The effects of nalmefene on emotion processing in alcohol use disorder – A randomized,controlled fMRI study

Nalmefene is a µ- and δ-opioid receptor antagonist and a partial κ-opioid receptor agonist. The drug is suggested to reduce the craving for, and the consumption of alcohol effectively, also alleviating anxiety and anhedonia. The present fMRI study is the first to investigate the processing of emotions as a possible mechanism of action of nalmefene in humans. Fifteen non-treatment-seeking participants suffering from alcohol use disorder (AUD) (24–66 years; 5 females) finished this randomized, placebo controlled, double blind study. Following a cross over design, participants received either a single dose nalmefene or a placebo, with an interval of one week between sessions. Using fMRI, we investigated neural reactivity during the presentation of emotional faces picture sets. Additionally, we performed a visual dot-probe task to detect nalmefene's effects on attentional bias. We detected an increase in the response to emotional faces in the supramarginal gyrus, the angular gyrus as well as the putamen in the nalmefene vs. placebo condition. However, contradictory to our initial hypotheses, amygdala activation was not altered significantly in the placebo condition – a limitation, which might be associated with a lack of activation in the placebo condition maybe due to the small sample size. Attentional bias analyses revealed an interaction effect by trend, which was driven by a significant effect in a sub-analysis showing increased attentional shift towards happy compared to fearful facial expressions under nalmefene. Nalmefene increased brain activation in areas responsible for empathy, social cognition and behavior, which might help alleviating the reinforcing properties of alcohol.     

A double-blind placebo controlled experimental study of nicotine: I—effects on incentive motivation

Rationale Brain reward pathways implicated in addiction appear to be less reactive in regular drug users; behavioural manifestations may include decreased sensitivity to natural reinforcers.Objectives This study aimed to replicate earlier findings of abstinence-associated incentive motivation deficits in smokers and to determine whether these can be reversed with nicotine in the form of lozenge.Methods One hundred forty-five smokers were each tested twice, once after receiving nicotine, and once after receiving placebo lozenge in counterbalanced order. Participants completed various tests of incentive motivational functioning: a measure of subjective enjoyment, the Snaith–Hamilton pleasure scale (SHAPS); a simple card sorting task, the card arranging reward responsivity objective test (CARROT) with and without financial incentive; the modified emotional Stroop test; a cue-reactivity task; and a novel reaction time task to explore effects of signals of reward, the incentive motivational enhancement of response speed task.Results Compared with performance during abstinence (placebo condition), nicotine was associated with: higher self-reported pleasure expectations on the SHAPS; enhanced responsiveness to financial reward on the CARROT in smokers who smoked 15 or more cigarettes a day; and greater interference from appetitive words on the Stroop task.Conclusions These results are generally consistent with contemporary neurobiological theories of addiction and suggest that short-term smoking abstinence is associated with impaired reward motivation which can be reversed with nicotine.     

Residual effects of zopiclone 7.5 mg on highway driving performance in insomnia patients and healthy controls: a placebo controlled crossover study

Rationale

Residual effects of hypnotics on driving performance have been mainly determined in studies using a standardized driving test with healthy good sleepers. Responses to effects may differ, however, between insomniacs and healthy volunteers due to the underlying sleep disorder. In addition, a majority of insomniacs uses hypnotics chronically resulting in the development of tolerance to impairing effects. Impaired driving performance in healthy volunteers may then be an overestimation of the actual effects in insomniacs.

Objectives

The present study aims to compare the residual effects of zopiclone 7.5 mg on on-the-road driving performance of 16 middle-aged insomniacs chronically using hypnotics (chronic users), 16 middle-aged insomniacs not or infrequently using hypnotics (infrequent users), and 16 healthy, age matched, good sleepers (controls).

Methods

The study was conducted according to a 3?×?2 double-blind, placebo controlled crossover design, with three groups and two treatment conditions. Treatments were single oral doses of zopiclone 7.5 mg and placebo administered at bedtime (2330 hours). Between 10 and 11 h after administration subjects performed a standardized highway driving test.

Results

Zopiclone 7.5 mg significantly impaired on-the-road driving performance in both insomnia groups and healthy controls. The magnitude of impairment was significantly less in the chronic users group as compared with the controls.

Conclusions

The smaller magnitude of effects suggests that investigating residual effects of hypnotics in healthy volunteers may yield a minor overestimation of the actual effects in insomnia patients.     

