Rivastigmine does not alter cocaine-induced subjective effects or self-administration.

BACKGROUND: Acetylcholinergic (ACh) neurons interface with the mesolimbic dopamine pathway implicated in addiction, and acetylcholinesterase inhibitors (AChEis) have been shown to reduce the immediate effects of cocaine and amount used. Our study is the first to examine if the safe and low-interaction AChEi rivastigmine (riv) alters the subjective effects produced by cocaine administration. METHODS: Cocaine-dependent subjects were randomized to daily placebo, riv 3 mg, or riv 6 mg, administered inpatient for 10 days. On day 1 (pre-dose) and day 9, subjects received both IV cocaine 40 mg or placebo in a randomized order with subsequent serial assessments of visual analog scale (VAS) subjective effects and pharmacokinetic measurements. On day 10 all participants received one baseline dose of cocaine 20 mg with assessment of subjective effects, and were then able to purchase additional doses at 15 min intervals with study earnings. RESULTS: 40 subjects were randomized to placebo (n = 16), riv 3 mg (n = 13), or riv 6 mg (n = 12). All subjects completed the study and there were no demographic differences between treatment groups. Pre- and post- treatment, there were no significant pharmacokinetic differences (blood levels of cocaine, BE, EME) following cocaine administration. In a two-way ANOVA, IV cocaine significantly increased positive VAS category ratings compared to placebo, but rivastigmine treatment at either dose had no significant effect on any VAS category ratings. Similarly, there was no significant rivastigmine effect on any category in the day 10 cocaine administration, and no effect on number of subsequent doses participants purchased. CONCLUSION: Rivastigmine 3 or 6 mg had no significant effect on the subjective effects of cocaine after 9 days of treatment. This is an important finding as other drugs in the AChEi class (donepezil, Huperzine A) have produced significant results, but differ in their receptor specificity and PK parameters.

Incidence of antiemetic-induced akathisia in patients at a comprehensive cancer center.

INTRODUCTION: Akathisia is a common and severely disabling medication-induced movement disorder. The condition is often missed, and patients suffer for a long time until diagnosed and managed properly. It is important to bring awareness to the clinicians for early detection and management of akathisia. METHODS: We reviewed a 4-year record of patients seen at a comprehensive cancer center for anxiety and restlessness. Patients diagnosed with akathisia and the medications causing akathisia were identified. Management of akathisia is discussed. RESULTS: The results showed that 4.7% of patients developed akathisia while taking antiemetic agents to control chemotherapy-induced nausea/vomiting. Early detection and management of akathisia resulted in quick recovery and reduced patients' suffering. CONCLUSION: Akathisia is an unpleasant feeling of motor restlessness with anxiety. Clinicians need to have a full understanding to identify the subtle difference between functional anxiety and akathisia.

IGF-1 modulates gene expression of proteins involved in inflammation, cytoskeleton, and liver architecture.

Even though the liver synthesizes most of circulating IGF-1, it lacks its receptor under physiological conditions. However, according to previous studies, a damaged liver expresses the receptor. For this reason, herein, we examine hepatic histology and expression of genes encoding proteins of the cytoskeleton, extracellular matrix, and cell-cell molecules and inflammation-related proteins. A partial IGF-1 deficiency murine model was used to investigate IGF-1's effects on liver by comparing wild-type controls, heterozygous igf1+/-, and heterozygous mice treated with IGF-1 for 10 days. Histology, microarray for mRNA gene expression, RT-qPCR, and lipid peroxidation were assessed. Microarray analyses revealed significant underexpression of igf1 in heterozygous mice compared to control mice, restoring normal liver expression after treatment, which then normalized its circulating levels. IGF-1 receptor mRNA was overexpressed in Hz mice liver, while treated mice displayed a similar expression to that of the controls. Heterozygous mice showed overexpression of several genes encoding proteins related to inflammatory and acute-phase proteins and underexpression or overexpression of genes which coded for extracellular matrix, cytoskeleton, and cell junction components. Histology revealed an altered hepatic architecture. In addition, liver oxidative damage was found increased in the heterozygous group. The mere IGF-1 partial deficiency is associated with relevant alterations of the hepatic architecture and expression of genes involved in cytoskeleton, hepatocyte polarity, cell junctions, and extracellular matrix proteins. Moreover, it induces hepatic expression of the IGF-1 receptor and elevated acute-phase and inflammation mediators, which all resulted in liver oxidative damage.

