A Double-Blind, Placebo-Controlled Trial to Evaluate the Safety, Tolerability, and Pharmacokinetics of Single, Escalating Oral Doses of JDTic

Buda, Jeffrey J; Carroll, F. Ivy; Kosten, Thomas R.; Swearingen, Dennis; Walters, Bradford

doi:10.1038/npp.2015.27

Cited by 47 publications

(39 citation statements)

References 38 publications

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“…Two clinical trials recently reported mixed results on the tolerability of two opiates with antagonist activity at the KOR (JDTic, Buda et al . , buprenorphine, Karp et al . ), with evidence for a potential cardiac toxicity (Buda et al .…”

Section: Discussionmentioning

confidence: 99%

Kappa opioid receptor antagonism and chronic antidepressant treatment have beneficial activities on social interactions and grooming deficits during heroin abstinence

et al. 2016

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Addiction is a chronic brain disorder that progressively invades all aspects of personal life. Accordingly, addiction to opiates severely impairs interpersonal relationships, and the resulting social isolation strongly contributes to the severity and chronicity of the disease. Uncovering new therapeutic strategies that address this aspect of addiction is therefore of great clinical relevance. We recently established a mouse model of heroin addiction in which, following chronic heroin exposure, ‘abstinent’ mice progressively develop a strong and long-lasting social avoidance phenotype. Here, we explored and compared the efficacy of two pharmacological interventions in this mouse model. Because clinical studies indicate some efficacy of antidepressants on emotional dysfunction associated with addiction, we first used a chronic 4-week treatment with the serotonergic antidepressant fluoxetine, as a reference. In addition, considering prodepressant effects recently associated with kappa opioid receptor signaling, we also investigated the kappa opioid receptor antagonist norbinaltorphimine (norBNI). Finally, we assessed whether fluoxetine and norBNI could reverse abstinence-induced social avoidance after it has established. Altogether, our results show that two interspaced norBNI administrations are sufficient both to prevent and to reverse social impairment in heroin abstinent animals. Therefore, kappa opioid receptor antagonism may represent a useful approach to alleviate social dysfunction in addicted individuals.

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Section: Discussionmentioning

confidence: 99%

Kappa opioid receptor antagonism and chronic antidepressant treatment have beneficial activities on social interactions and grooming deficits during heroin abstinence

et al. 2016

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“…JDTic was evaluated in phase I trials with the intent to develop this agent for the treatment of cocaine abuse. However, this effort was halted due to prohibitive adverse events including ventricular tachycardia . PF‐4455242 was evaluated in a human phase 1 trial with the intent to develop this agent for the treatment of mood disorders and substance use disorders.…”

Section: The Future: Translating Preclinical Discoveries To Human Drumentioning

confidence: 99%

“…However, this effort was halted due to prohibitive adverse events including ventricular tachycardia. [59,87] PF-4455242 was evaluated in a human phase 1 trial with the intent to develop this agent for the treatment of mood disorders and substance use disorders. However, as described above, these efforts were discontinued due to evidence of toxicity in animal studies when administered for over 90 days.…”

Section: Clinical Trials Completed With Kor Antagonists and Kor Antagmentioning

confidence: 99%

Kappa-Opioid Antagonists for Psychiatric Disorders: From Bench to Clinical Trials

2016

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Kappa-opioid receptor (KOR) antagonists are currently being considered for the treatment of a variety of neuropsychiatric conditions, including depressive, anxiety, and substance abuse disorders. A general ability to mitigate the effects of stress, which can trigger or exacerbate these conditions, may explain their putative efficacy across such a broad array of conditions. The discovery of their potentially therapeutic effects evolved from preclinical research designed to characterize the molecular mechanisms by which experience causes neuroadaptations in the nucleus accumbens (NAc), a key element of brain reward circuitry. This research established that exposure to drugs of abuse or stress increases the activity of the transcription factor CREB (cAMP response element binding protein) in the NAc, which leads to elevated expression of the opioid peptide dynorphin, which in turn causes core signs of depressive- and anxiety-related disorders. Disruption of KORs—the endogenous receptors for dynorphin—produces antidepressant- and anxiolytic-like actions in screening procedures that identify standard drugs of these classes, and reduces stress effects in tests used to study addiction and stress-related disorders. Although interest in this target is high, prototypical KOR antagonists have extraordinarily persistent pharmacodynamic effects that complicate clinical trials. The development of shorter-acting KOR antagonists together with more rapid designs for clinical trials may soon provide insight on whether these drugs are efficacious as would be predicted by preclinical work. If successful, KOR antagonists would represent a unique example in psychiatry where the therapeutic mechanism of a drug class is understood before it is shown to be efficacious in humans.

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“…Further investigation is needed to determine whether observed cardiac involvement is specific to JDTic or possibly represents a class effect of KOR antagonists. [104] …”

Section: Jdtic (17)mentioning

confidence: 99%

Major Depressive Disorder and Kappa Opioid Receptor

Li¹,

Huijiao²,

Hao³

et al. 2016

Transl Perioper & Pain Med

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Major depressive disorder (MDD) is a common psychiatric disease worldwide. The clinical use of tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs) and selective serotonin reuptake inhibitors (SSRIs)/ serotonin-norepinephrine reuptake inhibitor (SNRIs) for this condition have been widely accepted, but they were challenged by unacceptable side-effects, potential drug-drug interactions (DDIs) or slow onset/ lack of efficacy. The endogenous opioid system is involved in stress and emotion regulatory processes and its role in MDD has been implicated. Although several KOR antagonists including JDTic and PF-04455242 were discontinued in early clinical trials, ALKS 5461 and CERC-501(LY-2456302) survived and entered into Phase-III and Phase-II trials, respectively. Considering the efficacy and safety of early off-label use of buprenorphine in the management of the treatment-resistant depression (TRD), it will be not surprising to predict the potential success of ALKS 5461 (a combination of buprenorphine and ALKS-33) in the near future. Moreover, CERC-501 will be expected to be available as monotherapy or adjuvant therapy with other first-line antidepressants in the treatment of TRD, if ongoing clinical trials continue to provide positive benefit-risk profiles. Emerging new researches might bring more drug candidates targeting the endogenous opioid system to clinical trials to address current challenges in MDD treatment in clinical practice.

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A Double-Blind, Placebo-Controlled Trial to Evaluate the Safety, Tolerability, and Pharmacokinetics of Single, Escalating Oral Doses of JDTic

Cited by 47 publications

References 38 publications

Kappa opioid receptor antagonism and chronic antidepressant treatment have beneficial activities on social interactions and grooming deficits during heroin abstinence

Kappa opioid receptor antagonism and chronic antidepressant treatment have beneficial activities on social interactions and grooming deficits during heroin abstinence

Kappa-Opioid Antagonists for Psychiatric Disorders: From Bench to Clinical Trials

Major Depressive Disorder and Kappa Opioid Receptor

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