Three randomized controlled trials evaluating the impact of "spin" in health news stories reporting studies of pharmacologic treatments on patients'/caregivers' interpretation of treatment benefit.

BACKGROUND: News stories represent an important source of information. We aimed to evaluate the impact of "spin" (i.e., misrepresentation of study results) in health news stories reporting studies of pharmacologic treatments on patients'/caregivers' interpretation of treatment benefit. METHODS: We conducted three two-arm, parallel-group, Internet-based randomized trials (RCTs) comparing the interpretation of news stories reported with or without spin. Each RCT considered news stories reporting a different type of study: (1) pre-clinical study, (2) phase I/II non-RCT, and (3) phase III/IV RCT. For each type of study, we identified news stories reported with spin that had earned mention in the press. Two versions of the news stories were used: the version with spin and a version rewritten without spin. Participants were patients/caregivers involved in Inspire, a large online community of more than one million patients/caregivers. The primary outcome was participants' interpretation assessed by one specific question "What do you think is the probability that 'treatment X' would be beneficial to patients?" (scale, 0 [very unlikely] to 10 [very likely]). RESULTS: For each RCT, 300 participants were randomly assigned to assess a news story with spin (n = 150) or without spin (n = 150), and 900 participants assessed a news story. Participants were more likely to consider that the treatment would be beneficial to patients when the news story was reported with spin. The mean (SD) score for the primary outcome for abstracts reported with and without spin for pre-clinical studies was 7.5 (2.2) versus 5.8 (2.8) (mean difference [95% CI] 1.7 [1.0-2.3], p < 0.001); for phase I/II non-randomized trials, 7.6 (2.2) versus 5.8 (2.7) (mean difference 1.8 [1.0-2.5], p < 0.001); and for phase III/IV RCTs, 7.2 (2.3) versus 4.9 (2.8) (mean difference 2.3 [1.4-3.2], p < 0.001). CONCLUSIONS: Spin in health news stories reporting studies of pharmacologic treatments affects patients'/caregivers' interpretation. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03094078 , NCT03094104 , NCT03095586.

Negative allosteric modulation of metabotropic glutamate receptor 5 results in broad spectrum activity relevant to treatment resistant depression.

Evidence suggests that 30-50% of patients suffering from major depressive disorder (MDD) are classified as suffering from treatment resistant depression (TRD) as they have an inadequate response to standard antidepressants. A key feature of this patient population is the increased incidence of co-morbid symptoms like anxiety and pain. Recognizing that current standards of care are largely focused on monoaminergic mechanisms of action (MOAs), innovative approaches to drug discovery for TRD are targeting glutamate hyperfunction. Here we describe the in vitro and in vivo profile of GRN-529, a novel negative allosteric modulator (NAM) of metabotropic glutamate receptor 5 (mGluR5). In cell based pharmacology assays, GRN-529 is a high affinity (Ki 5.4 nM), potent (IC50 3.1 nM) and selective (>1000-fold selective vs mGluR1) mGluR5 NAM. Acute administration of GRN-529 (0.1-30 mg/kg p.o.) had dose-dependent efficacy across a therapeutically relevant battery of animal models, comprising depression (decreased immobility time in tail suspension and forced swim tests) and 2 of the co-morbid symptoms overrepresented in TRD, namely anxiety (attenuation of stress-induced hyperthermia, and increased punished crossings in the four plate test) and pain (reversal of hyperalgesia due to sciatic nerve ligation or inflammation). The potential side effect liability of GRN-529 was also assessed using preclinical models: GRN-529 had no effect on rat sexual behavior or motor co-ordination (rotarod), however it impaired cognition in mice (social odor recognition). Efficacy and side effects of GRN-529 were compared to standard of care agents (antidepressant, anxiolytic or analgesics) and the tool mGluR5 NAM, MTEP. To assess the relationship between target occupancy and efficacy, ex vivo receptor occupancy was measured in parallel with efficacy testing. This revealed a strong correlation between target engagement, exposure and efficacy across behavioral endpoints, which supports the potential translational value of PET imaging to dose selection in patients. Collectively this broad spectrum profile of efficacy of GRN-529 supports our hypothesis that negative allosteric modulation of mGluR5 could represent an innovative therapeutic approach to the treatment of TRD. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'.