Insulin-like growth factor-1 deficiency and metabolic syndrome.

Consistent evidence associates IGF-1 deficiency and metabolic syndrome. In this review, we will focus on the metabolic effects of IGF-1, the concept of metabolic syndrome and its clinical manifestations (impaired lipid profile, insulin resistance, increased glucose levels, obesity, and cardiovascular disease), discussing whether IGF-1 replacement therapy could be a beneficial strategy for these patients. The search plan was made in Medline for Pubmed with the following mesh terms: IGF-1 and "metabolism, carbohydrate, lipids, proteins, amino acids, metabolic syndrome, cardiovascular disease, diabetes" between the years 1963-2015. The search includes animal and human protocols. In this review we discuss the relevant actions of IGF-1 on metabolism and the implication of IGF-1 deficiency in the establishment of metabolic syndrome. Multiple studies (in vitro and in vivo) demonstrate the association between IGF-1 deficit and deregulated lipid metabolism, cardiovascular disease, diabetes, and an altered metabolic profile of diabetic patients. Based on the available data we propose IGF-1 as a key hormone in the pathophysiology of metabolic syndrome; due to its implications in the metabolism of carbohydrates and lipids. Previous data demonstrates how IGF-1 can be an effective option in the treatment of this worldwide increasing condition. It has to distinguished that the replacement therapy should be only undertaken to restore the physiological levels, never to exceed physiological ranges.

Intrauterine Growth Retardation (IUGR) as a Novel Condition of Insulin-Like Growth Factor-1 (IGF-1) Deficiency.

Insulin-like growth factor 1 (IGF-1) is an anabolic hormone with several biological activities, such as proliferation, mitochondrial protection, cell survival, tissue growth and development, anti-inflammatory, antioxidant, antifibrogenic and antiaging. This hormone plays an important role in embryological and postnatal states, being essential for normal foetal and placental growth and differentiation. During gestation, the placenta is one of the major sources of IGF-1, among other hormones. This intrauterine organ expresses IGF-1 receptors and IGF-1 binding proteins (IGFBPs), which control IGF-1 activities. Intrauterine growth restriction (IUGR) is the second most frequent cause of perinatal morbidity and mortality, defined as the inability to achieve the expected weight for gestational age. Different studies have revealed that IUGR infants have placental dysfunction and low circulating levels of insulin, IGF-1, IGF-2 and IGFBPs. Such data suggest that IGF-1 deficiency in gestational state may be one of the major causes of foetal growth retardation. The aim of this review is to study the epidemiology, physiopathology and possible causes of IUGR. Also, it intends to study the possible role of the placenta as an IGF-1 target organ. The purpose is to establish if IUGR could be considered as a novel condition of IGF-1 deficiency and if its treatment with low doses of IGF-1 could be a suitable therapeutic strategy.

A variant in ANKK1 modulates acute subjective effects of cocaine: a preliminary study.

This study aimed to evaluate whether functional variants in the ankyrin repeat and kinase domain-containing 1 (ANKK1) gene and/or the dopamine receptor D2 (DRD2) gene modulate the subjective effects (reward or non-reward response to a stimulus) produced by cocaine administration. Cocaine-dependent participants (N = 47) were administered 40 mg of cocaine or placebo at time 0, and a subjective effects questionnaire (visual analog scale) was administered 15 min prior to cocaine administration, and at 5, 10, 15 and 20 min following administration. The influence of polymorphisms in the ANKK1 and DRD2 genes on subjective experience of cocaine in the laboratory was tested. Participants with a T allele of ANKK1 rs1800497 experienced greater subjective 'high' (P = 0.00006), 'any drug effect' (P = 0.0003) and 'like' (P = 0.0004) relative to the CC genotype group. Although the variant in the DRD2 gene was shown to be associated with subjective effects, linkage disequilibrium analysis revealed that this association was driven by the ANKK1 rs1800497 variant. A participant's ANKK1 genotype may identify individuals who are likely to experience greater positive subjective effects following cocaine exposure, including greater 'high' and 'like', and these individuals may have increased vulnerability to continue using cocaine or they may be at greater risk to relapse during periods of abstinence. However, these results are preliminary and replication is necessary to confirm these findings.