High‐ and low‐dose Mazindol for cocaine dependence in methadone‐maintained patients: A preliminary evaluation

We conducted a preliminary investigation comparing high‐dose mazindol (8 mg/day), low dose mazindol (1 mg/day), and placebo for cocaine abstinence initiation in a 12‐week, double‐blind, randomized clinical trial enrolling 17 cocaine‐dependent, methadone‐maintained patients. Outcome data did not support a difference between the two dose levels on percentage positive urine screens positive for cocaine (1 mg mazindol=68%, 8 mg mazindol=75%, placebo=91%). Doses of mazindol greater than 8 mg may be needed for a cocaine blocking effect, although potential pressor effects may be a limiting factor.     

Antisense‐mediated reduction of proprotein convertase subtilisin/kexin type 9 (PCSK9): a first‐in‐human randomized,placebo‐controlled trial

AimsLDL‐receptor expression is inhibited by the protease proprotein convertase subtilisin/kexin type 9 (PCSK9), which is considered a pharmacological target to reduce LDL‐C concentrations in hypercholesterolaemic patients. We performed a first‐in‐human trial with SPC5001, a locked nucleic acid antisense inhibitor of PCSK9.MethodsIn this randomized, placebo‐controlled trial, 24 healthy volunteers received three weekly subcutaneous administrations of SPC5001 (0.5, 1.5 or 5 mg kg^–1) or placebo (SPC5001 : placebo ratio 6 : 2). End points were safety/tolerability, pharmacokinetics and efficacy of SPC5001.ResultsSPC5001 plasma exposure (AUC(0,24 h)) increased more than dose‐proportionally. At 5 mg kg^–1, SPC5001 decreased target protein PCSK9 (day 15 to day 35: −49% vs. placebo, P < 0.0001), resulting in a reduction in LDL‐C concentrations (maximal estimated difference at day 28 compared with placebo −0.72 mmol l^–1, 95% confidence interval − 1.24, −0.16 mmol l^–1; P < 0.01). SPC5001 treatment (5 mg kg^–1) also decreased ApoB (P = 0.04) and increased ApoA1 (P = 0.05). SPC5001 administration dose‐dependently induced mild to moderate injection site reactions in 44% of the subjects, and transient increases in serum creatinine of ≥20 μmol l^–1 (15%) over baseline with signs of renal tubular toxicity in four out of six subjects at the highest dose level. One subject developed biopsy‐proven acute tubular necrosis.ConclusionsSPC5001 treatment dose‐dependently inhibited PCSK9 and decreased LDL‐C concentrations, demonstrating human proof‐of‐pharmacology. However, SPC5001 caused mild to moderate injection site reactions and renal tubular toxicity, and clinical development of SPC5001 was terminated. Our findings underline the need for better understanding of the molecular mechanisms behind the side effects of compounds such as SPC5001, and for sensitive and relevant renal toxicity monitoring in future oligonucleotide studies.     

Randomized controlled trial on the effects of a skills‐based workshop on medical students’ management of problem drinking and alcohol dependence

The purpose of this study was to determine whether a skills‐based workshop will improve medical students' management of problem drinking and alcohol dependence in simulated patients. Seventy‐six 3rd and 4th year Ontario medical students were randomized to receive a 3‐h workshop on either problem drinking and alcohol dependence or depression (control condition). Students then completed eight simulated office visits (OSCE stations) with simulated patients presenting with depression, problem drinking or alcohol dependence. Examiners completed a checklist of the questions asked and advice given by the student, and simulated patients and examiners completed a global rating scale. Four months later, students were sent a survey on their knowledge, attitudes, and behavior towards patients with alcohol problems. The alcohol group received significantly higher assessment and management checklist scores and global rating scores than did the depression group (p < 0.01) and performed better on almost all aspects of clinical management of both problem drinking and alcohol dependence. On the follow‐up survey (n = 55) the alcohol group showed a significant increase in beliefs about self‐efficacy in managing alcohol problems (p < 0.05) and had greater knowledge of reduced drinking strategies, but the two groups did not differ on other measures. A skills‐based workshop causes marked short‐term improvements in medical students' management of problem drinking and alcohol dependence, an increase from baseline to postworkshop in self‐efficacy beliefs that was sustained through to follow‐up, and greater knowledge of reduced drinking strategies. Repeated reinforcement of clinical skills may be required for a long‐term impact on clinical behavior.     

