024.02.297 -
Journal of the Academy of... Feb 2024
PubMed: 38417703
DOI: 10.1016/j.jaclp.2024.02.006 -
Journal of Veterinary Emergency and... 2024To describe the presentation, management, and postmortem examination findings in a dog with confirmed lisdexamfetamine dimesylate (LDX) toxicosis.
OBJECTIVE
To describe the presentation, management, and postmortem examination findings in a dog with confirmed lisdexamfetamine dimesylate (LDX) toxicosis.
CASE SUMMARY
A 3-year-old female neutered mixed breed dog initially presented with neurological signs suspected to be secondary to LDX toxicosis. The dog was treated as typical for amphetamine toxicoses but developed severe respiratory and cardiovascular signs throughout their hospitalization. The progression of the cardiopulmonary signs led to cardiopulmonary arrest, for which CPR was unsuccessful. Postmortem examination exhibited severe hemorrhage throughout multiple organ systems. Toxicology testing confirmed the presence of unaltered LDX and its metabolite, amphetamine.
NEW OR UNIQUE INFORMATION PROVIDED
This is the first case report documenting a severe progression of clinical signs and postmortem examination findings in a case of confirmed LDX toxicosis in a dog. Although the patient did not survive treatment, postmortem examination and microscopic evaluation of tissues allowed visualization of the extent of systemic pathophysiology. With prompt treatment, the prognosis of amphetamine toxicosis in dogs is generally considered good; however, this case report demonstrates a severe case in which even prompt and appropriate treatment did not prevent mortality. This suggests a need to establish negative prognostic indicators for which to monitor in cases of amphetamine toxicosis. Finally, this report is also unique in the fact that the LDX toxicosis was confirmed using a toxicological analysis technique not previously described clinically in dogs.
Topics: Humans; Female; Dogs; Animals; Lisdexamfetamine Dimesylate; Central Nervous System Stimulants; Dextroamphetamine; Attention Deficit Disorder with Hyperactivity; Treatment Outcome
PubMed: 38412018
DOI: 10.1111/vec.13370 -
Journal of Attention Disorders Apr 2024To compare PRC-063 (multilayer-release methylphenidate) and lisdexamfetamine dimesylate (LDX) on the driving performance of young adults with attention deficit... (Randomized Controlled Trial)
Randomized Controlled Trial
A Randomized, Phase 3, Double-Blind, Crossover Comparison of Multilayer, Extended-Release Methylphenidate (PRC-063), and Lisdexamfetamine in the Driving Performance of Young Adults With ADHD.
OBJECTIVE
To compare PRC-063 (multilayer-release methylphenidate) and lisdexamfetamine dimesylate (LDX) on the driving performance of young adults with attention deficit hyperactivity disorder (ADHD) in a randomized, double-blind, crossover study.
METHOD
Following up to 21 days of each treatment in each treatment course (PRC-063/LDX or LDX/PRC-063), subjects completed a 15-hour driving simulator laboratory assessment. The primary outcome measure was the Tactical Driving Quotient (TDQ) and the Clinical Global Impressions-Improvement (CGI-I) scale was a secondary outcome measure.
RESULTS
Forty-four subjects completed the study. PRC-063 and LDX had equivalent effects on driving performance through a 15-hour time period (least square mean difference -0.3 [standard error 1.08], 95% confidence interval [-2.4, 1.8], = .793). Consistent improvement in CGI-I was observed. The incidence of treatment-emergent adverse events was similar for each treatment sequence.
CONCLUSIONS
PRC-063 and LDX had comparable effects on driving performance, from 1 through 15 hours, the last time point measured.
Topics: Humans; Young Adult; Attention Deficit Disorder with Hyperactivity; Central Nervous System Stimulants; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Lisdexamfetamine Dimesylate; Methylphenidate; Treatment Outcome
PubMed: 38404033
DOI: 10.1177/10870547241226634 -
Expert Review of Neurotherapeutics Apr 2024Amphetamine preparations are one of the two categories of stimulant medications approved for the treatment of attention deficit hyperactivity disorder (ADHD). Optimal... (Review)
Review
INTRODUCTION
Amphetamine preparations are one of the two categories of stimulant medications approved for the treatment of attention deficit hyperactivity disorder (ADHD). Optimal treatment of ADHD aims to reduce core symptoms for as much of the waking hours as possible, leading to longer-acting delivery formats. In addition, the pediatric population commonly has difficulty swallowing pills and manufacturers have developed a variety of options to facilitate this concern. These include chewable tablets, capsules that may be sprinkled on soft food, liquids and transdermal patches.