Plasma brain derived neurotrophic factor (BDNF) and response to ketamine in treatment-resistant depression.

Ketamine produces rapid antidepressant effects in treatment-resistant depression (TRD), but the magnitude of response varies considerably between individual patients. Brain-derived neurotrophic factor (BDNF) has been investigated as a biomarker of treatment response in depression and has been implicated in the mechanism of action of ketamine. We evaluated plasma BDNF and associations with symptoms in 22 patients with TRD enrolled in a randomized controlled trial of ketamine compared to an anaesthetic control (midazolam). Ketamine significantly increased plasma BDNF levels in responders compared to non-responders 240 min post-infusion, and Montgomery-Åsberg Depression Rating Scale (MADRS) scores were negatively correlated with BDNF (r=-0.701, p = 0.008). Plasma BDNF levels at 240 min post-infusion were highly negatively associated with MADRS scores at 240 min (r = -0.897, p=.002), 24 h (r = -0.791, p = 0.038), 48 h (r = -0.944, p = 0.001) and 72 h (r = -0.977, p = 0.010). No associations with BDNF were found for patients receiving midazolam. These data support plasma BDNF as a peripheral biomarker relevant to ketamine antidepressant response.

Assessment of safety, cardiovascular and subjective effects after intravenous cocaine and lofexidine.

The primary objective of this study was to determine the safety of lofexidine, an α2 receptor agonist, alone and concurrent with cocaine in non-treatment seeking cocaine-dependent or cocaine-abusing participants. After screening, eligible participants received double-blind, randomized infusions of saline and 20mg of cocaine on Day 1, and saline and 40mg of cocaine on Day 2. Subjects were randomized and started receiving daily administration of placebo (N=4) or lofexidine on Day 3 and continued on this schedule until Day 7. Two dosing regimens for lofexedine were investigated: 0.8 QID (N=3) and 0.2mg QID (N=11). On Days 6 and 7, subjects received double-blind infusions of saline and 20mg of cocaine on Day 6, and saline and 40mg of cocaine on Day 7. The data reveal a notable incidence of hemodynamic-related AEs over the course of the study. Two of the three participants at the 0.8mg dose level discontinued, and five of 11 participants at the 0.2mg dose level were withdrawn (or voluntarily discontinued) after hemodynamic AEs. Subjective effects and cardiovascular data were derived from all participants who were eligible to receive infusions (i.e., did not meet stopping criteria) on Days 6 and 7 (6 received lofexidine 0.2mg, QID and 4 received placebo, QID). As expected, cocaine significantly increased heart rate and blood pressure, as well as several positive subjective effects. There was a trend for lofexidine to decrease cocaine-induced cardiovascular changes and cocaine-induced ratings for "any drug effect", "good effects", and "desire cocaine", but sample size issues limit the conclusions that can be drawn. Despite the trends to reduce cocaine-induced subjective effects, cardiovascular AEs may limit future utility of lofexidine as a treatment for this population.

Neurocognitive effects following an overnight call shift on faculty anesthesiologists.

BACKGROUND: The impact of sleep deprivation on neurocognitive performance is a significant concern to both the health of patients and to the physicians caring for them, as demonstrated by the Accreditation Council for Graduate Medical Education enforced resident work hours. This study examined the effects of an overnight call at a level 1 trauma hospital on neurocognitive performance of faculty anesthesiologists. METHODS: Eleven faculty anesthesiologists completed a series of computerized tests that were designed to evaluate different areas of neurocognition, such as working memory, verbal learning, and concentration. The anesthesiologists completed the tests following an overnight call in the morning at 6:30 and again following a normal night's rest at 6:30 on a different date. RESULTS: Within-subjects, repeated measures analysis of variance revealed a significant difference on post-call vs. control performance on measures of learning and memory (P = 0.04). However, there were no significant differences on performance on measures of working memory or sustained attention and vigilance. Pre-call vs. control performances were also evaluated, but no significant differences were detected. CONCLUSIONS: Following a night call shift, performance on learning and memory was significantly reduced. Other areas were not significantly affected, which may have been due to certain possibilities, such as practice effect or variability in the call shifts. The real-world relevance of the decline in performance on these measures remains unclear.