Novel medication targets for the treatment of alcoholism: preclinical studies.

Alcoholism is a complex heterogeneous disease and a number of neurotransmitter and neuromodulator systems have been implicated in its manifestation. Consequently, it is unlikely that existing medications such as disulfiram (Antabuse®), naltrexone (ReVia®), acamprosate (Campral®)) can be efficacious in every individual. Thus, the development of novel therapeutic agents with greater selectivity and less unwanted effects for the treatment of this disease is one of the major objectives of alcohol research. This review summarizes the findings of five novel compounds with different neuronal targets for treating alcoholism. These compounds include sazetidine-A, which selectively desensitizes α4ß2 nicotinic receptors; carisbamate, a novel anti-epileptic agent; JNJ5234801, a novel anxiolytic agent; GS-455534, a highly selective inhibitor of mitochondrial aldehyde dehydrogenase; and JNJ-39220675, a selective histamine H3 antagonist. Inbred alcohol-preferring rats (iP), Fawn-Hooded (FH) rats, and P rats were used to evaluate the compounds. Naltrexone was used as a positive control in some experiments. All five compounds reduced alcohol consumption and preference. The mechanisms thought to underlie these effects suggest that, in addition to dopaminergic and opioidergic systems, other neuronal systems such as sodium channels (carisbamate), mitochondrial aldehyde dehydrogenase (GS-455534), 5-HT2 receptors (JNJ-5234801), histamine H3 receptors (JNJ-39220675), and α4ß2 nicotinic receptors (sazetidine-A) can be involved in alcohol drinking. Further work is necessary to confirm the exact mechanisms of action of each drug and to determine any viable targets for putative treatment of alcohol-use disorders. The article presents some promising patents on novel medication targets for the treatment of alcoholism.

Polyamine modulation of NMDARs as a mechanism to reduce effects of alcohol dependence.

Relapse and neurodegeneration are two of the major therapeutic targets in alcoholism. Fortuitously, the roles of glutamate/NMDA receptors (NMDARs) in withdrawal, conditioning and neurotoxicity mean that NMDAR inhibitors are potentially valuable for both targets. Preclinical studies further suggest that inhibitory modulators that specifically reduce the co-agonist effects of polyamines on NMDARs are potential non-toxic medications. Using agmatine as a lead compound, over 1000 novel compounds based loosely on this structure were synthesized using feedback from a molecular screen. A novel series of aryliminoguanidines with appropriate NMDAR activity in the molecular screen were discovered (US patent application filed 2007). The most potent and selective aryliminoguanidine, JR 220 [4- (chlorobenzylidenamino)- guanidine hydrochloride], has now been tested in a screening hierarchy for anti-relapse and neuroprotective activity, ranging from cell-based assay, through tissue culture to animal behavior. This hierarchy has been validated using drugs with known, or potential, clinical value at these targets (acamprosate (N-acetyl homotaurine), memantine and topiramate). JR220 was non-toxic and showed excellent activity in every screen with a potency 5-200x that of the FDA-approved anti-relapse agent, acamprosate. This chapter will present a review of the background and rationale for this approach and some of the findings garnered from this approach as well as patents targeting the glutamatergic system especially the NMDAR.

Hyperdynamic microtubules, cognitive deficits, and pathology are improved in tau transgenic mice with low doses of the microtubule-stabilizing agent BMS-241027.

