Microdosing, Isotopic Labeling, Radiotracers and Metabolomics: Relevance in Drug Discovery, Development and Safety

Wotherspoon, Andrew T.L.; Safavi-Naeini, Mitra; Bánati, Richard B.

doi:10.4155/bio-2017-0137

Cited by 9 publications

(7 citation statements)

References 121 publications

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“…Intriguingly, our data indicate that extremely low concentrations of (2R,6R)-HNK (0.025 mg/kg in female mice and 0.075 mg/kg in male mice) can still have a significant impact on behavior despite resulting in non-detectable levels in the brain and plasma following administration. Due to technical limitations, our LC-MS method may not be sensitive enough to detect brain or plasma concentrations of (2R,6R)-HNK within the picogram range, and future studies may have more success using accelerated mass spectrometry (39,40). Although, to our knowledge, these microdoses of (R,S)-ketamine and its metabolites have not previously been studied, there has been a recent resurgence in examining the potential benefit of microdosing, in which small quantities of psychedelic substances are repeatedly ingested (39)(40)(41)(42)(43)(44)(45)(46)(47).…”

Section: Discussionmentioning

confidence: 99%

“…Due to technical limitations, our LC-MS method may not be sensitive enough to detect brain or plasma concentrations of (2R,6R)-HNK within the picogram range, and future studies may have more success using accelerated mass spectrometry (39,40). Although, to our knowledge, these microdoses of (R,S)-ketamine and its metabolites have not previously been studied, there has been a recent resurgence in examining the potential benefit of microdosing, in which small quantities of psychedelic substances are repeatedly ingested (39)(40)(41)(42)(43)(44)(45)(46)(47). This unique method of administration is reported to exert a myriad range of benefits, including improved mood, heightened creativity, and increased focus, without inducing nonspecific psychotropic or addictive side effects (43,46,47).…”

Section: Discussionmentioning

confidence: 99%

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Ovarian hormones mediate the prophylactic efficacy of (R,S)-ketamine and (2R,6R)-hydroxynorketamine in female mice

et al. 2019

Preprint

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Number of words in the abstract: 227 (250 max)Number of words in the text: 3812 (4000 max) ABSTRACT BACKGROUND: Females are more likely than males to develop major depressive disorder (MDD) after exposure to stress. We previously reported that the administration of (R,S)-ketamine before stress can prevent stress-induced depressive-like behavior in male mice but have yet to assess efficacy in female mice or for other compounds, such as the metabolites of (R,S)-ketamine. METHODS:We administered (R,S)-ketamine or its metabolites (2R,6R)hydroxynorketamine ((2R,6R)-HNK) and (2S,6S)-HNK at various doses 1 week before one of a number of stressors, including contextual fear conditioning (CFC), learned helplessness (LH), and chronic immobilization stress (CIS), in male and female 129S6/SvEv mice. To examine the interaction between ovarian hormones and stress resilience, female mice also underwent ovariectomy surgery (OVX) and a hormone replacement protocol prior to drug administration. RESULTS: (R,S)-ketamine and (2S,6S)-HNK, but not (2R,6R)-HNK, attenuated learned fear in male mice. (R,S)-ketamine and (2R,6R)-HNK, but not (2S,6S)-HNK, significantly reduced stress-induced depressive-like behavior in male and female mice. (R,S)ketamine and (2R,6R)-HNK) were prophylactically effective at a lower dose (10 mg/kg and 0.025 mg/kg, respectively) in female mice than in male mice (30 mg/kg and 0.075 mg/kg, respectively). Moreover, ovarian-derived hormones were necessary and sufficient for prophylaxis in female mice. CONCLUSIONS:Our results suggest that prophylactics against stress-induced depressive-like behavior can be developed in a sex-specific manner and that ovarian hormones mediate prophylactic efficacy in females. To our knowledge, this is the first