Modafinil, but not escitalopram, improves working memory and sustained attention in long-term, high-dose cocaine users.

OBJECTIVE: The purpose of the present study was to determine the effects of modafinil, escitalopram, and modafinil + escitalopram administration on neurocognition in a sample of long-term, high-dose cocaine users. METHOD: Sixty-one cocaine-dependent individuals were randomly assigned to receive placebo (n = 14), modafinil, 200 mg, once daily (n = 16), escitalopram, 20 mg, once daily (n = 16), or modafinil and escitalopram, once daily (n = 15), for five days on an inpatient basis. Urinanalysis was used to confirm abstinence from cocaine on the day of admission and the next five days. Baseline neurocognitive assessment, which included measures of attention/information processing, episodic memory, and working memory, was conducted immediately after the washout phase and prior to the administration of modafinil. The follow-up assessment was conducted after participants had received modafinil or placebo for five days. RESULTS: Repeated-measures, mixed model analysis of variance showed that modafinil administration was associated with significantly improved performance on two measures of working memory span (mean n-back span, maximum n-back span) and a trend toward significant improvement on a measure of visual working memory (visual accuracy) and two measures of sustained attention, consistency of response time (Variability) and reduced impulsivity (Perseveration). Modafinil administration did not modulate performance on measures of information processing speed or episodic memory. Escitalopram did not modulate performance on measures of cognition, either alone or in combination with modafinil. CONCLUSIONS: This study provides initial data showing that, in a sample of long-term, high-dose cocaine users, administration of psychotropic medications, such as modafinil, can improve performance on measures of working memory. Moreover, it confirms the utility of studying the interactive effects of psychotropic medications to confirm the manner in which the candidate medications independently and interactively affect neurocognition. These effects are likely relevant in the treatment of cocaine dependence, in which the remediation of impaired working memory may be associated with improved treatment outcomes. This article is part of a Special Issue entitled 'Cognitive Enhancers'.

d-Cycloserine administration does not affect neurocognition in concurrent cocaine- and nicotine-dependent volunteers.

Neurocognitive impairment is a well-documented consequence of long-term, repeated cocaine exposure and has been identified as an important target of treatment. Thus, this study sought to determine whether the N-methyl-d-aspartate (NMDA) partial agonist, d-cycloserine could improve neurocognitive performance in a sample of 27 long-term, high dose cocaine dependent individuals who were not seeking treatment at the time of enrollment in the study. This double-blind, placebo-controlled study evaluated whether a single dose of 0 or 50mg of d-cycloserine would enhance performance on measures of attention/information processing speed, episodic memory, and executive/frontal lobe functioning relative to test performance at baseline. The results revealed that d-cycloserine did not modulate neurocognition in this cohort, though there are a number of factors that may have mitigated the effects of d-cycloserine in this particular study. The negative findings notwithstanding, the current study serves as a springboard for future investigations that will examine whether other medications that can modulate neurocognition in cocaine-dependent study participants.

Rivastigmine reduces "Likely to use methamphetamine" in methamphetamine-dependent volunteers.

