ABSTRACT
RATIONALE: Understanding mechanisms of drug use decisions will inform the development of treatments for opioid use disorder (OUD). Decision-making experiments using neurobehavioral approaches require many trials or events of interest for statistical analysis, but the pharmacokinetics of most opioids limit dosing in humans. OBJECTIVES: This experiment characterized the effects of repeated infusions of the ultra-short acting opioid remifentanil in people with OUD and physical opioid dependence. METHODS: An inpatient study using a within-subjects, single-blind, escalating, within-session, pre-post design was conducted. Seven (3 female) subjects were maintained on oral oxycodone (40-60 mg, 4x/day = 160-240 total mg/day) for seven days prior to the dose-ranging session. Subjects received infusions of three ascending remifentanil doses (0.03, 0.1, 0.3 mcg/kg/infusion in 2 subjects; 0.1, 0.3, 1.0 mcg/kg/infusion in 5 subjects) every minute for 40 min per dose, with infusions administered over 5 s to model naturalistic delivery rates. End tidal carbon dioxide, respiration rate, oxygen saturation (SpO2) and heart rate were measured continuously. Blood pressure (BP), pupil diameter and self-reported drug effects were measured every 5 min. RESULTS: Pupil diameter, SpO2 and systolic BP decreased, and ratings on prototypic subjective effects questionnaire items increased, as a function of remifentanil dose. The number of infusions held because of sedation or physiological parameters exceeding predetermined cutoffs also increased with dose. CONCLUSIONS: This experiment established doses and procedures for the safe delivery of rapid, repeated remifentanil infusions to individuals with OUD and physical fentanyl dependence, which can be applied to the mechanistic study of opioid use decisions.
Subject(s)
Analgesics, Opioid , Blood Pressure , Dose-Response Relationship, Drug , Fentanyl , Heart Rate , Opioid-Related Disorders , Piperidines , Remifentanil , Humans , Remifentanil/administration & dosage , Remifentanil/pharmacology , Female , Male , Adult , Opioid-Related Disorders/drug therapy , Fentanyl/administration & dosage , Fentanyl/pharmacokinetics , Analgesics, Opioid/administration & dosage , Analgesics, Opioid/pharmacokinetics , Piperidines/administration & dosage , Piperidines/pharmacokinetics , Piperidines/pharmacology , Single-Blind Method , Heart Rate/drug effects , Blood Pressure/drug effects , Infusions, Intravenous , Middle Aged , Self Report , Young Adult , Oxycodone/administration & dosage , Oxycodone/pharmacokineticsABSTRACT
OBJECTIVE: Early adversity, such as adverse childhood experiences (ACEs), is a risk factor for the development of substance use disorder (SUD). ACEs are associated with earlier initiation of substance use. This study examined the relationship between ACEs and age of initiation of substance use using survival analysis. It is hypothesized that individuals with higher ACEs will have an earlier age of initiation. METHOD: Participants were recruited from the University of Kentucky's Laboratory for Human Behavioral Pharmacology. Participants were 18 years or older, English speaking, and actively engaged in substance use. Participants were not in substance abuse treatment nor were they seeking treatment. ACE scores were calculated, and age of substance use initiation was recorded. A Cox proportional hazard model was used to examine the effect of ACE score on age of substance use initiation. RESULTS: A total of 107 participants completed the study. An average number of 2.3 ACEs (SD = 2.2) were endorsed with 24% of participants reporting 4 or more ACEs. Higher ACE scores were associated with cigarette smoking and non-medical prescription opioid use onset ( hazard ratio (HR) = 1.14, 95% CI=1.02-1.28, p = 0.02, and HR=1.19, 95% CI = 1.04-1.37, p = 0.01, respectively. CONCLUSIONS: A significant association was found between higher ACE scores and earlier initiation of cigarette and non-medical prescription opioid use, consistent with prior research. Primary prevention of ACEs, screening for ACEs during childhood, and interventions for ACEs if detected, may help to reduce the risk of substance use/SUD in adulthood.