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Ovarian hormones mediate the prophylactic efficacy of (R,S)-ketamine and (2R,6R)-hydroxynorketamine in female mice

et al. 2019

Preprint

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“…Therefore, the primary goal of developing conventional pharmaceuticals is the efficacy and safety profile of the drug. By contrast, molecular imaging probes represent a special class of pharmaceuticals, which retain the selectivity and affinity of traditional pharmaceuticals but because they are often labeled with radioisotopes [ 155 ], require dose levels that are far below the amount required to elicit either a pharmacological or toxicological response [ 155 ], and typically operate at levels significantly below the No Effect Level (NOEL) [ 155 , 156 ]. This microdosing approach is only possible if the specific activity (i.e., the activity per quantity of a radionuclide) is sufficiently high to permit non-invasive detection while minimizing the on-target effect of the unlabeled probes mass [ 157 , 158 ].…”

Section: From Preclinical Validation To First In Man Testing—checkmentioning

confidence: 99%

Beta Cell Imaging—From Pre-Clinical Validation to First in Man Testing

Demine

Schulte

Territo

et al. 2020

IJMS

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There are presently no reliable ways to quantify human pancreatic beta cell mass (BCM) in vivo, which prevents an accurate understanding of the progressive beta cell loss in diabetes or following islet transplantation. Furthermore, the lack of beta cell imaging hampers the evaluation of the impact of new drugs aiming to prevent beta cell loss or to restore BCM in diabetes. We presently discuss the potential value of BCM determination as a cornerstone for individualized therapies in diabetes, describe the presently available probes for human BCM evaluation, and discuss our approach for the discovery of novel beta cell biomarkers, based on the determination of specific splice variants present in human beta cells. This has already led to the identification of DPP6 and FXYD2ga as two promising targets for human BCM imaging, and is followed by a discussion of potential safety issues, the role for radiochemistry in the improvement of BCM imaging, and concludes with an overview of the different steps from pre-clinical validation to a first-in-man trial for novel tracers.

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“…One out of four drug development failures is because of pharmacokinetic issues such as penetration into the target organ or absorption; microdosing with sensitive tests could solve this problem and eliminate these failures, and help us to save our patients, our money, and innocent animals in labs [127][128][129].…”

Section: Phase 0 Studies: Microdosingmentioning

confidence: 99%

Inappropriate modeling of chronic and complex disorders: How to reconsider the approach in the context of predictive, preventive and personalized medicine, and translational medicine

Seifirad

Haghpanah

2019

EPMA Journal

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Preclinical investigations such as animal modeling make the basis of clinical investigations and subsequently patient care. Predictive, preventive, and personalized medicine (PPPM) not only highlights a patient-tailored approach by choosing the right medication, the right dose at the right time point but it as well essentially requires early identification, by the means of complex and state-of-the-art technologies of unmanifested pathological processes in an individual, in order to deliver targeted prevention early enough to reverse manifestation of a pathology. Such an approach can be achieved by taking into account clinical, pathological, environmental, and psychosocial characteristics of the patients or an individual who has a suboptimal health condition. Inappropriate modeling of chronic and complex disorders, in this context, may diminish the predictive potential and slow down the development of PPPM and consequently modern healthcare. Therefore, it is the common goal of PPPM and translational medicine to find the solution for the problem we present in our review. Both, translational medicine and PPPM in parallel, essentially need accurate surrogates for misleading animal models. This study was therefore undertaken to provide shreds of evidence against the validity of animal models. Limitations of current animal models and drug development strategies based on animal modeling have been systematically discussed. Finally, a variety of potential surrogates have been suggested to change the unfavorable situation in medical research and consequently in healthcare.

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Microdosing, Isotopic Labeling, Radiotracers and Metabolomics: Relevance in Drug Discovery, Development and Safety

Cited by 9 publications

References 121 publications

Ovarian hormones mediate the prophylactic efficacy of (R,S)-ketamine and (2R,6R)-hydroxynorketamine in female mice

Ovarian hormones mediate the prophylactic efficacy of (R,S)-ketamine and (2R,6R)-hydroxynorketamine in female mice

Beta Cell Imaging—From Pre-Clinical Validation to First in Man Testing

Inappropriate modeling of chronic and complex disorders: How to reconsider the approach in the context of predictive, preventive and personalized medicine, and translational medicine

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