Assessment of antioxidant supplementation on the neuropathic pain score and quality of life in diabetic neuropathy patients – A randomized controlled study

BackgroundDiabetes is a chronic disease characterized by elevated blood glucose levels. The appropriate goals in the management of diabetes include maintaining blood glucose levels as close to the normal range as possible, minimizing the adverse effects of free radicals by enhancing antioxidant defenses. Supplementation with appropriate vitamins may therefore be of value in the prevention and treatment of diabetes.MethodsA total of 92 patients with diabetic neuropathy were enrolled in this randomized controlled study from the general medicine department of a tertiary care hospital. Patients were randomized into two groups viz., usual care (n = 46) and intervention group (n = 46). Usual care group patients received pregabalin with oral hypoglycemic agents. Patients in the intervention group received vitamin-E along with their regular medicines. Pain intensity and quality of life (QoL) of patients were assessed using Neuropathy Pain Score and RAND 36 questionnaire. Blood samples were analyzed for the levels of random blood sugar level and HbA_1c at the baseline and on the 12th week.ResultsSignificant (p < 0.05) decrease in the random blood sugar level was observed in intervention group when compared with the usual care group and a significant (p < 0.01) reduction in total pain score, and a significant (p < 0.05) improvement in physical health after 12 week treatment of vitamin-E was observed.ConclusionThe study concluded that vitamin-E is a natural antioxidant and it is found to be effective in reducing pain score in diabetic neuropathy patients. The future studies may be directed towards extended duration of action.     

The endocannabinoid system and emotional processing: A pharmacological fMRI study with ∆9-tetrahydrocannabinol

Various psychiatric disorders such as major depression are associated with abnormalities in emotional processing. Evidence indicating involvement of the endocannabinoid system in emotional processing, and thus potentially in related abnormalities, is increasing. In the present study, we examined the role of the endocannabinoid system in processing of stimuli with a positive and negative emotional content in healthy volunteers. A pharmacological functional magnetic resonance imaging (fMRI) study was conducted with a placebo-controlled, cross-over design, investigating effects of the endocannabinoid agonist ?9-tetrahydrocannabinol (THC) on brain function related to emotional processing in 11 healthy subjects. Performance and brain activity during matching of stimuli with a negative (‘fearful faces’) or a positive content (‘happy faces’) were assessed after placebo and THC administration. After THC administration, performance accuracy was decreased for stimuli with a negative but not for stimuli with a positive emotional content. Our task activated a network of brain regions including amygdala, orbital frontal gyrus, hippocampus, parietal gyrus, prefrontal cortex, and regions in the occipital cortex. THC interacted with emotional content, as activity in this network was reduced for negative content, while activity for positive content was increased. These results indicate that THC administration reduces the negative bias in emotional processing. This adds human evidence to support the hypothesis that the endocannabinoid system is involved in modulation of emotional processing. Our findings also suggest a possible role for the endocannabinoid system in abnormal emotional processing, and may thus be relevant for psychiatric disorders such as major depression.     

Acquisition of cocaine self-administration in male Sprague–Dawley rats: effects of cocaine dose but not initial locomotor response to cocaine

Rationale  

We have previously described a model in which adult outbred male Sprague–Dawley rats are classified as either low or high cocaine responders (LCRs or HCRs, respectively) based on acute cocaine-induced open-field activation. This model revealed important individual differences in cocaine's effects, including that LCRs exhibited greater responding than HCRs on a progressive ratio schedule of cocaine reinforcement. However, no LCR/HCR differences in acquisition of cocaine self-administration (0.25 mg/kg/12 s infusion) were observed under these conditions.     

A qualitative study of smokers’ views on brain-based explanations of tobacco dependence

BackgroundThe role the brain plays in the creation and maintenance of tobacco dependence has become increasingly prominent in explanations of smoking that are presented to the public. The potential for brain-based explanations of smoking to influence smokers’ understandings of their addiction, their sense of self-efficacy, and perhaps even their treatment preferences, has been raised by some working in the addiction field. However, little empirical evidence exists in this area.MethodsThis paper reports on semi-structured interviews with 29 daily smokers. Participants were shown a brief presentation about the neuroscience of nicotine dependence. They were then queried about their awareness of the role of the brain in smoking, and the consequences of this knowledge for their understandings of smoking and their treatment preferences.ResultsOur results indicated that many participants displayed some awareness of the link between the brain and addiction. While there was a diversity of ideas about the potential impacts of neuroscience knowledge about smoking, there was an overall tendency to maintain pre-existing treatment preferences, and to assert individual responsibility for smoking. Emergent themes that arose were the brain as a special organ, the discourse of the “other” smoker, and the distinction between physical and psychological facets of addiction.ConclusionWhile brain-based explanations of smoking are unlikely to revolutionise lay understandings of smoking, neuroscience information should be presented in a way that does not negate people's sense of agency and self-efficacy in relation to quitting smoking.     