Subject(s)
Adverse Childhood Experiences , Child Abuse , Substance-Related Disorders , Humans , Child , Analgesics, Opioid , Substance-Related Disorders/epidemiology , Survival AnalysisABSTRACT
Commodity purchase tasks provide a useful method for evaluating behavioral economic demand in the human laboratory. Recent research has shown how responding to purchase tasks for blinded drug administration can be used to study abuse liability. This analysis uses data from a human laboratory study to highlight how similar procedures may be particularly useful for understanding momentary changes in drug valuation when screening novel interventions. Eight nontreatment-seeking participants with cocaine use disorder (one with partial data) were enrolled in a cross-over, double-blind, randomized inpatient study. Participants were maintained on the Food and Drug Administration-approved insomnia medication suvorexant (oral; 0, 5, 10, 20â mg/day) in randomized order with experimental sessions completed after at least 3â days of maintenance on each suvorexant dose. Experimental sessions included administration of a sample dose of 0, 10 and 30â mg/70â kg intravenous cocaine. Analyses focused on purchase tasks for the blinded sample dose as well as alcohol, cigarettes and chocolate completed 15â min after the sample dose. As expected based on abuse liability, near zero demand was observed for placebo with dose-related increases in cocaine demand. Suvorexant maintenance increased cocaine demand in a dose-related manner with the greatest increase observed for the 10â mg/kg cocaine dose. Increased demand under suvorexant maintenance was also observed for alcohol. No effect of cocaine administration was observed for alcohol, cigarette, or chocolate demand. These data support the validity of demand procedures for measuring blinded drug demand. Findings also parallel self-administration data from this study by showing increases in cocaine use motivation under suvorexant maintenance.
Subject(s)
Cocaine-Related Disorders , Cocaine , Humans , Cocaine/pharmacology , Pharmaceutical Preparations , Orexins , Cocaine-Related Disorders/drug therapy , Motivation , EthanolABSTRACT
The FDA has not yet approved a pharmacotherapy for cocaine use disorder despite nearly four decades of research. This study determined the initial efficacy, safety, and tolerability of naltrexone-bupropion combinations as a putative pharmacotherapy for cocaine use disorder. Thirty-one (31) non-treatment seeking participants with cocaine use disorder completed a mixed-design human laboratory study. Participants were randomly assigned to the naltrexone conditions (i.e., 0, 50 mg/day; between-subject factor) and maintained on escalating doses of bupropion (i.e., 0, 100, 200, 400 mg/day; within-subject factor) for at least four days prior to the conduct of experimental sessions. Cocaine self-administration (IN, 0, 40, 80 mg) was then determined using a modified progressive ratio and relapse procedure. Subjective and cardiovascular effects were also measured. Cocaine produced prototypical dose-related increases in self-administration, subjective outcomes (e.g., "Like Drug"), and cardiovascular indices (e.g., heart rate, blood pressure) during placebo maintenance. Naltrexone and bupropion alone, or in combination, did not significantly decrease self-administration on either procedure. Low doses of bupropion (i.e., 100 mg) blunted the effects of the cocaine on subjective measures of "Like Drug" and "Stimulated". No unexpected adverse effects were observed with naltrexone and bupropion, alone and combined, in conjunction with cocaine. Together, these results do not support the use of these bupropion-naltrexone combinations for the treatment of cocaine use disorder. Future research should determine if novel drug combinations may decrease cocaine self-administration.