AREAS COVERED
This article reviews the once-daily extended-release preparations currently available for amphetamine compounds, their pharmacodynamics, and common adverse effects.
EXPERT OPINION
There is an extensive evidence base supporting use of amphetamine preparations in the treatment of ADHD. Rapid onset of action and a favorable side effect profile make these widely used. The availability of once-daily extended-release chewable tablets, capsules that can be opened and sprinkled, and liquid formulations provides clinicians with multiple options to meet the specific needs of patients with difficulty swallowing whole pills.
Topics: Humans; Child; Attention Deficit Disorder with Hyperactivity; Amphetamine; Central Nervous System Stimulants; Methylphenidate; Delayed-Action Preparations; Tablets
PubMed: 38391788
DOI: 10.1080/14737175.2024.2321921 -
Journal of Clinical Psychopharmacology
Review
Serum Transaminase Monitoring and Successful Treatment of ADHD With Dextroamphetamine in a Patient With Progressive Familial Intrahepatic Cholestasis Type 3: A Case Report and Literature Review.
Topics: Humans; ATP Binding Cassette Transporter, Subfamily B; Attention Deficit Disorder with Hyperactivity; Cholestasis, Intrahepatic; Dextroamphetamine
PubMed: 38385789
DOI: 10.1097/JCP.0000000000001806 -
Toxicology and Applied Pharmacology Mar 2024Lisdexamfetamine (LDX) is a d-amphetamine prodrug used to treat attention deficit and hyperactivity disorder, a common neurodevelopmental disorder in children and...
Lisdexamfetamine (LDX) is a d-amphetamine prodrug used to treat attention deficit and hyperactivity disorder, a common neurodevelopmental disorder in children and adolescents. Due to its action mediated by elevated levels of catecholamines, mainly dopamine and noradrenaline, which influence hormonal regulation and directly affect the gonads, this drug may potentially disrupt reproductive performance. This study evaluated the effects of exposure to LDX from the juvenile to peripubertal period (critical stages of development) on systemic and reproductive toxicity parameters in male rats. Male Wistar rats (23 days old) were treated with 0; 5.2; 8.6 or 12.1 mg/kg/day of LDX from post-natal day (PND) 23 to 53, by gavage. LDX treatment led to reduced daily food and water consumption, as well as a decrease in social behaviors. The day of preputial separation remained unaltered, although the treated animals exhibited reduced weight. At PND 54, the treated animals presented signs of systemic toxicity, evidenced by a reduction in body weight gain, increase in the relative weight of the liver, spleen, and seminal gland, reduction in erythrocyte and leukocyte counts, reduced total protein levels, and disruptions in oxidative parameters. In adulthood, there was an increase in immobile sperm, reduced sperm count, morphometric changes in the testis, and altered oxidative parameters, without compromising male sexual behavior and fertility. These findings showed that LDX-treatment during the juvenile and peripubertal periods induced immediate systemic toxicity and adversely influenced reproductive function in adult life, indicating that caution is necessary when prescribing this drug during the peripubertal phase.
Topics: Humans; Adult; Child; Adolescent; Male; Rats; Animals; Lisdexamfetamine Dimesylate; Central Nervous System Stimulants; Dextroamphetamine; Treatment Outcome; Rats, Wistar; Semen
PubMed: 38378049
DOI: 10.1016/j.taap.2024.116867 -
Human Psychopharmacology May 2024Stimuli received beyond a very short timeframe, known as temporal binding windows (TBWs), are perceived as separate events. In previous audio-visual multisensory... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
Stimuli received beyond a very short timeframe, known as temporal binding windows (TBWs), are perceived as separate events. In previous audio-visual multisensory integration (McGurk effect) studies, widening of TBWs has been observed in people with schizophrenia. The present study aimed to determine if dexamphetamine could increase TBWs in unimodal auditory and unimodal visual illusions that may have some validity as experimental models for auditory and visual hallucinations in psychotic disorders.