The effects of berberine on inflammatory markers in Chinese patients with metabolic syndrome and related disorders: a meta‑analysis of randomized controlled trials

Inflammopharmacology - A meta-analysis of randomized controlled trials (RCTs) was conducted to systematically evaluate the effects of berberine on the inflammatory markers of metabolic syndrome...     

Differential effects of self-administered cocaine in adolescent and adult rats on stimulus–reward learning

Rationale Adult cocaine addicts, abstinent at the time of testing, show a variety of neurocognitive impairments. Less clear is whether there are differences in the degree of impairment if cocaine use is initiated during adolescence rather than adulthood. Objectives Using a preclinical model, we evaluated if stimulus–reward learning was impacted differently in rats exposed to cocaine during adolescence (beginning on postnatal day 37) vs adulthood (beginning on postnatal days 74–79) and then tested after a drug-free period. Materials and methods A yoked-triad design of intravenous cocaine self-administration in adult (n = 8 triads) and adolescent (n = 8 triads) rats was used. Sets of three animals either contingently self-administered cocaine or received cocaine or saline in a noncontingent manner. Rats self-administering 1-mg/kg doses of cocaine responded under a fixed-ratio 5, timeout 20-s schedule of reinforcement. After 18 2-h drug or saline sessions, all rats (now adults) began the drug-free period in their home environments. Testing in a stimulus–reward learning task (conditioned cue preference) began 19 days later. Results Self-administration behavior was similar in adolescent and adult rats. Lever responses were not significantly different, and both age groups averaged approximately 20 infusions per session. Rats contingently self-administering cocaine or passively exposed to cocaine during adulthood showed stimulus–reward learning deficits in the conditioned cue preference task. Rats exposed to contingent or noncontingent cocaine during adolescence had normal learning, showing strong preferences for a Froot Loops-paired cue. Conclusions These findings suggest that adolescents are insensitive to cocaine-induced impairment of learning related to amygdala memory system functioning.     

Self-administration of fentanyl, cocaine and ketamine: effects on the pituitary–adrenal axis in rhesus monkeys

Rationale Drugs of abuse can affect the functioning of the hypothalamic–pituitary–adrenal (HPA) axis. Acute administration of drugs that serve as reinforcers have been observed to stimulate the rat HPA axis, leading to the suggestion that these stimulatory effects may contribute to the development of drug-maintained behaviors.Objectives To determine whether reinforcing drugs that are dissimilar with respect to their mechanisms of action have similar effects on HPA axis activity at doses that are self-administered. Rhesus monkeys were randomly assigned to self-administer the -opioid agonist fentanyl, the psychomotor stimulant cocaine, or the NMDA antagonist ketamine.Methods Each monkey was trained to press a lever in order to receive an intravenous injection of drug or saline. Blood samples were obtained before, during, and after the self-administration sessions and assayed for ACTH and cortisol by radioimmunoassay.Results Fentanyl, cocaine, and ketamine were each self-administered across a range of doses. However, the three drugs differed in their effects on ACTH and cortisol. Cocaine stimulated ACTH and cortisol secretion, a finding that is consistent with previous rat and primate studies. Self-administration of both fentanyl and ketamine inhibited HPA axis activity. HPA inhibition by fentanyl is consistent with other monkey and human studies, and contrasts with the stimulatory effects of -opioids in rodents. The inhibitory effect of ketamine on ACTH and cortisol secretion contrasts with findings in the few primate studies that have evaluated NMDA antagonists. Neither fentanyl nor cocaine, at doses that maintained maximum rates of responding, produced significant changes in ACTH and cortisol levels.Conclusions There appears to be little commonality between different classes of abused drugs and their effects on the HPA axis, which calls into question the necessity for HPA axis stimulation in the reinforcement of drug-maintained behavior.Results from this paper were first presented at the annual meeting of CPDD, Scottsdale, Ariz., USA, in June 2001.     

Sodium hyaluronate’s effect on xerophthalmia: a meta-analysis of randomized controlled trials

Background and aims:

Several studies in the past have attempted to demonstrate the efficacy of sodium hyaluronate in the treatment of xerophthalmia. However, results have been conflicting and a definite conclusion has not yet been reached. In order to provide integrated evidence for the effectiveness of sodium hyaluronate and to judge the methodological value of relevant randomized controlled trials (RCTs) in nearly thirty years, we conducted this meta-analysis.