Tau is a microtubule (MT)-stabilizing protein that is altered in Alzheimer's disease (AD) and other tauopathies. It is hypothesized that the hyperphosphorylated, conformationally altered, and multimeric forms of tau lead to a disruption of MT stability; however, direct evidence is lacking in vivo. In this study, an in vivo stable isotope-mass spectrometric technique was used to measure the turnover, or dynamicity, of MTs in brains of living animals. We demonstrated an age-dependent increase in MT dynamics in two different tau transgenic mouse models, 3xTg and rTg4510. MT hyperdynamicity was dependent on tau expression, since a reduction of transgene expression with doxycycline reversed the MT changes. Treatment of rTg4510 mice with the epothilone, BMS-241027, also restored MT dynamics to baseline levels. In addition, MT stabilization with BMS-241027 had beneficial effects on Morris water maze deficits, tau pathology, and neurodegeneration. Interestingly, pathological and functional benefits of BMS-241027 were observed at doses that only partially reversed MT hyperdynamicity. Together, these data suggest that tau-mediated loss of MT stability may contribute to disease progression and that very low doses of BMS-241027 may be useful in the treatment of AD and other tauopathies.

Novel use of a lipid-lowering fibrate medication to prevent nicotine reward and relapse: preclinical findings.

Experimental drugs that activate α-type peroxisome proliferator-activated receptors (PPARα) have recently been shown to reduce the rewarding effects of nicotine in animals, but these drugs have not been approved for human use. The fibrates are a class of PPARα-activating medications that are widely prescribed to improve lipid profiles and prevent cardiovascular disease, but these drugs have not been tested in animal models of nicotine reward. Here, we examine the effects of clofibrate, a representative of the fibrate class, on reward-related behavioral, electrophysiological, and neurochemical effects of nicotine in rats and squirrel monkeys. Clofibrate prevented the acquisition of nicotine-taking behavior in naive animals, substantially decreased nicotine taking in experienced animals, and counteracted the relapse-inducing effects of re-exposure to nicotine or nicotine-associated cues after a period of abstinence. In the central nervous system, clofibrate blocked nicotine's effects on neuronal firing in the ventral tegmental area and on dopamine release in the nucleus accumbens shell. All of these results suggest that fibrate medications might promote smoking cessation. The fact that fibrates are already approved for human use could expedite clinical trials and subsequent implementation of fibrates as a treatment for tobacco dependence, especially in smokers with abnormal lipid profiles.

Prolame ameliorates anxiety and spatial learning and memory impairment induced by ovariectomy in rats.

N-(3-hydroxy-1, 3, 5 (10) estratrien-17beta-yl)-3-hydroxypropylamine (17ß aminoestrogen, prolame) is a steroidal compound with weak estrogen-related trophic-proliferative effects in uterus. Contrasting with 17ß-estradiol (E2) pro-coagulant effects, this compound has high anticoagulant and antiplatelet effects. It has been extensively demonstrated that E2 plays important roles in brain function. However, prolame's influence on central nervous system has not been documented. In this study, we evaluated the effects of prolame replacement in young ovariectomized rats on spatial learning and memory and anxiety, correlating pyramidal cell dendritic spine density changes and neuronal nitric oxide synthase (nNOS) expression in the hippocampus. Ovariectomized young rats were treated with prolame for 4 weeks. Three other groups were used as physiological, pathological, and pharmacological references as follow: gonadally intact cycling females, ovariectomized, and ovariectomized with 17ß-estradiol treatment respectively, for the same time period. Experiment 1 investigated the behavioral effects of prolame on anxiety and spatial learning using elevated plus maze (EPM) and Morris water maze (MWM) paradigms respectively. Experiment 2 studied the dendritic spine density and neuronal nitric oxide synthase expression in the hippocampus of the 4 experimental groups. Similar to estradiol, prolame reversed the anxiogenic effects of ovariectomy, evaluated by EPM, and enhanced MWM performance to the level of gonadally intact subjects. Hippocampi from prolame-treated rats exhibited enhanced nNOS immunoreactivity and its relocation in dendritic compartments, as well as recovery of dendritic spine density loss in pyramidal neurons. Hence, prolame may provide an alternative option for ameliorating neurological symptoms caused by surgical menopause.

