P.2.c.003 A placebo-controlled study of EB-1010, a novel triple re-uptake inhibitor, in patients with major depressive disorder

Tran, Phuong Nam; Bradshaw, Mark; McKinney, Alexander S.; Bymaster, Frank P.; Skolnick, Phil; Czobor, Pál; Huang, Naya; Manthis, Joan D; Fava, Maurizio

doi:10.1016/s0924-977x(11)70617-4

Cited by 2 publications

(4 citation statements)

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“…In the ABA model, the long term exposure (few days) to low leptin and high ghrelin levels, induced a tissue-specific expression pattern of ghrelin and leptin receptors (Pardo et al, 2010). Furthermore, Verhagen et al (2011) found that plasma ghrelin levels are highly associated with food anticipatory behavior, measured by running wheel activity in rats. This effect is dependent of the central ghrelin signaling system via growth hormone secretagogue receptor 1a (GHS-R1A).…”

Section: Physiological Alterations In Anorexia Nervosamentioning

confidence: 99%

“…Recently, Costantini et al (2011) detailed an unexpected effect of GSK1614343, a novel ghrelin receptor antagonist with no partial agonist properties, that induced both in rats and dogs an increase of food intake, body weight, and reduced the POMC mRNA levels in the hypothalamus of rats chronically treated with the compound. Although it may seem counterintuitive to consider the use of ghrelin antagonists in this disease area, one study in rodents suggested that suppressed ghrelin signaling reduces (food anticipatory) hyperlocomotor activity in the ABA model (Verhagen et al, 2011). Barnett et al (2010) demonstrated that the administration of a GOAT inhibitor improved glucose tolerance and decreased weight gain in wild type mice but not in ghrelin KO mice.…”

Section: Conclusion: Ghrelin As a Potential Treatment For Anorexia Nementioning

confidence: 99%

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Ghrelin: Central and Peripheral Implications in Anorexia Nervosa

Méquinion¹,

Langlet²,

Zgheib³

et al. 2013

Front. Endocrinol.

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Increasing clinical and therapeutic interest in the neurobiology of eating disorders reflects their dramatic impact on health. Chronic food restriction resulting in severe weight loss is a major symptom described in restrictive anorexia nervosa (AN) patients, and they also suffer from metabolic disturbances, infertility, osteopenia, and osteoporosis. Restrictive AN, mostly observed in young women, is the third largest cause of chronic illness in teenagers of industrialized countries. From a neurobiological perspective, AN-linked behaviors can be considered an adaptation that permits the endurance of reduced energy supply, involving central and/or peripheral reprograming. The severe weight loss observed in AN patients is accompanied by significant changes in hormones involved in energy balance, feeding behavior, and bone formation, all of which can be replicated in animals models. Increasing evidence suggests that AN could be an addictive behavior disorder, potentially linking defects in the reward mechanism with suppressed food intake, heightened physical activity, and mood disorder. Surprisingly, the plasma levels of ghrelin, an orexigenic hormone that drives food-motivated behavior, are increased. This increase in plasma ghrelin levels seems paradoxical in light of the restrained eating adopted by AN patients, and may rather result from an adaptation to the disease. The aim of this review is to describe the role played by ghrelin in AN focusing on its central vs. peripheral actions. In AN patients and in rodent AN models, chronic food restriction induces profound alterations in the « ghrelin » signaling that leads to the development of inappropriate behaviors like hyperactivity or addiction to food starvation and therefore a greater depletion in energy reserves. The question of a transient insensitivity to ghrelin and/or a potential metabolic reprograming is discussed in regard of new clinical treatments currently investigated.

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Section: Physiological Alterations In Anorexia Nervosamentioning

confidence: 99%

Section: Conclusion: Ghrelin As a Potential Treatment For Anorexia Nementioning

confidence: 99%

Ghrelin: Central and Peripheral Implications in Anorexia Nervosa

Méquinion¹,

Langlet²,

Zgheib³

et al. 2013

Front. Endocrinol.

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show abstract

“…The assumption that lack of efficacy leads to noncompliance does not obtain in a phase 1 safety and tolerability study conducted in healthy volunteers; rejecting the argument that compliance should be monitored at every stage of clinical development can lead to missing potential efficacy signals (Figure 1). Further, confirmation that the drug discussed above proved safe and well tolerated in a larger cohort of depressed individuals (11) suggests that the noncompliance observed in a safety and tolerability study is not necessarily a reflection of side effects. Recognition of the "professional trial subject," for example (see above), demands that we be aware of the social and economic realities of the current clinical trials environment.…”

mentioning

confidence: 88%

“…The effective dose range in these obesity models overlaps doses active in rodent models of behavioral despair (9), such as the forced swim and tail suspension tests, which are frequently employed to predict an antidepressant action (10). The weight loss signal observed in medication-compliant subjects proved valuable (6) for setting the doses of DOV 21947 in phase 2, where a robust antidepressant effect was subsequently evinced (11).…”

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confidence: 99%

The Secrets of a Successful Clinical Trial: Compliance, Compliance, and Compliance

Czobor¹,

Skolnick²

2011

Molecular Interventions

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Technological advances have brought unprecedented rigor to target interrogation, providing the means for linking a specific target to a disease, for establishing that a medication occupies and engages its target at appropriate doses, and for marshaling pharmacokinetic information in order to predict optimum dosing prior to initiating proof-of-efficacy studies. Nevertheless, drug development remains a high cost and risky undertaking (1, 2), and if a compound does not elicit the desired efficacy signal in the clinic, blame is most often cast on the inability to appropriately interrogate the targets, and particularly on the lack of translational fidelity of animal models (3). Critical "go/no-go" decisions, such as first-in-man studies to obtain information about the pharmacokinetics, safety, and tolerability of a drug, as well as imaging studies to measure target engagement, are typically executed in well controlled clinical settings, with subjects dosed in clinic. In contrast, once a compound has progressed to efficacy trials, both economic and logistic considerations most often dictate that studies will be done in an outpatient population. The current nature of commercially sponsored clinical trials, including strict sponsor-imposed timelines and competition among sites for eligible subjects, has created an environment that can provide significant economic rewards for both the subject and trial site (4). An unfortunate byproduct of this environment is the "professional subject" (4). Although more commonly considered to be a phase 1 phenomenon (4), efficacy trials also attract professional subjects, particularly when entry criteria and endpoints are "soft," such as trials using subjective rating scales which can be "gamed." It has become apparent that many subjects enrolling in clinical trials are simply not medication-compliant, with a significant proportion failing to take even a single dose of medication over the course of the study. In the following, we illustrate the effect of noncompliance on clinical trial outcome, and propose solutions, however imperfect, that can be readily implemented for more accurate assessment of drug safety and efficacy. Our first illustration of the problem relates to a phase 1b safety and tolerability study in which patient noncompliance had the effect of masking a potential efficacy signal. The eight-week study in this instance, using the triple uptake inhibitor DOV 21947 (5), was conducted as a single-site outpatient trial. Subjects

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P.2.c.003 A placebo-controlled study of EB-1010, a novel triple re-uptake inhibitor, in patients with major depressive disorder

Cited by 2 publications

References 0 publications

Ghrelin: Central and Peripheral Implications in Anorexia Nervosa

Ghrelin: Central and Peripheral Implications in Anorexia Nervosa

The Secrets of a Successful Clinical Trial: Compliance, Compliance, and Compliance

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