Naama Levy-Cooperman

Lesion Explorer: a comprehensive segmentation and parcellation package to obtain regional volumetrics for subcortical hyperintensities and intracranial tissue.

Subcortical hyperintensities (SH) are a commonly observed phenomenon on MRI of the aging brain (Kertesz et al., 1988). Conflicting behavioral, cognitive and pathological associations reported in the literature underline the need to develop an intracranial volumetric analysis technique to elucidate pathophysiological origins of SH in Alzheimers disease (AD), vascular cognitive impairment (VCI) and normal aging (De Leeuw et al., 2001; Mayer and Kier, 1991; Pantoni and Garcia, 1997; Sachdev et al., 2008). The challenge is to develop processing tools that effectively and reliably quantify subcortical small vessel disease in the context of brain tissue compartments. Segmentation and brain region parcellation should account for SH subtypes which are often classified as: periventricular (pvSH) and deep white (dwSH), incidental white matter disease or lacunar infarcts and Virchow-Robin spaces. Lesion Explorer (LE) was developed as the final component of a comprehensive volumetric segmentation and parcellation image processing stream built upon previously published methods (Dade et al., 2004; Kovacevic et al., 2002). Inter-rater and inter-method reliability was accomplished both globally and regionally. Volumetric analysis showed high inter-rater reliability both globally (ICC=.99) and regionally (ICC=.98). Pixel-wise spatial congruence was also high (SI=.97). Whole brain pvSH volumes yielded high inter-rater reliability (ICC=.99). Volumetric analysis against an alternative kNN segmentation revealed high inter-method reliability (ICC=.97). Comparison with visual rating scales showed high significant correlations (ARWMC: r=.86; CHIPS: r=.87). The pipeline yields a comprehensive and reliable individualized volumetric profile for subcortical vasculopathy that includes regionalized (26 brain regions) measures for: GM, WM, sCSF, vCSF, lacunar and non-lacunar pvSH and dwSH.

Functional correlates of instrumental activities of daily living in mild Alzheimer's disease

Instrumental activities of daily living (IADL) includes the integration of task-initiation, -planning, and -performance. Little is known on the cerebral perfusion correlates of these subcomponents of IADL in Alzheimers disease (AD). In 121 AD patients, cerebral perfusion, using single-photon emission computed tomography, in 13 bilateral regions of interest (ROI) and the perfusion correlates of IADL subcomponents, rated on the Disability Assessment in Dementia scale, were explored. Significant correlations were observed between IADL initiation and multiple bilateral prefrontal-striatal-anterior cingulate ROI (p < 0.01), IADL planning and right occipital ROI (p < 0.05), and IADL performance and right parietal ROI (p < 0.05). Multiple regression, accounting for age, cognitive impairment, and depression severity, revealed significant relationship between right basal ganglia perfusion and IADL-initiation (R = 0.6, R(2) = 0.39, F(4,117) = 17.8, SE = 1.56; p < 0.001) and right occipital perfusion and IADL-planning (R = 0.6, R(2) = 0.34, F(4,117) = 19.5, SE = 1.47; p < 0.001). In AD, perfusion correlates of these subcomponents may be linked to the heterogenous cognitive processes involved in IADL.

Intranasal administration of crushed ALO-02 (extended-release oxycodone with sequestered naltrexone): A randomized, controlled abuse-potential study in nondependent recreational opioid users.

ALO‐02 is an abuse‐deterrent formulation consisting of capsules filled with pellets of extended‐release oxycodone surrounding sequestered naltrexone. This randomized, double‐blind, placebo‐/active‐controlled, 4‐way crossover study examined the abuse potential of crushed ALO‐02 administered intranasally to healthy, nondependent, recreational opioid users. Following drug discrimination and naloxone challenge, eligible participants (n = 32) entered a 4‐way crossover treatment phase: crushed single dose of 1 of 2 placebos, ALO‐02 30 mg/3.6 mg (oxycodone/naltrexone) or oxycodone immediate‐release (IR) 30 mg. Primary end points were Drug Liking and High, measured on visual analog scales (VAS) summarized as maximum effect (Emax) and effect occurring over 2 hours postdose (AUE0–2 h). Crushed ALO‐02 resulted in significantly lower scores versus oxycodone IR on Drug Liking (Emax, 60.5 vs 92.8; AUE0–2 h, 105.4 vs 160.0, respectively) and High (Emax, 25.2 vs 86.9; AUE0–2 h, 27.1 vs 136.4, respectively; n = 28; P < .0001). Adverse events occurred most frequently with oxycodone IR, followed by ALO‐02, then placebo, and were considered mild and consistent with opioid therapy. Crushed ALO‐02 administered intranasally to nondependent recreational opioid users resulted in significantly lower scores on Drug Liking/High VAS and other positive subjective measures versus crushed oxycodone IR, suggesting less abuse potential. Demonstration of actual abuse deterrence in the real world requires further research.

