Image classification and reconstruction from low-density EEG.

Recent advances in visual decoding have enabled the classification and reconstruction of perceived images from the brain. However, previous approaches have predominantly relied on stationary, costly equipment like fMRI or high-density EEG, limiting the real-world availability and applicability of such projects. Additionally, several EEG-based paradigms have utilized artifactual, rather than stimulus-related information yielding flawed classification and reconstruction results. Our goal was to reduce the cost of the decoding paradigm, while increasing its flexibility. Therefore, we investigated whether the classification of an image category and the reconstruction of the image itself is possible from the visually evoked brain activity measured by a portable, 8-channel EEG. To compensate for the low electrode count and to avoid flawed predictions, we designed a theory-guided EEG setup and created a new experiment to obtain a dataset from 9 subjects. We compared five contemporary classification models with our setup reaching an average accuracy of 34.4% for 20 image classes on hold-out test recordings. For the reconstruction, the top-performing model was used as an EEG-encoder which was combined with a pretrained latent diffusion model via double-conditioning. After fine-tuning, we reconstructed images from the test set with a 1000 trial 50-class top-1 accuracy of 35.3%. While not reaching the same performance as MRI-based paradigms on unseen stimuli, our approach greatly improved the affordability and mobility of the visual decoding technology.

Dose Proportionality and Steady-State Pharmacokinetics of Serdexmethylphenidate/Dexmethylphenidate, a Novel Prodrug Combination to Treat Attention-Deficit/Hyperactivity Disorder.

Objective: The study was designed to determine (1) the pharmacokinetic (PK) profile of dexmethylphenidate (d-MPH) after oral administration of three dosage strengths of a new treatment containing d-MPH and a novel prodrug, serdexmethylphenidate (SDX); (2) the dose proportionality of the different SDX/d-MPH dosages; and (3) the steady-state PK profile of d-MPH and SDX after multiple dosing of SDX/d-MPH. Methods: Twenty-three healthy volunteers (aged 18-55 years) under fasted conditions received in a crossover design SDX/d-MPH 26.1/5.2 mg (Treatment A), 39.2/7.8 mg (Treatment B), and 52.3/10.4 mg (Treatment C) for a total d-MPH hydrochloride equivalent dose of 20, 30, and 40 mg, respectively. After a 96-hour washout period, all participants received four consecutive daily doses of SDX/d-MPH 52.3/10.4 mg. Blood samples were collected for measurement of plasma d-MPH and SDX and for PK analysis. Results: Administration of all three doses of SDX/d-MPH resulted in a rapid rise and slow decline in the plasma concentration of d-MPH. For Treatments A, B, and C, mean (± standard deviation) maximum concentrations (Cmax) were 7.1 ± 2.1, 9.8 ± 2.8, and 13.8 ± 3.8 ng/mL, and overall exposures (AUC0-last) were 97.2 ± 28.8, 142.5 ± 41.2, and 199.8 ± 57.2 h*ng/mL, respectively. Dose-normalized Cmax, AUC0-last, and AUC0-inf for d-MPH were similar when comparing the high and low doses versus the middle dose. Power model regression analysis revealed that Cmax and AUC0-inf proportionally increased with an increase in SDX/d-MPH dose. In the multiple-dose study, d-MPH reached steady state before the third dose, and SDX after the first dose. Conclusion: The PK profile of SDX/d-MPH is characterized by a rapid rise and a gradual decline in d-MPH concentration, with proportional Cmax and AUC0-inf across doses. The PK attributes of SDX/d-MPH may optimize symptom control from early morning to early evening, while the demonstrated dose proportionality may facilitate initial dose titration and ongoing dose adjustment.

Oral, intranasal, and intravenous abuse potential of serdexmethylphenidate, a novel prodrug of d-methylphenidate.

