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


CONCLUSIONS
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.
Kim
Grace H
GH
Department of Neurological Surgery, Columbia University Medical Center, New York, New York 10032, USA.
Kellner
Christopher P
CP
Hickman
Zachary L
ZL
Zacharia
Brad E
BE
Starke
Robert M
RM
Hwang
Brian Y
BY
Ducruet
Andrew F
AF
Fernandez
Luis
L
Mayer
Stephan A
SA
Tracey
Kevin J
KJ
Connolly
E Sander
ES
D000328:Adult; D000368:Aged; D000447:Aldehydes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D015331:Cohort Studies; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D018696:Neuroprotective Agents / Q000008:administration & dosage* / Q000009:adverse effects; D011437:Propylamines / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013345:Subarachnoid Hemorrhage / Q000150:complications* / Q000503:physiopathology; D008625:Tiopronin / Q000008:administration & dosage* / Q000009:adverse effects; D020301:Vasospasm, Intracranial / Q000150:complications* / Q000503:physiopathology
D000447:Aldehydes; D018696:Neuroprotective Agents; D011437:Propylamines; D008625:Tiopronin; C050862:3-aminopropionaldehyde