Subject(s)
Bupropion , Cocaine , Naltrexone , Humans , Blood Pressure , Bupropion/adverse effects , Drug Combinations , Naltrexone/pharmacology , Naltrexone/therapeutic useABSTRACT
Preclinical research has sought to understand the role of the orexin system in cocaine addiction given the connection between orexin producing cells in the lateral hypothalamus and brain limbic areas. Exogenous administration of orexin peptides increased cocaine self-administration whereas selective orexin-1 receptor antagonists reduced cocaine self-administration in non-human animals. The first clinically available orexin antagonist, suvorexant (a dual orexin-1 and orexin-2 receptor antagonist), attenuated motivation for cocaine and cocaine conditioned place preference, as well as cocaine-associated impulsive responding, in rodents. This study aimed to translate those preclinical findings and determine whether suvorexant maintenance altered the pharmacodynamic effects of cocaine in humans. Seven non-treatment seeking subjects with cocaine use disorder completed this within-subject human laboratory study, and a partial data set was obtained from one additional subject. Subjects were maintained for at least three days on 0, 5, 10 and 20 mg oral suvorexant administered at 2230 h daily in random order. Subjects completed experimental sessions in which cocaine self-administration of 0, 10 and 30 mg/70 kg of intravenous cocaine was evaluated on a concurrent progressive ratio drug versus money choice task. Subjective and physiological effects of cocaine were also determined. Cocaine functioned as a reinforcer and produced prototypic dose-related subjective and physiological effects (e.g., increased ratings of "Stimulated" and heart rate). Suvorexant (10, 20 mg) increased self-administration of 10 mg/70 kg cocaine and decreased oral temperature but did not significantly alter any other effects of cocaine. Future research may seek to evaluate the effects of orexin-1 selective antagonists in combination with cocaine.
Subject(s)
Cocaine , Animals , Azepines/pharmacology , Cocaine/pharmacology , Humans , Orexin Receptor Antagonists/pharmacology , Orexin Receptors , Orexins , TriazolesABSTRACT
RATIONALE: Cocaine use disorder is an unrelenting public health concern. Despite nearly four decades of research, an FDA approved medication is not yet available. OBJECTIVES: The objective of this human laboratory study was to demonstrate the initial efficacy, safety and tolerability of topiramate-phentermine combinations for cocaine use disorder. METHODS: Thirty-one (31) participants with cocaine use disorder completed this mixed-model inpatient laboratory study. Participants were maintained on topiramate (0 [N = 11], 50 [N = 9] or 100 [N = 11] mg/day). Each topiramate group was concurrently maintained on phentermine (0, 15, 30 mg). Drug self-administration, subjective responses and cardiovascular effects following acute doses of intranasal cocaine (0, 40, 80 mg) were determined during separate experimental sessions after at least seven (7) days of maintenance on each condition. RESULTS: The three groups of participants were well matched demographically and generally did not differ significantly in their responses to a range of doses of intranasal cocaine (0, 10, 20, 40, 80 mg) during a medical safety session. Maintenance on topiramate and phentermine alone significantly decreased cocaine self-administration although these effects were modest in magnitude. Combining topiramate and phentermine robustly decreased cocaine self-administration. Topiramate and phentermine were well tolerated alone and combined, as well as in conjunction with cocaine. CONCLUSIONS: The results of the present study support advancing topiramate-phentermine combinations as a putative pharmacotherapeutic for cocaine use disorder.
Subject(s)
Cocaine-Related Disorders/drug therapy , Cocaine/administration & dosage , Phentermine/therapeutic use , Self Administration , Topiramate/therapeutic use , Adult , Drug Combinations , Female , Fructose/therapeutic use , Humans , Male , Middle Aged , Young AdultABSTRACT
RATIONALE: Glutamate systems play an important role in the abuse related effects of alcohol. n-Acetylcysteine, a drug that promotes glutamate homeostasis, attenuates a range of alcohol effects in preclinical models. OBJECTIVES: This human laboratory study determined the influence of n-acetylcysteine maintenance on alcohol self-administration using a model predictive of treatment effectiveness, along with the subjective, performance and physiological effects of alcohol. We hypothesized that n-acetylcysteine would attenuate alcohol self-administration, as well as positive subjective effects of alcohol. METHODS: Nine subjects with alcohol use disorder completed this within-subjects study. Subjects were maintained on placebo, 1.2 and 2.4 g n-acetylcysteine in random order on an outpatient basis. After five days of maintenance on the target dose, subjects completed overnight inpatient experimental sessions in which the pharmacodynamic effects of alcohol were determined. RESULTS: Alcohol produced prototypic effects (e.g., increased breath alcohol concentration, increased ratings of Feel Drink). n-Acetylcysteine did not alter the effects of alcohol. CONCLUSIONS: These results indicate that although n-acetylcysteine can safely be combined with alcohol, it does not attenuate the abuse related effects of alcohol and is unlikely to be an effective standalone alcohol use disorder treatment. However, considering study limitations, future work is needed to further understand whether and how n-acetylcysteine might be used as a treatment for alcohol use disorder (e.g., in combination with a behavioral treatment or another pharmacological agent).