OBJECTIVES: Serdexmethylphenidate (SDX) chloride (Cl) is a novel prodrug of d-methylphenidate (d-MPH). These studies evaluated the abuse potential of SDX Cl when administered orally, intranasally (IN), and intravenously (IV). METHODS: Three randomized, double-blind, placebo- and active-controlled crossover studies were conducted in recreational drug users to evaluate the abuse-related effects of oral SDX (120 and 240 mg) vs. extended-release (ER) d-MPH (80 mg) and phentermine (60 mg); IN SDX (80 mg) vs. d-MPH (40 mg), and IV SDX (30 mg) vs. d-MPH (15 mg). Abuse-related subjective measures, pharmacokinetics, and safety were assessed. RESULTS: The primary endpoint of maximum (Emax) Drug Liking (DL) (0-100-point scale) was significantly higher following d-MPH vs. placebo, validating the studies. In the oral study, DL Emax was significantly higher following 80 mg ER d-MPH (Emax = 81.5) than 120 mg SDX (Emax = 62.8, p < .001) and 240 mg SDX (Emax = 63.8, p = .006); and following 60 mg phentermine (Emax = 80.2) than 120 mg SDX (p = .0195), but not 240 mg SDX (p = .0665). DL Emax scores were significantly higher following IN d-MPH vs SDX (Emax = 93.2 vs. 71.0, p < .0001) and following IV d-MPH vs. SDX (Emax = 84.3 vs. 56.6, p = .001). Intravenous SDX was non-inferior to placebo (p = .001) for DL Emax. Secondary endpoints (e.g. Take Drug Again) were generally consistent with the primary endpoint. Maximal and overall d-MPH exposure was lower for SDX than d-MPH for all routes. Adverse events typical of stimulants were more frequent with d-MPH than SDX. CONCLUSIONS: These findings indicate that the novel d-MPH prodrug, SDX, has lower abuse potential than d-MPH and support its classification as a C-IV controlled substance.

A Randomized, Controlled Laboratory Classroom Study of Serdexmethylphenidate and d-Methylphenidate Capsules in Children with Attention-Deficit/Hyperactivity Disorder.

Objectives: To evaluate the efficacy and safety of once-daily serdexmethylphenidate/dexmethylphenidate (SDX/d-MPH) capsules (Azstarys™) compared with placebo in children with attention-deficit/hyperactivity disorder (ADHD) in a randomized, double-blind, dose-optimized laboratory classroom study. Methods: Children ages 6-12 with ADHD were enrolled. During a 3-week, open-label, Dose Optimization Phase, subjects initiated treatment with 39.2 mg/7.8 mg/day of SDX/d-MPH and were titrated weekly to an optimal dose (maximum dose of 52.3/10.4 mg). During the double-blind Treatment Phase, subjects were randomized to receive their optimal dose of SDX/d-MPH or placebo for 7 days. On day 7, efficacy was assessed in the laboratory classroom using the Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) Rating Scale and Permanent Product Measure of Performance (PERMP). To evaluate safety, adverse events (AEs), vital signs, and electrocardiograms were assessed, and suicide risk was assessed. Results: A total of 149 subjects completed the study. In the primary efficacy analysis, the mean postdose change from baseline in SKAMP-Combined scores averaged over the laboratory classroom day was significantly improved with SDX/d-MPH versus placebo (least-squares mean treatment difference [95% confidence interval]: -5.41 [-7.10 to -3.71]; p < 0.001). A significant treatment effect for SDX/d-MPH compared with placebo was observed from 1 to 10 hours postdose. A post hoc analysis more comparable with that conducted in similar studies indicated a 0.5- to 13-hour onset and duration of efficacy. Both average postdose PERMP-Attempted and PERMP-Correct score changes from baseline were significantly improved among those treated with SDX/d-MPH versus placebo (p < 0.001 for both). No serious AEs were reported. During the Dose Optimization Phase, two-thirds of subjects reported AEs; the most common being insomnia and decreased appetite. Conclusions: SDX/d-MPH showed significant improvement in ADHD symptoms compared with placebo in children 6-12 years of age, with a rapid onset and extended duration of treatment effect. SDX/d-MPH was safe, with AEs comparable with those observed with other stimulant treatments.

Pharmacokinetics and Abuse Potential of Asalhydromorphone, a Novel Prodrug of Hydromorphone, After Intranasal Administration in Recreational Drug Users.

