A single 20 mg dose of dihydrexidine (DAR-0100), a full dopamine D1 agonist, is safe and tolerated in patients with schizophrenia

Mark S. George; Christine E. Molnar; Emily L. Grenesko; Berry Anderson; Qiwen Mu; Kevin Johnson; Ziad Nahas; Michael Knable; Prabhavathi Fernandes; Jorge Juncos; Xuemei Huang; David E. Nichols; Richard B. Mailman

doi:10.1016/j.schres.2007.03.011

A single 20 mg dose of dihydrexidine (DAR-0100), a full dopamine D₁ agonist, is safe and tolerated in patients with schizophrenia

Mark S. George, Christine E. Molnar, Emily L. Grenesko, Berry Anderson, Qiwen Mu, Kevin Johnson, Ziad Nahas, Michael Knable, Prabhavathi Fernandes, Jorge Juncos, Xuemei Huang, David E. Nichols, Richard B. Mailman

Psychiatry & Behavioral Sciences

Research output: Contribution to journal › Article › peer-review

82 Scopus citations

Abstract

The potential of dopamine D₁ receptor agonists to have beneficial effects on cognitive function has been suggested by a body of preclinical evidence. We now report the use of dihydrexidine (DAR-0100), the first full D₁ agonist, in a pilot study assessing single low dose safety and tolerability in patients with schizophrenia. A within-subject cross-over design was used in 20 adults (18-65 years) with SCID-IV diagnosed schizophrenia. Subjects were outpatients with a moderate level of residual negative symptoms, and were on stable dosing of non-D₁-blocking antipsychotic drugs. Following screening, subjects were hospitalized for 48 h, and at 0800 h each morning scanned on a 3 T MRI scanner for resting brain perfusion, followed by a Blood Oxygen Level Dependent (BOLD) fMRI scan during an N-Back working memory task. They then received 20 mg subcutaneously (SC) of dihydrexidine or placebo over 15 min, followed by 45 min of intermittent MRI scans of perfusion and BOLD activity during the working memory task. Blood was drawn for serum drug levels and subjects were evaluated for clinical and cognitive changes. The procedure was repeated using the opposite challenge 2 days later. Dihydrexidine was well tolerated with no serious adverse events although three subjects had mild dizziness and five subjects experienced nausea. There was no significant effect of drug on clinical interview ratings or delayed (afternoon) neuropsychological performance. No medication interactions were seen. Thus, a single subcutaneous dose of dihydrexidine is tolerated and safe in patients with schizophrenia and does not produce delayed clinical or neuropsychological improvements.

Original language	English (US)
Pages (from-to)	42-50
Number of pages	9
Journal	Schizophrenia Research
Volume	93
Issue number	1-3
DOIs	https://doi.org/10.1016/j.schres.2007.03.011
State	Published - Jul 2007

Bibliographical note

Funding Information:
This study was funded by a grant from the Stanley Medical Research Institute to Dr. George at MUSC. Darpharma provided the compound, and access to prior safety and drug testing data needed for FDA IND approval. Dr. George and the MUSC group had full autonomy for this study, and directly carried out all recruitment, study procedures, and data entry and analysis without any involvement from Darpharma or the Stanley Foundation. Specifically, Drs. Fernandes, Mailman, Nichols, and Huang, and the Stanley Medical Research Institute (the employer of Dr. Knable) all have a financial interest in DarPharma Holdings LLC, a subsidiary of Biovalve Technologies that holds license rights to dihydrexidine. None of these individuals participated in the recruitment or testing of subjects, in the gathering of data, or in the primary data analysis. The participation of Drs. Fernandes, Mailman, Nichols, Huang, and Knable was restricted to: 1) project conception; 2) experimental design; 3) discussion and interpretation of data subsequent to statistical analysis; and/or 4) writing of this manuscript.

Copyright:
Copyright 2010 Elsevier B.V., All rights reserved.