Subject(s)
Acetylcysteine/administration & dosage , Alcoholism/drug therapy , Ethanol/administration & dosage , Free Radical Scavengers/administration & dosage , Acetylcysteine/pharmacology , Adult , Alcoholism/etiology , Blood Pressure/drug effects , Double-Blind Method , Drug-Seeking Behavior/drug effects , Ethanol/adverse effects , Female , Free Radical Scavengers/pharmacology , Glutamic Acid/metabolism , Heart Rate/drug effects , Humans , Male , Middle Aged , Reinforcement, Psychology , Self Administration , Time Factors , Treatment Outcome , Young AdultSubject(s)
Cystic Fibrosis , Mental Disorders , Aminophenols , Benzodioxoles , Cystic Fibrosis/complications , Drug Combinations , Humans , Indoles , Pyrazoles , Pyridines , QuinolinesABSTRACT
Diagnosis of cerebrovascular disease (CVD) at early stages is essential for preventing sequential complications. CVD is often associated with abnormal cerebral microvasculature, which may impact cerebral-autoregulation (CA). A novel hybrid near-infrared diffuse optical instrument and a finger plethysmograph were used to simultaneously detect low-frequency oscillations (LFOs) of cerebral blood flow (CBF), oxy-hemoglobin concentration ([HbO2 ]), deoxy-hemoglobin concentration ([Hb]) and mean arterial pressure (MAP) in older adults before, during and after 70° head-up-tilting (HUT). The participants with valid data were divided based on Framingham risk score (FRS, 1-30 points) into low-risk (FRS ≤15, n = 13) and high-risk (FRS >15, n = 11) groups for developing CVD. The LFO gains were determined by transfer function analyses with MAP as the input, and CBF, [HbO2 ] and [Hb] as the outputs (CA â 1/Gain). At resting-baseline, LFO gains in the high-risk group were relatively lower compared to the low-risk group. The lower baseline gains in the high-risk group may attribute to compensatory mechanisms to maintain stronger steady-state CAs. However, HUT resulted in smaller gain reductions in the high-risk group compared to the low-risk group, suggesting weaker dynamic CAs. LFO gains are potentially valuable biomarkers for early detection of CVD based on associations with CAs.
Subject(s)
Cerebrovascular Circulation , Homeostasis , Spectroscopy, Near-Infrared , Aged , Blood Pressure , Humans , Microvessels , Risk AssessmentABSTRACT
Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS) is a recently described autosomal dominant disorder caused by mutations in the nuclear receptor subfamily 2 group F member 1 (NR2F1) gene. Its common features include optic atrophy and/or hypoplasia, developmental delay, intellectual disability, attention deficit disorder, autism spectrum disorder, seizures, hearing defects, spasticity, hypotonia, and thinning of the corpus callosum. Mitochondrial involvement has also been described with BBSOAS. Currently, 31 cases of BBSOAS have been described in the literature. Here we report a case of undiagnosed BBSOAS presenting as psychosis in a 32-year-old man with a history of bilateral optic nerve atrophy, intellectual disability, epilepsy, and mitochondrial complex I abnormality on muscle biopsy. Whole-genome sequencing identified a heterozygous de novo nonsense mutation in the NR2F1 gene [c.253 G>T (guanine to thymine mutation in coding position 253) in exon 1, p.E85X variant (GAG>TAG) (glutamic acid to stop codon mutation; protein truncated to 85 amino acids)]. A pathogenic nonsense mutation has not previously been reported in the literature in association with BBSOAS and represents an expansion of clinically relevant variants. Psychosis has also not been previously reported in this syndrome and may represent a phenotypic expansion of BBSOAS, a manifestation of prolonged disease, or a result of disease management.