Oral Human Abuse Potential of Oxycodone DETERx(®) (Xtampza(®) ER).

Oxycodone DETERx® (Collegium Pharmaceutical Inc, Canton, Massachusetts) is an extended‐release, microsphere‐in‐capsule, abuse‐deterrent formulation designed to retain its extended‐release properties after tampering (eg, chewing/crushing). This randomized, double‐blind, placebo‐controlled, triple‐dummy study evaluated the oral abuse potential of intact and chewed oxycodone DETERx capsules compared with crushed immediate‐release oxycodone. Subjects with a history of recreational opioid use who were nondependent/nontolerant to opioids were enrolled. Treatments included intact oxycodone DETERx (high‐fat, high‐calorie meal and fasted), chewed oxycodone DETERx (high‐fat, high‐calorie meal and fasted), crushed immediate‐release oxycodone (fasted), and placebo (high‐fat, high‐calorie meal). Plasma samples were collected to determine pharmacokinetic parameters. The primary endpoint was drug liking at the moment; other endpoints included drug effects questionnaire scores, Addiction Research Center Inventory/Morphine Benzedrine Group score, pupillometry measurements, and safety. Thirty‐eight subjects completed the study. Chewed and intact oxycodone DETERx were bioequivalent, unlike crushed immediate‐release oxycodone, which yielded higher peak oxycodone plasma concentrations compared with all methods of oxycodone DETERx administration. The mean maximum (peak) effect (Emax) for drug liking was significantly lower for chewed and intact oxycodone DETERx than for crushed immediate‐release oxycodone (P < .01). The time to Emax was significantly longer for chewed and intact oxycodone DETERx than for crushed immediate‐release oxycodone (P < .0001). Scores for feeling high and Addiction Research Center Inventory/Morphine Benzedrine Group scores demonstrated lower abuse potential for chewed and intact oxycodone DETERx compared with crushed immediate‐release oxycodone. Study treatments were well tolerated; no subjects experienced serious adverse events. These results demonstrate the lower oral abuse potential of chewed and intact oxycodone DETERx than crushed immediate‐release oxycodone.

Brain Network Activation (BNA) Reveals Scopolamine-Induced Impairment of Visual Working Memory

The overarching goal of this event-related potential (ERP) study was to examine the effects of scopolamine on the dynamics of brain network activation using a novel ERP network analysis method known as Brain Network Activation (BNA). BNA was used for extracting group-common stimulus-activated network patterns elicited to matching probe stimuli in the context of a delayed matching-to-sample task following placebo and scopolamine treatments administered to healthy participants. The BNA extracted networks revealed the existence of two pathophysiological mechanisms following scopolamine, disconnection, and compensation. Specifically, weaker frontal theta and parietal alpha coupling was accompanied with enhanced fronto-centro-parietal theta activation relative to placebo. In addition, using the characteristic BNA network of each treatment as well as corresponding literature-guided selective subnetworks as combined biomarkers managed to differentiate between individual responses to each of the treatments. Behavioral effects associated with scopolamine included delayed response time and impaired response accuracy. These results indicate that the BNA method is sensitive to the effects of scopolamine on working memory and that it may potentially enable diagnosis and treatment assessment of dysfunctions associated with cholinergic deficiency.

Subcortical hyperintensities in Alzheimer's disease: no clear relationship with executive function and frontal perfusion on SPECT.

Background/Aims: To investigate relationships between subcortical hyperintensities (SH), frontal perfusion and executive function (EF) in a sample of Alzheimer’s disease (AD) patients with varying severities of SH. Methods: A sample of 63 AD patients underwent brain imaging with magnetic resonance imaging (MRI) and single photon emission computed tomography (SPECT) scans. Severity of SH was assessed using a standardized visual rating scale on MRI. Patients were classified into severe (n = 20), moderate (n = 23) or no SH (n = 20) groups. Four frontal SPECT regions of interest (anterior cingulate cortex, dorsolateral prefrontal cortex) and neuropsychological assessment of EF were analyzed. Results: Overall, no significant relationships were found between severity of SH and measures of SPECT perfusion or EF, except for one subsection of the Dementia Rating Scale, with severe SH scoring slightly worse than the other two groups. Conclusion: These findings support previous studies which suggest minimal adverse effects of SH on brain function and cognition. Global severity of SH on MRI in AD was not associated with decline in frontal perfusion and only mildly related to a decline in a specific EF task. More accurate measures of SH volume, not just global severity of SH, may be necessary to capture such complex brain behavior relationships; if they do indeed exist.

