A phase I clinical trial of tiopronin, a putative neuroprotective agent, in aneurysmal subarachnoid hemorrhage.

Abstract

BACKGROUND:

The neurotoxic aldehyde 3-aminopropanal (3-AP) contributes to brain injury following cerebral ischemia. Tiopronin (N-2-mercaptopropionyl-glycine[N-2-MPG]) is a US Food and Drug Administration (FDA)-approved drug for the treatment of cystinuria and a putative neuroprotective agent that has been shown to bind and neutralize 3-AP and reduce infarct volumes.

OBJECTIVE:

The objective of this trial was to establish the safety of tiopronin administration in patients with aneurysmal subarachnoid hemorrhage (aSAH) in preparation for further trials of its efficacy as a neuroprotective agent in this disease process.

METHODS:

This Phase I dose-escalation trial enrolled three-patient cohorts using a conventional "3+3" study design. Tiopronin dose began at 1 g/d until aSAH Day 14. Each subsequent cohort received a dose of tiopronin based on predetermined guidelines. A maximum dose of 3 g/d was selected, because this is the maximum FDA-approved dose for long-term cystinuria treatment. Subjects were monitored for known side effects of tiopronin.

RESULTS:

Nine patients were enrolled, the minimum number required based on the study design. None of these patients experienced serious side effects attributable to tiopronin, and no adverse events were noted that could not be attributed to the pathophysiology of aSAH.

CONCLUSION:

The administration of 3 g/d of tiopronin following aSAH for up to 14 days appears to be safe and without the side effects associated with long-term use. Plans for a randomized, placebo-controlled Phase II trial of tiopronin for neuroprotection following aSAH are underway.

• Authors: Grace H Kim, Christopher P Kellner, Zachary L Hickman, Brad E Zacharia, Robert M Starke, Brian Y Hwang, Andrew F Ducruet, Luis Fernandez, Stephan A Mayer, Kevin J Tracey, E Sander Connolly Jr
• Journal: Neurosurgery (Neurosurgery) Vol. 67 Issue 1 Pg. 182-5; discussion 186 (Jul 2010) ISSN: 1524-4040 [Electronic] United States
• PMID: 20559104 (Publication Type: Clinical Trial, Phase I, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Aldehydes
• Neuroprotective Agents
• Propylamines
• Tiopronin
• 3-aminopropionaldehyde

Topics

• Adult
• Aged
• Aldehydes (antagonists & inhibitors, metabolism)
• Brain Ischemia (drug therapy, metabolism, physiopathology)
• Cohort Studies
• Female
• Humans
• Male
• Middle Aged
• Neuroprotective Agents (administration & dosage, adverse effects)
• Propylamines (antagonists & inhibitors, metabolism)
• Subarachnoid Hemorrhage (complications, physiopathology)
• Tiopronin (administration & dosage, adverse effects)
• Vasospasm, Intracranial (complications, physiopathology)