Evaluation of antidepressant-like activity of novel water-soluble curcumin formulations and St. John's wort in behavioral paradigms of despair.

BACKGROUND: Curcumin is the active principle of Curcuma longa, one of the widely used components in the traditional system of medicine in India. Despite its efficacy in experimental studies aiming at neuronal disorders like depression, curcu-min's poor water solubility challenges the production of therapeutic formulations. This study investigates the antidepressant-like activity of novel water-soluble curcumin formulations, dispensed in three different concentrations. Further, the study comparatively evaluates St. John's wort (SJW), another herbal preparation. METHODS: These compounds were evaluated in the forced swimming test in mice, and the corresponding changes in the neurotransmitter levels were measured. RESULTS: Three water-soluble curcumin formulations, C-5, C-20 and C-50 (50-200 mg/kg p.o.) decreased the immobility period, and increased serotonin and dopamine levels in the brain tissues. A subeffective dose (50 mg/kg) of these formulations enhanced the antidepressant-like effect of classical antidepressants with varied mechanisms of action. In addition, an SJW dose of 25 mg/kg showed a significant antidepressant-like effect in all the behavioral studies and also significantly increased brain neurotransmitter levels, especially that of serotonin. The effects produced by C-5 were comparable with those of SJW and fluoxetine, respectively. CONCLUSION: In all these observations, the water-soluble formulations showed a significant antidepressant-like effect, including enhancement of neurotransmitter levels as compared to the similar dose of a conventional curcumin preparation. Thus, these formulations may be used as a novel treatment option in the management of mental depression.

Comparative psychology and the grand challenge of drug discovery in psychiatry and neurodegeneration.

Drug discovery for brain disorders is undergoing a period of upheaval. Faced with an empty drug pipeline and numerous failures of potential new drugs in clinical trials, many large pharmaceutical companies have been shrinking or even closing down their research divisions that focus on central nervous system (CNS) disorders. In this paper, we argue that many of the difficulties facing CNS drug discovery stem from a lack of robustness in pre-clinical (i.e., non-human animal) testing. There are two main sources for this lack of robustness. First, there is the lack of replicability of many results from the pre-clinical stage, which we argue is driven by a combination of publication bias and inappropriate selection of statistical and experimental designs. Second, there is the frequent failure to translate results in non-human animals to parallel results in humans in the clinic. This limitation can only be overcome by developing new behavioral tests for non-human animals that have predictive, construct, and etiological validity. Here, we present these translational difficulties as a "grand challenge" to researchers from comparative cognition, who are well positioned to provide new methods for testing behavior and cognition in non-human animals. These new experimental protocols will need to be both statistically robust and target behavioral and cognitive processes that allow for better connection with human CNS disorders. Our hope is that this downturn in industrial research may represent an opportunity to develop new protocols that will re-kindle the search for more effective and safer drugs for CNS disorders.

Uliginosin B, a phloroglucinol derivative from Hypericum polyanthemum: a promising new molecular pattern for the development of antidepressant drugs.