Methods:

A range of electronic databases were searched: MEDLINE, the Cochrane Library Database, EMBASE, CINAHL, Web of Science and the Chinese Biomedical Database (CBM) without language restrictions. Two independent reviewers assessed trials for eligibility and quality, and meta-analysis was performed using the STATA 12.0 software. An integrated odds ratio (OR) with its corresponding 95% confidence interval (95% CI) was calculated.

Results:

Six RCTs were included with a total of 839 xerophthalmia patients. The meta-analysis results revealed that patients with xerophthalmia who received the intervention of sodium hyaluronate eye drops didn’t have significantly higher remission rate of dry eye symptoms than those in controlled groups (OR?=?1.811, 95% CI?=?0.741–4.429, p?=?0.193). Sensitivity analysis suggested that the statistical results were robust. No publication bias was detected in this meta-analysis (p?>?0.05).

Conclusion:

Although sodium hyaluronate can be used to help relieve the symptoms of dry eyes, present evidence cannot show in unequivocal terms that patients with xerophthalmia can benefit more from the clinical application of sodium hyaluronate than other eye drops or therapies.     

Efficacy and Safety of hydroxychloroquine sulphate in rheumatoid arthritis: a randomized,double-blind,placebo controlled clinical trial – an Indian experience

ABSTRACT

Objective: Hydroxychloroquine (HCQ) has been used for a long time worldwide as a therapy for rheumatoid arthritis (RA). This trial was designed to determine whether HCQ was efficacious and safe in Indian patients with RA.

Research design and methods: The trial was a multicentre, placebo controlled, randomized and double-blind study. One hundred and twenty-two patients with RA were enrolled in 3 different centres for the trial (26 males and 96 females in the age group of 18–60 years). Patients were randomized to receive either hydroxychloroquine tablets (n = 61) two tablets of 200?mg daily or placebo (n = 61) two tablets daily. After 8 weeks all patients received one tablet of hydroxychloroquine 200?mg daily for 4 weeks. Every patient also received one tablet of Nimesulide 100?mg twice daily.

Main outcome measures: Assessment of response at 12 weeks using modified ACR 20 (American College of Rheumatology 20) criteria where Health Assessment Questionnaire (HAQ) was replaced by ARA (American Rheumatology Association) functional class.

Results: 40.4% of patients on hydroxychloroquine showed improvement by modified ACR response criteria whereas only 20.7% (?p = 0.02) showed improvement in the placebo group. No significant side effects were observed in any of the patients. There were no ocular toxicities.

Conclusions: Hydroxychloroquine was found to be an effective and well-tolerated drug in rheumatoid arthritis in Indian patients.     

Improving asthma control in patients suboptimally controlled on inhaled steroids and long-acting β2‐agonists: addition of montelukast in an open-label pilot study

ABSTRACT

Background: Airway inflammation and symptoms often persist in asthma patients despite treatment with inhaled corticosteroids (ICS) and long-acting β₂-agonists (LABA). It is hypothesized that the leukotriene receptor antagonist montelukast, treating a pathway of inflammation distinct from that of ICS, might confer additional benefit.

Objective: To evaluate the efficacy of montelukast in improving asthma control in patients symptomatic on a fixed-association (FA) medium dose of ICS and LABA.

Methods: A 2-month, open-label, real-life observational study was undertaken by 131 Belgian pulmonologists. Patients (≥ 15 years old) suffering from persistent asthma (pre-bronchodilator FEV₁ ≥ 60% of predicted value) and insufficiently controlled on a FA therapy of fluticasone/salmeterol or budesonide/formoterol were given montelukast 10?mg daily as add-on therapy. Asthma control was assessed by the standardized Juniper asthma control questionnaire (ACQ) at baseline and after a 2-month treatment with montelukast. Global evaluation of therapy was made both by the patients and physicians.

Results: A total of 313 patients were eligible for analysis. Forty-nine per cent received inhaled fluticasone/salmeterol and the rest budesonide/formoterol. Mean ACQ score decreased significantly on montelukast (13.9 ± 5.1 at baseline versus 7.4 ± 4.7 on montelukast, p < 0.001), with a significant improvement in all individual symptom scores (?p < 0.001) and in pre-bronchodilator FEV₁ score (from 2.2 ± 1.5 to 1.6 ± 1.4; p < 0.001). Parallel to these results, 78.6% of the patients reported a global improvement of their asthma. The same proportion of improvement was observed in the global evaluation made by the physicians (κ = 0.66).

Conclusion: This pilot study suggests that addition of montelukast in patients symptomatic on a FA of ICS and LABA may result in significant improvements in asthma control. A randomised, placebo-controlled clinical trial seems warranted.