Assessment of the Abuse Potential of the Orexin Receptor Antagonist, Suvorexant, Compared With Zolpidem in a Randomized Crossover Study.

Abstract Suvorexant is a dual orexin receptor antagonist approved in the United States and Japan for the treatment of insomnia at a maximum dose of 20 mg. This randomized double-blind crossover study evaluated the abuse potential of suvorexant in 36 healthy recreational polydrug users with a history of sedative and psychedelic drug use. Single doses of suvorexant (40, 80, and 150 mg: 2–7.5 × maximum dose), zolpidem (15 and 30 mg: 1.5–3 × maximum dose), and placebo were administered, with a 10-day washout between treatments. Subjective and objective measures, including visual analog scales (VASs), Addiction Research Center Inventory, and cognitive/psychomotor tests, were evaluated for 24-hour postdose. Suvorexant had significantly greater peak effects on “drug liking” VAS (primary endpoint) than placebo. Although effects of suvorexant on abuse potential measures were generally similar to zolpidem, they remained constant across doses, whereas zolpidem often had greater effects at higher doses. Suvorexant (all doses) had significantly fewer effects than zolpidem 30 mg on secondary measures, such as “high” VAS, Bowdle VAS, and Addiction Research Center Inventory morphine-benzedrine group. The overall incidence of abuse-related adverse events, such as euphoric mood and hallucination, was numerically lower with suvorexant than zolpidem. In agreement with its classification as a schedule IV drug, suvorexant demonstrated abuse potential, compared with placebo. The abuse potential was similar to zolpidem using certain measures, but with a reduced incidence of abuse-related adverse events. Although this suggests that the overall abuse liability of suvorexant may be lower than zolpidem, the actual abuse rates will be assessed with the postmarketing experience.

Self-reports of prescription opioid abuse and diversion among recreational opioid users in a Canadian and a United States city

OBJECTIVE To explore behaviors related to prescription opioid abuse and diversion in individuals who self-reported past recreational (nonmedical) opioid use. DESIGN A questionnaire was developed and included in two abuse potential clinical studies conducted in Canada (Toronto, ON, August 2010 to January, 2011) and the United States (Salt Lake City, UT, February-May 2011). PARTICIPANTS Recreational opioid users. MAIN OUTCOME MEASURE(S) Self-reported behaviors related to prescription opioid abuse and diversion. RESULTS The questionnaire was completed by 174 participants in the Canadian study and 80 participants in the US study. Most participants reported that they used prescription opioids for nonmedical purposes a few times a month. Most had taken their first prescription opioid between the ages of 12 and 24 years and the two most common reasons were to treat pain or to feel high/stoned. When asked about specific opioids taken for nonmedical purposes in the past year, oxycodone, acetaminophen with codeine, and morphine were commonly used by both cohorts, whereas hydrocodone use was substantially greater in the US cohort versus the Canadian cohort. Participants reported various tampering methods and routes of administration, with swallowed whole, crushed and snorted, and chewed/crushed and swallowed as the most prevalent. Most participants indicated taking other drugs with prescription opioids to get high, most commonly marijuana and alcohol. The most common sources for obtaining prescription opioids were family/friends. CONCLUSIONS Two cohorts of recreational opioid users from Canada and the United States reported similar experiences with various prescription opioids and indicated a predominance of diversion from family/friends.