In this study we have demonstrated that cyclohexane extract of Hypericum polyanthemum (POL) and its main phloroglucinol derivative uliginosin B (ULI) present antidepressant-like activity in rodent forced swimming test (FST). The involvement of monoaminergic neurotransmission on the antidepressant-like activity of ULI was evaluated in vivo and in vitro. POL 90 mg/kg (p.o.) and ULI 10 mg/kg (p.o.) reduced the immobility time in the mice FST without altering locomotion activity in the open-field test. The combination of sub-effective doses of POL (45 mg/kg, p.o.) and ULI (5 mg/kg, p.o.) with sub-effective doses of imipramine (10 mg/kg, p.o.), bupropion (3 mg/kg, p.o.) and fluoxetine (15 mg/kg, p.o.) induced a significant reduction on immobility time in FST. The pretreatment with SCH 23390 (15 µg/kg, s.c., dopamine D1 receptor antagonist), sulpiride (50 mg/kg, i.p., dopamine D2 receptor antagonist), prazosin (1mg/kg, i.p., α1-adrenoceptor antagonist), yohimbine (1mg/kg, i.p., α2-adrenoceptor antagonist) and pCPA (100 mg/kg/day, i.p., p-chlorophenilalanine methyl ester, inhibitor of serotonin synthesis, for four consecutive days) before ULI administration (10 mg/kg, p.o.) significantly prevented the anti-immobility effect in FST. ULI was able to inhibit synaptosomal uptake of dopamine (IC50 = 90 ± 38 nM), serotonin (IC50 = 252 ± 13 nM) and noradrenaline (280 ± 48 nM), but it did not bind to any of the monoamine transporters. These data firstly demonstrated the antidepressant-like effect of POL and ULI, which depends on the activation of the monoaminergic neurotransmission in a different manner from the most antidepressants.

Preclinical pharmacology of TP1, a novel potent triple reuptake inhibitor with antidepressant properties.

Triple reuptake inhibitors (TRIs) that block the dopamine transporter (DAT), norepinephrine transporter (NET), and serotonin transporter (SERT) are being developed as a new class of antidepressant that may have better efficacy and fewer side effects compared with traditional antidepressants. The purpose of this study was to characterize a new chemical entity, 4-[2-(dimethylamino)-1-(1-hydroxycyclohexyl)ethyl] phenyl 4-methoxybenzoate hydrochloride (TP1). TP1 was designed as a prodrug of desvenlafaxine. Competitive radioligand binding assays were performed using cells expressing the human dopamine (DA) transporter (hDAT), the human serotonin (5-HT) transporter (hSERT), and the human norepinephrine (NE) transporter (hNET) with K(i) values for TP1 of 190 nM, 2076 nM, and 1023 nM, respectively. Uptake assays were performed with IC(50) values for TP1 of 712 nM, 521 nM, and 628 nM, respectively. TP1 (0.06 mmol/kg, orally) rapidly penetrated rat brain and hypothalamus, translated into desvenlafaxine within 1 h, and demonstrated higher bioavailability and better pharmacokinetic properties than desvenlafaxine succinate (DVS). TP1 (0.06 mmol/kg, orally) significantly increased extracellular levels of DA, NE, and 5-HT compared with baseline in the rat hypothalamus by microdialysis assay. In dose-response assays, oral administration of TP1 reduced the time of immobility in a dose-dependent manner during tail suspension test and forced swimming test (FST). This antidepressant-like effect manifests in the absence of significant increases in motor activity even at doses of up to 32 mg/kg. The ability of TP1 to inhibit the reuptake of three biogenic amines closely linked to the etiology of depression may result in a therapeutic profile different from antidepressants that inhibit the reuptake of serotonin and/or NE.

Validation of the French version of the alcohol, smoking and substance involvement screening test (ASSIST).

BACKGROUND: The Alcohol, Smoking and Substance Involvement Screening Test (ASSIST) was developed to detect substance use disorders. AIMS: The objective of the present study was to evaluate the psychometric properties of the French version of ASSIST in various clinical groups with different levels of substance use. METHODS: 150 subjects were recruited from clients attending primary health care, psychiatric and addiction treatment facilities. Measures included ASSIST, Addiction Severity Index (ASI), Mini-International Neuropsychiatric Interview (MINI-Plus), Alcohol Use Disorders Identification Test (AUDIT) and Revised Fagerstrom Tolerance Questionnaire-Smoking (RTQ). RESULTS AND CONCLUSION: Concurrent validity was demonstrated by significant correlations between ASSIST scores and scores from ASI, AUDIT and RTQ, as well as significantly greater ASSIST scores for patients with a MINI-Plus diagnosis of abuse or dependence. The ASSIST questionnaire was found to have high internal consistency for the total substance involvement as well as for specific substance involvement as assessed with Cronbach's α, ranging from 0.74 to 0.93. When possibly computed, ASSIST cutoff scores have interesting sensitivity and specificity for discrimination between use and abuse and between abuse and dependence. The findings demonstrated that the French version of ASSIST is a valid screening test for identifying substance use disorders in various health care settings, including psychiatric settings.