Subject(s)
COUP Transcription Factor I/genetics , Intellectual Disability/genetics , Optic Atrophy , Psychotic Disorders/diagnosis , Adult , Epilepsy , Hallucinations/etiology , Humans , Male , Mutation/genetics , Optic Atrophy/diagnosis , Optic Atrophy/geneticsABSTRACT
Drug self-administration procedures are the gold standard for laboratory research to study mechanisms of drug use disorders and evaluate candidate medications. However, preclinical-to-clinical translation has been hampered by a lack of coordination. To address this limitation, we previously developed homologous intravenous (IV) cocaine choice self-administration procedures in rhesus monkeys and humans, and then demonstrated their functional equivalence. The present studies sought to determine the sensitivity of these procedures to d-amphetamine maintenance. Three (N = 3) rhesus monkeys with histories of cocaine self-administration and 16 (N = 16) humans with cocaine use disorder completed the studies. Monkeys were maintained on IV d-amphetamine (0, 0.019, 0.037 and 0.074 mg/kg/h), and then completed 7 sessions during each condition in which they completed 9 choice trials to receive 0.14 mg/kg/injection IV cocaine (corresponding to 10 mg/70 kg in humans) or 10 food pellets under independent, concurrent progressive-ratio schedules. Humans were maintained on oral extended release d-amphetamine (0, 30 and 60 mg/day, corresponding to the lowest 3 doses in monkeys) and participated in 12 sessions in which they chose money ($6.00) or IV cocaine (0, 3, 10 and 30 mg/70 kg). Blood samples were taken to compare d-amphetamine plasma levels across species. In monkeys and humans, d-amphetamine reduced the number of cocaine choices and produced comparable blood levels at equivalent daily doses. d-Amphetamine had similar efficacy, though lower potency, at reducing choice for an equivalent cocaine dose in monkeys relative to humans. These coordinated studies support the utility of these procedures as a translational model for cocaine use disorder. (PsycInfo Database Record (c) 2020 APA, all rights reserved).
Subject(s)
Choice Behavior/drug effects , Cocaine-Related Disorders/drug therapy , Cocaine/administration & dosage , Dextroamphetamine/therapeutic use , Administration, Intravenous , Adolescent , Adult , Animals , Dextroamphetamine/pharmacology , Female , Humans , Macaca mulatta , Male , Middle Aged , Self Administration , Young AdultABSTRACT
Background: Exposure to adverse childhood experiences (ACEs) increases health risk behavior in adulthood and is a risk for premature mortality. For example, ACEs are associated with both tobacco smoking and obesity, which remain significant health challenges for many adults, despite widespread knowledge about the risks. Objective: The present investigation used a novel online crowdsourcing platform (Amazon.com mechanical turk) to study the relationship between ACEs and later tobacco smoking and obesity. Methods: Participants were recruited based on smoking (n = 74 smokers; n = 75 nonsmokers) and stratified based on obesity (n = 52 BMI ≥ 30; n = 97 BMI < 30). Participants had no recent history of other substance use, except alcohol. The relationship between ACE score and smoking and obesity categories was analyzed using logistic regression. Results: The average age of the sample was 38.6-years old and was mostly female (66.4%), employed (82.6%) and college educated (63.1%). Those with 4+ ACEs had a significantly greater odds of cigarette use. Any ACEs exposure was associated with a significantly greater odds of obesity. Conclusions/Importance: Findings are concordant with previous studies and suggest crowdsourcing is a viable platform for studying ACEs and health behavior. Access to large samples and specific populations provided by crowdsourcing could help examine theoretical models about how exposure to ACEs could be connected to later adoption of high-risk behaviors such as tobacco cigarette smoking and obesity.
