Michael Knable

Publications (2)9.5 Total impact

• Article: A single 20 mg dose of the full D1 dopamine agonist dihydrexidine (DAR-0100) increases prefrontal perfusion in schizophrenia.

  Qiwen Mu, Kevin Johnson, Paul S Morgan, Emily L Grenesko, Christine E Molnar, Berry Anderson, Ziad Nahas, F Andrew Kozel, Samet Kose, Michael Knable, Prabhavathi Fernandes, David E Nichols, Richard B Mailman, Mark S George
  [show abstract] [hide abstract]
  ABSTRACT: Dopamine D1 receptors play an important role in memory and cognition in non-human primates. Dopamine D1 agonists have been shown to reverse performance deficits in both aged non-human primates and in primates with lesions to dopamine systems. This study explored whether a single dose of the first full D1 agonist dihydrexidine (DAR-0100) would cause changes in brain activity (perfusion) in dopamine-rich brain regions. We used a new gadolinium-contrast magnetic resonance perfusion scanning technique to measure brain activity. A within-subject cross-over double-blind randomized design was used in 20 adults with SCID-diagnosed schizophrenia. Each morning at 0800 h, they were scanned on a 3.0 T MRI scanner for perfusion. They then received either 20 mg of dihydrexidine, or placebo, subcutaneously over 15 min. Over the next 45 min, they had intermittent MRI scans. Two days later, they had a repeat of the Day 1 schedule, but received the opposite treatment from that given on the first day. Within-day, as well as between-day, comparisons were made to test for perfusion effects of dihydrexidine. Analysis revealed that dihydrexidine induced a significant increase in both prefrontal and non-prefrontal perfusion compared to placebo. The greatest increases occurred approximately 20 min after dihydrexidine infusion, consistent with the short pharmacokinetic half-life of dihydrexidine. These data are consistent with the hypothesis formulated from studies of non-human primates that dihydrexidine and other D1 agonists may be able to modulate prefrontal dopaminergic function.
  Schizophrenia Research 09/2007; 94(1-3):332-41. · 4.75 Impact Factor
• Article: 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
  [show abstract] [hide abstract]
  ABSTRACT: The potential of dopamine D(1) 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 D(1) 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-D(1)-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.
  Schizophrenia Research 08/2007; 93(1-3):42-50. · 4.75 Impact Factor