OBJECTIVES: Hydromorphone (HM) is a potent µ-opioid receptor agonist with high susceptibility for abuse. A prodrug of hydromorphone, asalhydromorphone (ASAL-HM), has been designed to deter nonoral forms of abuse associated with hydromorphone. This study evaluated the intranasal (IN) pharmacokinetics and exploratory abuse potential of ASAL-HM compared with HM. DESIGN: Single-center, randomized, double-blind, crossover study. SETTING: Clinical research site. SUBJECTS: Healthy adult, nondependent recreational opioid users. METHODS: Subjects (N = 26) were randomized to receive IN administration of 16.1 mg of ASAL-HM and 8.0 mg of HM (molar-equivalent with respect to hydromorphone). Blood samples were taken through 24 hours postdose, and pharmacodynamic end points (Drug Liking, Feeling High, Take Drug Again, Overall Drug Liking) were assessed through eight hours postdose. Nasal irritation and safety were also assessed. RESULTS: Relative to IN HM, the rate (Cmax) and extent (area under the curve [AUC0-last, AUC0-inf]) of exposure to hydromorphone following IN ASAL-HM were reduced by ≥50%. Consistent with these findings, scores on "at-the-moment" (i.e., Drug Liking Emax, High Emax) and retrospective (i.e., Take Drug Again, Overall Drug Liking) end points were statistically significantly lower for IN ASAL-HM, with mean/median differences ranging from 11.4 to 25.0 points. ASAL-HM produced greater nasal-related effects, such as nasal burning and facial pain, and a lower incidence of typical opioid-related adverse events such as euphoria, pruritus, and somnolence. CONCLUSIONS: The novel hydromorphone prodrug ASAL-HM produced marked reductions in hydromorphone exposure and abuse-related effects following IN administration compared with HM. ASAL-HM has desirable molecular features for incorporation into putative abuse-deterrent immediate-release and extended-release hydromorphone products.

Pharmacokinetics and Abuse Potential of Benzhydrocodone, a Novel Prodrug of Hydrocodone, After Intranasal Administration in Recreational Drug Users.

Objective: Developing an acetaminophen-free, immediate-release hydrocodone product remains an unmet medical need; however, new opioid analgesics should not introduce new abuse risks. Benzhydrocodone is a prodrug of hydrocodone that must be metabolized into hydrocodone by enzymes in the intestinal tract to optimally deliver its pharmacologic effects. This study evaluated the intranasal pharmacokinetics and abuse potential of benzhydrocodone active pharmaceutical ingredient (API) compared with hydrocodone bitartrate (HB) API. Design: Single-center, randomized, double-blind, crossover study. Setting: Clinical research site. Subjects: Healthy adult, nondependent, recreational opioid users. Methods: Subjects (N = 51 Completers) were randomized to receive 13.34 mg of intranasal benzhydrocodone API and 15.0 mg of intranasal HB API (molar-equivalent doses of hydrocodone). Blood samples were taken, and Drug Liking scores (assessed on a bipolar visual analog scale) were obtained throughout each dosing interval. Nasal irritation and safety were assessed. Results: Peak hydrocodone plasma concentration (Cmax) was 36.0% lower, and total hydrocodone exposures (AUClast and AUCinf) were 20.3% and 19.5% lower, respectively, for benzhydrocodone API compared with HB API (P < 0.0001). All partial AUC values were lower for benzhydrocodone API, with a ≥ 75% reduction in hydrocodone exposure at all time intervals up to one hour postdose (P < 0.0001). Median Tmax of hydrocodone following benzhydrocodone API was delayed by more than one hour compared with HB. Drug Liking score, as assessed by maximal liking (Emax), was significantly lower for benzhydrocodone API vs HB API (P = 0.004), with 45% of subjects showing a ≥ 30% reduction in Drug Liking Emax. Conclusion: Reductions in hydrocodone exposure and associated decreases in Drug Liking relative to HB suggest that the prodrug benzhydrocodone may deter intranasal abuse.

Relative Bioavailability, Intranasal Abuse Potential, and Safety of Benzhydrocodone/Acetaminophen Compared with Hydrocodone Bitartrate/Acetaminophen in Recreational Drug Abusers.