Subject(s)
Adverse Childhood Experiences/statistics & numerical data , Crowdsourcing/statistics & numerical data , Obesity/epidemiology , Smoking/epidemiology , Tobacco Use/epidemiology , Adult , Female , Humans , Male , United States/epidemiology , Young AdultABSTRACT
RATIONALE: No pharmacotherapies are approved for cocaine use disorder. Phendimetrazine, a prodrug of the monoamine-releaser phenmetrazine, attenuates the reinforcing effects of cocaine in preclinical models, has minimal abuse potential, and is safe when combined with cocaine. OBJECTIVES: This study determined the influence of phendimetrazine maintenance on the reinforcing effects of cocaine (i.e., choice to self-administer cocaine), along with the subjective, performance, and physiological effects of cocaine. We hypothesized that phendimetrazine would attenuate the reinforcing effects of cocaine. METHODS: Twenty-nine subjects with cocaine use disorder completed this within-subject, inpatient study. The subjects were maintained on placebo and 210 mg phendimetrazine in a counterbalanced order. After at least 7 days of maintenance on the target dose, the subjects completed experimental sessions in which the effects of single doses of 0, 20, 40, and 80 mg of intranasal cocaine were determined. RESULTS: Cocaine functioned as a reinforcer, producing significant dose-related increases in self-administration. Cocaine increased prototypic effects (e.g., ratings of stimulated and blood pressure). Phendimetrazine attenuated ratings on a select set of subjective outcomes (e.g., ratings of talkative/friendly), but failed to reduce the reinforcing effects of cocaine or a majority of positive subjective cocaine effects. Phendimetrazine increased heart rate, indicating a physiologically active dose was tested, but heart rate increases were not clinically significant. CONCLUSIONS: These results indicate that although phendimetrazine can safely be combined with cocaine, it does not attenuate the abuse-related effects of cocaine. It is unlikely, then, that phendimetrazine will be an effective standalone treatment for cocaine use disorder.
Subject(s)
Central Nervous System Stimulants/administration & dosage , Cocaine/administration & dosage , Dopamine Uptake Inhibitors/administration & dosage , Morpholines/administration & dosage , Psychomotor Performance/drug effects , Reinforcement, Psychology , Administration, Intranasal , Adult , Blood Pressure/drug effects , Blood Pressure/physiology , Dose-Response Relationship, Drug , Double-Blind Method , Drug Synergism , Female , Humans , Male , Middle Aged , Psychomotor Performance/physiology , Self AdministrationABSTRACT
BACKGROUND: Disrupted glutamate homeostasis is thought to contribute to cocaine-use disorder, in particular, by enhancing the incentive salience of cocaine stimuli. n-Acetylcysteine might be useful in cocaine-use disorder by normalizing glutamate function. In prior studies, n-acetylcysteine blocked the reinstatement of cocaine seeking in laboratory animals and reduced the salience of cocaine stimuli and delayed relapse in humans. METHODS: The present study determined the ability of maintenance on n-acetylcysteine (0 or 2400mg/day, counterbalanced) to reduce the incentive salience of cocaine stimuli, as measured by an attentional bias task, and attenuate intranasal cocaine self-administration (0, 30, and 60mg). Fourteen individuals (N=14) who met criteria for cocaine abuse or dependence completed this within-subjects, double-blind, crossover-design study. RESULTS: Cocaine-cue attentional bias was greatest following administration of 0mg cocaine during placebo maintenance, and was attenuated by n-acetylcysteine. Cocaine maintained responding during placebo and n-acetylcysteine maintenance, but the reinforcing effects of cocaine were significantly attenuated across both maintenance conditions in participants maintained on n-acetylcysteine first compared to participants maintained on placebo first. CONCLUSIONS: These results collectively suggest that a reduction in the incentive salience of cocaine-related stimuli during n-acetylcysteine maintenance may be accompanied by reductions in cocaine self-administration. These results are in agreement with, and link, prior preclinical and clinical trial results suggesting that n-acetylcysteine might be useful for preventing cocaine relapse by attenuating the incentive salience of cocaine cues.