Abuse Potential Study of ALO-02 (Extended-Release Oxycodone Surrounding Sequestered Naltrexone) Compared with Immediate-Release Oxycodone Administered Orally to Nondependent Recreational Opioid Users

Abstract Objective. To evaluate the abuse potential of ALO-02, an abuse-deterrent formulation comprising pellets of extended-release oxycodone hydrochloride surrounding sequestered naltrexone hydrochloride. Design. Randomized, double-blind, placebo-/active-controlled, 6-way crossover study, with naloxone challenge, drug discrimination, and treatment phases. Subjects. Nondependent, recreational opioid users. Methods. Oral administration of crushed and intact ALO-02, crushed immediate-release (IR) oxycodone, and placebo. Primary endpoints were Drug Liking and High measured on visual analog scales and reported as maximum effect (Emax) and area-under-the-effect-curve from 0 to 2 hours (AUE0-2h). Other pharmacodynamic, pharmacokinetic and safety assessments were included. Results. Drug Liking and High (Emax) for crushed oxycodone IR 40 mg were significantly higher compared with placebo, confirming study validity (P < 0.0001). Drug Liking and High (Emax, AUE0-2h) for crushed ALO-02 (40 mg/4.8 mg and 60 mg/7.2 mg) were significantly lower compared to corresponding doses of crushed oxycodone IR (40 and 60 mg; P < 0.0001). Likewise, Drug Liking and High (Emax and AUE0-2h) for intact ALO-02 60 mg/7.2 mg were significantly lower compared with crushed oxycodone IR 60 mg (P < 0.0001). Secondary pharmacodynamic endpoints and plasma concentrations of oxycodone and naltrexone were consistent with these results. Fewer participants experienced adverse events (AEs) after ALO-02 (crushed or intact: 71.1–91.9%) compared with crushed oxycodone IR (100%). Most common AEs following crushed ALO-02 and oxycodone IR were euphoric mood, pruritus, somnolence, and dizziness. Conclusions. The results suggest that ALO-02 (crushed or intact) has lower abuse potential than crushed oxycodone IR when administered orally in nondependent, recreational opioid users.

Abuse potential assessment of cannabidiol (CBD) in recreational polydrug users: A randomized, double-blind, controlled trial

RATIONALE Treatment with a highly purified oral solution of cannabidiol (CBD), derived from the plant Cannabis sativa L., demonstrated some evidence of central nervous system (CNS)-related adverse events in patients enrolled in phase 3 trials for treatment of childhood-onset epilepsy. Cannabidiol was categorized as a Schedule 1 substance by the United States Drug Enforcement Administration; therefore, it was important to test CBD for human abuse potential. METHODS This was a single-dose, randomized, double-blind, double-dummy, placebo- and active-controlled crossover trial. The abuse potential of single oral doses of plant-derived pharmaceutical formulations of highly purified CBD (Epidiolex®; 750 mg, 1500 mg, and 4500 mg) was compared with that of single oral doses of alprazolam (2 mg), dronabinol (10 mg and 30 mg), and placebo in healthy recreational polydrug users. The primary endpoint to assess abuse potential was the maximum effect (Emax) on Drug-Liking visual analog scale (VAS). Other measurements included Emax on Overall Drug-Liking VAS, Take Drug Again VAS, positive and negative effects, other subjective effects, and Drug Similarity VAS. Cognitive and psychomotor functions were assessed using the Divided Attention Test, the Hopkins Verbal Learning Test-Revised, and the Digit-Symbol Substitution Task. Pharmacokinetic parameters were determined for CBD and its major metabolites. Standard safety measures and adverse events were assessed. PRINCIPAL RESULTS Of 95 eligible subjects, 43 qualified for the treatment phase, received at least 1 dose of investigational medicinal product, and were included in safety assessments; 35 subjects were included in the pharmacodynamic analysis. Subjects receiving alprazolam and dronabinol had significantly higher Drug-Liking Emax (P < 0.0001) compared with those receiving placebo, confirming study validity. Compared with placebo, Drug-Liking was not significantly different for subjects taking 750-mg CBD (P = 0.51). Drug-Liking Emax values for 1500-mg and 4500-mg CBD were significantly different from placebo (P = 0.04 and 0.002, respectively); however, the mean differences were <10 points on VAS compared with >18-point differences between positive controls and placebo. Alprazolam and dronabinol had significantly higher Drug-Liking, Overall-Liking, and Take Drug Again VAS Emax values compared with all doses of CBD (P ≤ 0.004). In contrast to alprazolam, CBD administration had no observable effect on cognitive/psychomotor tests. Pharmacokinetic parameters for CBD in this trial were consistent with previous studies. The majority of adverse events reported during the trial were of mild or moderate severity; no serious adverse events or deaths were reported. CONCLUSION Administration of a therapeutic dose of CBD (750 mg) showed significantly low abuse potential in a highly sensitive population of polydrug users. Although high and supratherapeutic doses of CBD (1500 mg and 4500 mg, respectively) had detectable subjective effects compared with placebo; the effects were significantly lower than those observed with alprazolam and dronabinol.