Objectives: Benzhydrocodone is a hydrocodone prodrug that has been combined with acetaminophen (APAP) in a novel immediate-release analgesic. This study evaluated the relative bioavailability, intranasal abuse potential, and safety of benzhydrocodone/APAP compared with commercially available hydrocodone bitartrate (HB)/APAP. Design: Single-center, randomized, double-blind, double-dummy, two-part study comprising a Dose Selection (Part A) phase and a Main Study (Part B) phase. Setting: Clinical research site. Subjects: Healthy adult, nondependent, recreational opioid users with a history of intranasal abuse. Methods: Subjects (N = 42) in Part B received five in-clinic treatments consisting of intranasal and oral benzhydrocodone/APAP (13.34/650 mg), intranasal and oral hydrocodone/APAP (15/650 mg), and placebo, with four or more days of washout between treatments. Pharmacodynamic assessments included subjective effects of Drug Liking, Overall Drug Liking, and Take Drug Again (assessed on visual analog scale [VAS]), as well as nasal irritation. Pharmacokinetics and safety were also assessed. Results: Hydrocodone Cmax was 11% lower for intranasal benzhydrocodone/APAP vs intranasal HB/APAP (P = 0.0027). Early cumulative hydrocodone exposures for intranasal benzhydrocodone/APAP through 0.5, 1, and 2 hours were reduced by approximately 50%, 29%, and 15%, respectively (P ≤ 0.0024). Correspondingly, Drug Liking VAS values up to two hours postdose were significantly lower for intranasal benzhydrocodone/APAP vs intranasal HB/APAP (P ≤ 0.0079), although peak Drug Liking VAS (Emax) scores were not different (P = 0.2814). Adverse nasal effects were more frequent for intranasal benzhydrocodone/APAP vs intranasal HB/APAP. Conclusions: Reduced hydrocodone exposure and drug liking at early time intervals, coupled with adverse nasal effects, can be expected to provide a level of deterrence to the intranasal route of abuse for benzhydrocodone/APAP.

Patterns of abuse and routes of administration for immediate-release hydrocodone combination products.

PURPOSE: Prescriptions for hydrocodone immediate-release (IR) combination products have recently decreased, yet they represent the majority of opioid prescriptions dispensed and are commonly abused analgesics among both adults and adolescents. Little data exist to understand the contribution of IR products to the problem of prescription opioid abuse. This study aimed to better understand abuse patterns for hydrocodone IR combination products among adult and adolescent substance abusers. METHODS: This cross-sectional study examines abuse prevalence (including abuse adjusted for prescription volume and morphine milligram equivalents) and abuse characteristics for hydrocodone IR combination products and other prescription opioids among separate samples of adults and adolescents assessed for substance abuse problems or entering treatment from January 2012 through June 2015. RESULTS: Results indicate higher abuse for hydrocodone IR combination products than other opioid categories per 100 assessments but lower per prescriptions dispensed. Hydrocodone IR combination products had similar abuse prevalence to all extended-release and long-acting opioids when considering abuse measured per morphine milligram equivalents dispensed. An upward trend in hydrocodone IR combination product abuse was observed among adult substance abusers comparing the period prior to and after Drug Enforcement Administration rescheduling of these products in October 2014. Most individuals reported oral abuse of hydrocodone IR combination products, but snorting, reported by 23% of hydrocodone IR combination product abusers, also appears to be a route of abuse that may have public health relevance. CONCLUSIONS: Given their high prescription volume, hydrocodone IR combination products, even at a relatively low prevalence of abuse, may contribute substantially to the overall problem of prescription opioid abuse. Additional public health interventions, including development of abuse-deterrent formulations for these types of opioid products may aid in reducing their abuse.

A new approach for the synthesis of novel 5-substituted isodeoxyuridine analogs.

Cyclic sulfates of carbohydrates provide excellent synthons for the preparation of isodeoxyuridines through direct nucleophilic substitution reactions. These substitution reactions have exceptional regioselectivity. The products of the reactions served as key precursors for the synthesis of 5-substituted isodeoxyuridines via the Stille and Heck coupling reactions. Interestingly, unprotected nucleosides could be used in these metal-mediated functionalizations. The methodologies are general and allow ready access to a variety of C-5 functionalized isomeric deoxyuridines, but also have the potential to be extended to other nucleoside analogs.

A thymidine phosphorylase-stable analogue of BVDU with significant antiviral activity.

(E)-5-(2-Bromovinyl)isodideoxyuridine (BVisoDDU), synthesized on the basis of molecular modeling, is selectively active against HSV-1 (three different strains) but inactive against HSV-2. Unlike BVDU, BVisoDDU is completely resistant to cleavage by thymidine phosphorylase. BVisoDDU is also the first nucleoside analogue lacking OH groups at both the 2'- and 3'-position that shows pronounced activity against HSV-1 replication.

Binding modes of two novel dinucleotide inhibitors of HIV-1 integrase.

Insights into the binding modes on HIV-1 integrase of our novel dinucleotide inhibitors (pisodApdC and pdCpisodU) have been obtained using molecular docking experiments. In contrast to their base-stacked unbound state, these dinucleotides in their integrase-bound state prefer unstacked conformations for a more extensive interaction with the active site. The calculated free energies of binding are in concert with the experimentally acquired anti-HIV-1 integrase data.