Subject(s)
Acetylcysteine/pharmacology , Cocaine-Related Disorders/drug therapy , Cocaine/administration & dosage , Glutamic Acid/chemistry , Animals , Attentional Bias , Cocaine/chemistry , Cocaine-Related Disorders/psychology , Cues , Double-Blind Method , Humans , Motivation , Rats, Sprague-Dawley , Reinforcement, Psychology , Self AdministrationABSTRACT
RATIONALE: Phendimetrazine appears to have limited abuse potential and reduces cocaine self-administration in preclinical studies. No human studies have evaluated the safety and tolerability of cocaine in combination with phendimetrazine, which is a necessary next step in evaluating the efficacy of phendimetrazine for treating cocaine use disorder. OBJECTIVES: This study determined the safety and tolerability of acute cocaine doses during chronic phendimetrazine treatment. METHODS: Ten subjects completed this within-subject, placebo-controlled, inpatient study. Subjects were maintained on ascending oral phendimetrazine doses (0, 70, 140, and 210 mg/day). After at least seven maintenance days at each dose, subjects received ascending doses of intranasal cocaine (0, 10, 20, 40, and 80 mg), separated by 90 min, within one session. RESULTS: Cocaine produced prototypical cardiovascular and subject-rated effects (e.g., increased blood pressure and ratings of like drug). The cardiovascular effects of cocaine alone were not clinically significant for an acute drug response (e.g., average heart rate did not approach tachycardia, 100 beats/min). Phendimetrazine enhanced peak heart rate following placebo and low cocaine doses, but these effects were also not clinically significant. Phendimetrazine was otherwise devoid of effects alone and did not alter the subject-rated effects of cocaine or hypothetical demand for cocaine on a purchase task. CONCLUSIONS: Cocaine was safe and well tolerated during maintenance on a threefold range of phendimetrazine doses. Given this safety profile, the reduced abuse potential of phendimetrazine and promising preclinical research, future human laboratory studies, and possibly clinical trials should evaluate the efficacy of phendimetrazine for reducing cocaine use.
Subject(s)
Central Nervous System Stimulants/pharmacology , Cocaine/toxicity , Morpholines/pharmacology , Administration, Intranasal , Adult , Central Nervous System Stimulants/administration & dosage , Central Nervous System Stimulants/adverse effects , Cocaine/administration & dosage , Cocaine/pharmacology , Cocaine-Related Disorders/drug therapy , Cocaine-Related Disorders/economics , Cocaine-Related Disorders/psychology , Dose-Response Relationship, Drug , Female , Hemodynamics/drug effects , Humans , Male , Middle Aged , Morpholines/administration & dosage , Morpholines/adverse effects , Self AdministrationABSTRACT
There is rising evidence of patients' use of alternative and complementary medicine. The percentage of the U.S. population who used at least one dietary supplement increased from 42% in 1988-1994 to 53% in 2003-2006. We present a case of an Asian female in her 40s, with no previous psychiatric illness, who presented to the emergency room following a brief psychotic episode, during which she self-amputated the tips of her fingers, after using multivitamins and herbal supplements including ginseng, gui yuan rou (Chinese herb), astaxanthin, goji (Chinese fruit), selenium, saw palmetto, grape seed extract, citrus bioflavanoid, lutein (zeaxantin), resvexatrol, sun chlorella, spirulina powder, phytoceramides, phytoestrogen, glucosatrin, bromelain plus, and American bee pollen. Comprehensive laboratory workup, drug screening, and diagnostic imaging were negative. Vital signs were stable. Other than the amputated finger tips, the remainder of her physical examination was unremarkable. Her mental status improved significantly after treatment with risperidone 1 mg twice daily, during a five-day psychiatric hospitalization. This case draws attention to the fact that supplements have the potential of producing frank psychosis and require close monitoring and study by physicians.
