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

Document Type

Article

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.

Medical Subject Headings

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)

Publication Date

7-1-2010

Publication Title

Neurosurgery

E-ISSN

1524-4040

Volume

67

Issue

1

First Page

182

Last Page

5; discussion 186

PubMed ID

20559104

Digital Object Identifier (DOI)

10.1227/01.NEU.0000370919.93259.3C

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