We previously reported that treatment with the cholinesterase inhibitor rivastigmine (3mg, PO for 5days) significantly attenuated "Desire for METH". Given that higher dosages of rivastigmine produce greater increases in synaptic ACh, we predicted that 6mg should have more pronounced effects on craving and other subjective measures. In the current study, we sought to characterize the effects of short-term exposure to rivastigmine (0, 3 or 6mg) on the subjective and reinforcing effects produced by administration of methamphetamine (METH) in non-treatment-seeking, METH-dependent volunteers. This was a double-blind, placebo-controlled, crossover study. Participants received METH on day 1, and were then randomized to placebo or rivastigmine on day 2 in the morning and treatment continued through day 8. METH dosing was repeated on day 6. The data indicate that METH (15 and 30mg), but not saline, increased several positive subjective effects, including "Any Drug Effect", "High", "Stimulated", "Desire METH", and "Likely to Use METH" (all p's<0.0001). In addition, during self-administration sessions, participants were significantly more likely to choose METH over saline (p<0.0001). Evaluating outcomes as peak effects, there was a trend for rivastigmine to reduce "Desire METH" (p=0.27), and rivastigmine significantly attenuated "Likely to Use METH" (p=0.01). These effects were most prominent for rivastigmine 6mg when participants were exposed to the low dose (15mg, IV), but not high dose (30mg, IV), of METH. The self-administration data reveal that rivastigmine did not alter total choices for METH (5mg, IV/choice). Overall, the results indicate some efficacy for rivastigmine in attenuating key subjective effects produced by METH, though additional research using higher doses and longer treatment periods is likely needed. These data extend previous findings and indicate that cholinesterase inhibitors, and other drugs that target acetylcholine systems, warrant continued consideration as treatments for METH dependence.

A practical approach to incidental findings in neuroimaging research.

OBJECTIVE: We describe the systematic approach to incidental findings (IFs) used at the Mind Research Network (MRN) where all MRI scans receive neuroradiologist interpretation and participants are provided results. METHODS: From 2004 to 2011, 8,545 MRI scans were acquired by 45 researchers. As mandated by MRN's external institutional review board, all structural sequences were evaluated by a clinical neuroradiologist who generated a report that included recommendations for referral if indicated. Investigators received a copy of their participants' reports, which were also mailed to participants unless they specifically declined. To better understand the impact of the radiology review process, a financial analysis was completed in addition to a follow-up phone survey to characterize participant perceptions regarding receiving their MRI scan results. RESULTS: The radiologist identified IFs in 34% of the 4,447 participants. Of those with IFs (n = 1,518), the radiologist recommended urgent or immediate referral for 2.5% and routine referral for 17%. For 80.5%, no referral was recommended. Estimated annual cost for this approach including support for the neuroradiologist, medical director, and ancillary staff is approximately $60,000 or $24/scan. The results of the retrospective phone survey showed that 92% of participants appreciated receiving their MRI report, and the majority stated it increased their likelihood of volunteering for future studies. CONCLUSIONS: Addressing IFs in a cost-effective and consistent manner is possible by adopting a policy that provides neuroradiology interpretation and offers participant assistance with clinical follow-up when necessary. Our experience suggests that an ethical, institution-wide approach to IFs can be implemented with minimal investigator burden.

Evaluation of the effects of rivastigmine on cigarette smoking by methamphetamine-dependent volunteers.

Compared to smokers alone, smokers with co-morbid substance use disorders are at greater risk of suffering from smoking-related death. Despite this, relatively few studies have examined smoking cessation treatments for those with stimulant dependence. In the current study, we sought to evaluate the effects produced by short-term exposure to the cholinesterase inhibitor rivastigmine (0, 3 or 6 mg) on cigarette smoking in non-treatment-seeking, methamphetamine-dependent volunteers. This was a double-blind, placebo-controlled, crossover study that took place over 9 days. The data indicate that rivastigmine treatment did not alter Fagerström Test for Nicotine Dependence scores, carbon monoxide readings, or cigarettes smoked per day, but a trend toward reduced urges to smoke (p<0.09) was detected during treatment with rivastigmine 3mg. These data, while preliminary, indicate that cholinesterase inhibitors warrant consideration as treatments for nicotine dependence, including use in stimulant-dependent individuals who exhibit significantly higher rates of smoking than the general population.

Novel WDR72 mutation and cytoplasmic localization.

The proven candidate genes for amelogenesis imperfecta (AI) are AMELX, ENAM, MMP20, KLK4, FAM83H, and WDR72. We performed mutation analyses on seven families with hypomaturation AI. A novel WDR72 dinucleotide deletion mutation (g.57,426_57,427delAT; c.1467_ 1468delAT; p.V491fsX497) was identified in both alleles of probands from Mexico and Turkey. Haplotype analyses showed that the mutations arose independently in the two families. The disease perfectly segregated with the genotype. Only persons with both copies of the mutant allele were affected. Their hypomineralized enamel suffered attrition and orange-brown staining following eruption. Expression of WDR72 fused to green fluorescent protein showed a cytoplasmic localization exclusively and was absent from the nucleus. We conclude that WDR72 is a cytoplasmic protein that is critical for dental enamel formation.