Subject(s)
Bromelains/adverse effects , Chlorella , Dietary Supplements/adverse effects , Functional Food/adverse effects , Plant Extracts/adverse effects , Psychoses, Substance-Induced/drug therapy , Adult , Antipsychotic Agents/therapeutic use , Female , Humans , Risperidone/therapeutic use , Serenoa , Treatment OutcomeABSTRACT
Association rule mining has received significant attention from both the data mining and machine learning communities. While data mining researchers focus more on designing efficient algorithms to mine rules from large datasets, the learning community has explored applications of rule mining to classification. A major problem with rule mining algorithms is the explosion of rules even for moderate sized datasets making it very difficult for end users to identify both statistically significant and potentially novel rules that could lead to interesting new insights and hypotheses. Researchers have proposed many domain independent interestingness measures using which, one can rank the rules and potentially glean useful rules from the top ranked ones. However, these measures have not been fully explored for rule mining in clinical datasets owing to the relatively large sizes of the datasets often encountered in healthcare and also due to limited access to domain experts for review/analysis. In this paper, using an electronic medical record (EMR) dataset of diagnoses and medications from over three million patient visits to the University of Kentucky medical center and affiliated clinics, we conduct a thorough evaluation of dozens of interestingness measures proposed in data mining literature, including some new composite measures. Using cumulative relevance metrics from information retrieval, we compare these interestingness measures against human judgments obtained from a practicing psychiatrist for association rules involving the depressive disorders class as the consequent. Our results not only surface new interesting associations for depressive disorders but also indicate classes of interestingness measures that weight rule novelty and statistical strength in contrasting ways, offering new insights for end users in identifying interesting rules.
ABSTRACT
The objective of this study was to adapt a novel near-infrared diffuse correlation spectroscopy (DCS) flow-oximeter for simultaneous and continuous monitoring of relative changes in cerebral blood flow (rCBF) and cerebral oxygenation (i.e. oxygenated/deoxygenated/total hemoglobin concentration: Δ[HbO2]/Δ[Hb]/ΔTHC) during overnight nocturnal polysomnography (NPSG) diagnostic test for obstructive sleep apnea-hypopnea (OSAH). A fiber-optic probe was fixed on subject's frontal head and connected to the DCS flow-oximeter through a custom-designed fiber-optic connector, which allowed us to easily connect/detach the optical probe from the device when the subject went to bathroom. To minimize the disturbance to the subject, the DCS flow-oximeter was remotely operated by a desktop located in the control room. The results showed that apneic events caused significant variations in rCBF and ΔTHC. Moreover, the degrees of variations in all measured cerebral variables were significantly correlated with the severity of OSAH as determined by the apnea-hypopnea index (AHI), demonstrating the OSAH influence on both CBF and cerebral oxygenation. Large variations in arterial blood oxygen saturation (SaO2) were also found during OSAH. Since frequent variations/disturbances in cerebral hemodynamics may adversely impact brain function, future study will investigate the correlations between these cerebral variations and functional impairments for better understanding of OSAH pathophysiology.
Subject(s)
Cerebrovascular Circulation , Hemodynamics , Sleep Apnea, Obstructive/physiopathology , Spectroscopy, Near-Infrared , Adult , Aged , Female , Hemoglobins/metabolism , Humans , Male , Middle Aged , Oxyhemoglobins/metabolism , Sleep , Sleep Apnea, Obstructive/metabolismABSTRACT
Significant drops in arterial blood pressure and cerebral hemodynamics have been previously observed during vasovagal syncope (VVS). Continuous and simultaneous monitoring of these physiological variables during VVS is rare, but critical for determining which variable is the most sensitive parameter to predict VVS. The present study used a novel custom-designed diffuse correlation spectroscopy flow-oximeter and a finger plethysmograph to simultaneously monitor relative changes of cerebral blood flow (rCBF), cerebral oxygenation (i.e., oxygenated/deoxygenated/total hemoglobin concentration: r[HbO2]/r[Hb]/rTHC), and mean arterial pressure (rMAP) during 70 deg head-up tilt (HUT) in 14 healthy adults. Six subjects developed presyncope during HUT. Two-stage physiological responses during HUT were observed in the presyncopal group: slow and small changes in measured variables (i.e., Stage I), followed by rapid and dramatic decreases in rMAP, rCBF, r[HbO2], and rTHC (i.e., Stage II). Compared to other physiological variables, rCBF reached its breakpoint between the two stages earliest and had the largest decrease (76±8%) during presyncope. Our results suggest that rCBF has the best sensitivity for the assessment of VVS. Most importantly, a threshold of â¼50% rCBF decline completely separated the subjects from those without presyncope, suggesting its potential for predicting VVS.