Keywords

Cognition
D dopamine agonists
D dopamine receptors
Dementia
Dopamine
Schizophrenia

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George, M. S., Molnar, C. E., Grenesko, E. L., Anderson, B., Mu, Q., Johnson, K., Nahas, Z., Knable, M., Fernandes, P., Juncos, J., Huang, X., Nichols, D. E., & Mailman, R. B. (2007). A single 20 mg dose of dihydrexidine (DAR-0100), a full dopamine D₁ agonist, is safe and tolerated in patients with schizophrenia. Schizophrenia Research, 93(1-3), 42-50. https://doi.org/10.1016/j.schres.2007.03.011

George, MS, Molnar, CE, Grenesko, EL, Anderson, B, Mu, Q, Johnson, K, Nahas, Z, Knable, M, Fernandes, P, Juncos, J, Huang, X, Nichols, DE & Mailman, RB 2007, 'A single 20 mg dose of dihydrexidine (DAR-0100), a full dopamine D₁ agonist, is safe and tolerated in patients with schizophrenia', Schizophrenia Research, vol. 93, no. 1-3, pp. 42-50. https://doi.org/10.1016/j.schres.2007.03.011

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abstract = "The potential of dopamine D1 receptor agonists to have beneficial effects on cognitive function has been suggested by a body of preclinical evidence. We now report the use of dihydrexidine (DAR-0100), the first full D1 agonist, in a pilot study assessing single low dose safety and tolerability in patients with schizophrenia. A within-subject cross-over design was used in 20 adults (18-65 years) with SCID-IV diagnosed schizophrenia. Subjects were outpatients with a moderate level of residual negative symptoms, and were on stable dosing of non-D1-blocking antipsychotic drugs. Following screening, subjects were hospitalized for 48 h, and at 0800 h each morning scanned on a 3 T MRI scanner for resting brain perfusion, followed by a Blood Oxygen Level Dependent (BOLD) fMRI scan during an N-Back working memory task. They then received 20 mg subcutaneously (SC) of dihydrexidine or placebo over 15 min, followed by 45 min of intermittent MRI scans of perfusion and BOLD activity during the working memory task. Blood was drawn for serum drug levels and subjects were evaluated for clinical and cognitive changes. The procedure was repeated using the opposite challenge 2 days later. Dihydrexidine was well tolerated with no serious adverse events although three subjects had mild dizziness and five subjects experienced nausea. There was no significant effect of drug on clinical interview ratings or delayed (afternoon) neuropsychological performance. No medication interactions were seen. Thus, a single subcutaneous dose of dihydrexidine is tolerated and safe in patients with schizophrenia and does not produce delayed clinical or neuropsychological improvements.",

keywords = "Cognition, D dopamine agonists, D dopamine receptors, Dementia, Dopamine, Schizophrenia",

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note = "Funding Information: This study was funded by a grant from the Stanley Medical Research Institute to Dr. George at MUSC. Darpharma provided the compound, and access to prior safety and drug testing data needed for FDA IND approval. Dr. George and the MUSC group had full autonomy for this study, and directly carried out all recruitment, study procedures, and data entry and analysis without any involvement from Darpharma or the Stanley Foundation. Specifically, Drs. Fernandes, Mailman, Nichols, and Huang, and the Stanley Medical Research Institute (the employer of Dr. Knable) all have a financial interest in DarPharma Holdings LLC, a subsidiary of Biovalve Technologies that holds license rights to dihydrexidine. None of these individuals participated in the recruitment or testing of subjects, in the gathering of data, or in the primary data analysis. The participation of Drs. Fernandes, Mailman, Nichols, Huang, and Knable was restricted to: 1) project conception; 2) experimental design; 3) discussion and interpretation of data subsequent to statistical analysis; and/or 4) writing of this manuscript. Copyright: Copyright 2010 Elsevier B.V., All rights reserved.",

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AU - Mu, Qiwen

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AU - Fernandes, Prabhavathi

AU - Juncos, Jorge

AU - Huang, Xuemei

AU - Nichols, David E.

AU - Mailman, Richard B.

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