METHODS
A double-blind, placebo-controlled, counter-balanced crossover design with permuted block randomisation for drug order was followed. Dexamphetamine (0.45 mg/kg, PO, q.d.) was administered to healthy participants. Phantom word illusion (speech illusion) and visual-induced flash illusion/VIFI (visual illusion) tests were measured to determine if TBWs were altered as a function of delay between stimuli presentations. Word emotional content for phantom word illusions was also analysed.
RESULTS
Dexamphetamine significantly increased the total number of phantom words/speech illusions (p < 0.01) for pooled 220-1100 ms ISIs in kernel density estimation and the number of positive valence words heard (beta = 2.20, 95% CI [1.86, 2.55], t = 12.46, p < 0.001) with a large effect size (std. beta = 1.05, 95% CI [0.89, 1.22]) relative to placebo without affecting the TBWs. For the VIFI test, kernel density estimation for pooled 0-801 ms ISIs showed a significant difference (p < 0.01) in the data distributions of number of target flash (es) perceived by participants after receiving dexamphetamine as compared with placebo.
CONCLUSIONS
Overall, healthy participants who were administered dexamphetamine (0.45 mg/kg, PO, q.d.) experienced increases in auditory and visual illusions in both phantom word illusion and VIFI tests without affecting their TBWs.
Topics: Humans; Double-Blind Method; Male; Adult; Cross-Over Studies; Female; Illusions; Young Adult; Dextroamphetamine; Visual Perception; Hallucinations; Time Factors; Photic Stimulation; Central Nervous System Stimulants; Acoustic Stimulation; Speech Perception; Auditory Perception; Adolescent
PubMed: 38353526
DOI: 10.1002/hup.2896 -
Experimental Neurology Apr 2024Executive function, including working memory, attention and inhibitory control, is crucial for decision making, thinking and planning. Lisdexamfetamine, the prodrug of...
Executive function, including working memory, attention and inhibitory control, is crucial for decision making, thinking and planning. Lisdexamfetamine, the prodrug of d-amphetamine, has been approved for treating attention-deficit hyperactivity disorder and binge eating disorder, but whether it improves executive function under non-disease condition, as well as the underlying pharmacokinetic and neurochemical properties, remains unclear. Here, using trial unique non-matching to location task and five-choice serial reaction time task of rats, we found lisdexamfetamine (p.o) enhanced spatial working memory and sustained attention under various cognitive load conditions, while d-amphetamine (i.p) only improved these cognitive performances under certain high cognitive load condition. Additionally, lisdexamfetamine evoked less impulsivity than d-amphetamine, indicating lower adverse effect on inhibitory control. In vivo pharmacokinetics showed lisdexamfetamine produced a relative stable and lasting release of amphetamine base both in plasma and in brain tissue, whereas d-amphetamine injection elicited rapid increase and dramatical decrease in amphetamine base levels. Microdialysis revealed lisdexamfetamine caused lasting release of dopamine within the medial prefrontal cortex (mPFC), whereas d-amphetamine produced rapid increase followed by decline to dopamine level. Moreover, lisdexamfetamine elicited more obvious efflux of noradrenaline than that of d-amphetamine. The distinct neurochemical profiles may be partly attributed to the different action of two drugs to membranous catecholamine transporters level within mPFC, detecting by Western Blotting. Taken together, due to its certain pharmacokinetic and catecholamine releasing profiles, lisdexamfetamine produced better pharmacological action to improving executive function. Our finding provided valuable evidence on the ideal pharmacokinetic and neurochemical characteristics of amphetamine-type psychostimulants in cognition enhancement.
Topics: Rats; Animals; Lisdexamfetamine Dimesylate; Executive Function; Dopamine; Central Nervous System Stimulants; Dextroamphetamine; Amphetamine; Catecholamines; Cognition
PubMed: 38336285
DOI: 10.1016/j.expneurol.2024.114718