Unrestricted access to methamphetamine or cocaine in the past is associated with increased current use.

Laboratory animals allowed to self-administer stimulants for extended periods of time escalate drug intake compared to animals that self-administer under temporally limited conditions. To our knowledge, this phenomenon has not been systematically investigated in humans. We interviewed 106 (77 male, 29 female) methamphetamine (Meth) and 96 (81 male, 15 female) cocaine (Coc) users to determine if they had experienced discrete period(s) of unrestricted access to unlimited quantities of Meth or Coc in the past. Fifty-eight Meth users and 53 Coc users reported having a discrete period of unrestricted access in the past, but not in the present. Meth-using participants with a prior history of unrestricted access reported significantly more current Meth use, compared to Meth users with no prior history of unrestricted access. Specifically, these participants reported more days used in the past 30 d, more days of use per week, greater use per day and greater total use per week (p<0.05 for each). Coc-using participants with a prior history of unrestricted access also reported significantly more current Coc use, compared to Coc users with no prior history of unrestricted access. This was true across all measures of current use for these participants, including more days used in the past 30 d, more days of use per week, greater use per day, and higher total use per week (p<0.02 for each). Taken together, these results suggest that a history of unrestricted access to stimulants is associated with long-lasting increases in stimulant use.

The acetylcholinesterase inhibitor rivastigmine does not alter total choices for methamphetamine, but may reduce positive subjective effects, in a laboratory model of intravenous self-administration in human volunteers.

A human laboratory model of intravenous methamphetamine self-administration may facilitate study of putative treatments for methamphetamine addiction. We conducted a double-blind, placebo-controlled, between groups investigation of the acetylcholinesterase (AChE) inhibitor rivastigmine in non-treatment-seeking volunteers who met criteria for methamphetamine abuse or dependence. Safety and subjective effects data derived from days 1-10 of this protocol are described in a separate publication. In this report, we describe self-administration outcomes in participants randomized to treatment with rivastigmine (0 mg, N=7; 1.5 mg, N=6; 3 mg, N=9); data that were collected on days 11-15 of the inpatient protocol. On day 11, participants sampled two infusions of methamphetamine (0 and 30 mg, i.v.). On days 12-15, participants made ten choices each day to receive an infusion of either methamphetamine (3 mg, IV) or saline or a monetary alternative ($0.05-$16). The study design allowed for evaluation of differences in behavior on days in which infusions were performed by the physician (experimenter-administered) versus by the participant using a PCA pump (self-administered), and when monetary alternatives were presented in either ascending or descending sequence. The data show that rivastigmine (1.5 and 3 mg), as compared to placebo, did not significantly alter total choices for methamphetamine (p=0.150). Importantly, the number of infusion choices was greater when methamphetamine was available then when saline was available (p<0.0001), and the number of money choices was greater when saline was available then when methamphetamine was available (p<0.0001). The total number of choices for methamphetamine was not altered as a function of a participant's preferred route of methamphetamine use (p=0.57), and did not differ significantly whether they were experimenter-administered or self-administered (p=0.30). In addition, total choices for methamphetamine were similar made when money was available in an ascending versus descending sequence (p=0.49). The participants' years of methamphetamine use, recent use of methamphetamine (in the past 30 days), or baseline craving (indexed here as "Desire") on the day of the self-administration task were not predictive of number of choices for methamphetamine. In a subset of participants (N=8) for which data was available, individual dose of methamphetamine (3 x 3 mg, i.v.) produced significant increases in positive subjective effects, and a preliminary analysis revealed that 3 mg rivastigmine was associated with reductions in these responses, as compared to placebo. In summary, the current report indicates that there were no effects of rivastigmine on total choices for methamphetamine, that there were low levels of methamphetamine self-administration but these were 8 times greater than saline, and that choice behavior was insensitive to alternative reinforcers. In addition, we showed that rivastigmine may reduce the positive subjective effects produced by methamphetamine during self-administration.