Speaking of research advance directives: planning for future research participation.

OBJECTIVE: To examine one model of research advance directive as a possible way to reduce the mismatch between patient and proxy choices and also to learn more about how patients with mild to moderate dementia may want to keep decision making or cede it to their proxies in the future. METHODS: Separate interviews were conducted with 149 dyads of dementia patients and family proxies about future enrollment in five types of research. Subsequent joint interviews were conducted with 69 of those dyads to discuss their separately articulated decisions and ask whether the patient prefers future enrollment decisions to be made as he or she directs today or as the proxy deems best in the future. RESULTS: Patients chose to cede future decision making to their proxies in 82.9% of the trials. Patients ceded decisions to their proxies in 80.7% of those trials about which the dyad had given opposite answers (n = 74, 49.7%). Patients who had expressed discomfort about the prospect of the proxy making an enrollment decision in a trial (n = 49, 32.9%) ceded decision making to their proxies in 45.7% of those trials. CONCLUSIONS: Both patients and proxies were willing to discuss future research enrollment in the context of an advance directive for research. Such a document may be helpful to proxies and researchers in the future to judge the types of research and associated risks patients are willing to enroll in. Although most patients willingly cede future decisions to their proxies, a sizeable minority do not wish to do so.

Application of an electronic nose system for evaluation of unpleasant odor in coated tablets.

The purpose of this study was to apply an electronic nose system for evaluation of unpleasant odor in tablets containing L-cysteine, an unpleasant odor drug, and demonstrate the odor masking ability of thin-layer sugarless coated tablets, which we have newly developed, by both electronic nose system and sensory evaluations. We demonstrated the qualitative evaluation of the unpleasant odor using air as a reference indicator and the quantitative evaluation of the unpleasant odor using the distances between air and samples in the electronic nose system evaluation. The electronic nose system evaluation was positively and well-correlated with the sensory evaluation by volunteers. We suggest that the electronic nose system evaluation is appropriate as an alternative or a support method for sensory evaluation by volunteers. As the results of both electronic nose system and sensory evaluations, we demonstrated that the thin-layer sugarless coated tablets have excellent masking ability of the unpleasant odor, equivalent to that of sugar-coated tablets due to the dense coating layers.

The pre-clinical behavioural pharmacology of 3,4-methylenedioxymethamphetamine (MDMA).

3,4-Methylenedioxymethamphetamine (MDMA) is a relatively novel drug of abuse and as such little is currently known of its behavioural pharmacology. This review aims to examine whether MDMA represents a novel class of abused drug. MDMA is known as a selective serotonergic neurotoxin in a variety of animal species but acutely it is a potent releaser and/or reuptake inhibitor of presynaptic serotonin, dopamine, noradrenaline, and acetylcholine. Interaction of these effects contributes to its behavioural pharmacology, in particular its effects on body temperature. Drug discrimination studies indicate that MDMA and related drugs produce unique interoceptive effects which have led to their classification as entactogens. This is supported by results from other behavioural paradigms although there is evidence for dose dependency of MDMA-specific effects. MDMA also produces conditioned place preference but is not a potent reinforcer in self-administration studies. These unique behavioural effects probably underlie its current popularity. MDMA is found in the street drug ecstasy but it may not be appropriate to equate the two as other drugs are routinely found in ecstasy tablets