Currently there is no treatment for the damage that follows cerebral ischemia. Many neurotoxins, including 3-aminopropanal (3AP), are produced in ischemic brain producing a vicious cycle of brain cell death. Clinical trials of putative neuroprotective drugs in the setting of acute stroke have thus far not succeeded. However, many of those drug trials were based on pre-clinical animal studies which showed promising results if drug was started before the onset of ischemia. Unlike in acute stroke, the ischemia that follows cerebral vasospasm following aSAH feasibly allows for pretreatment of the ischemia since the onset of the risk period for vasospasm starts approximately 72 hours after the onset of the initial bleed. It is the intention of this study to examine the effect of tiopronin, an FDA approved drug for the indication of cystine kidney stones, on clinical outcome and levels of the neurotoxin 3AP in the body following aSAH. The study will follow a Phase 2, multicenter, randomized, double-blinded, placebo-controlled drug trial format, enrolling 60 patients at three major academic medical centers. Patients who present with aSAH will be consented and randomized to either placebo or drug group. For up to 14 days after their initial bleed, they will be given drug or placebo and evaluated clinically. During this time, serum and (if the patient has a ventricular catheter) cerebrospinal fluid (CSF) will be collected along with the clinical draws. These samples will be analyzed with an enzyme-linked immunosorbent assay (ELISA) kit to determine 3AP levels. Patients will also be evaluated for clinical outcome with questionnaires at 14 days after the bleed (or discharge whichever comes first) and at 3 and 12 months after the initial bleed. The primary outcome will be to show a reduction in levels of 3AP in the CSF and blood of patients who received drug compared to placebo. Secondary outcomes will be to show clinical outcome differences between the drug and placebo group and to continue to validate the safety of tiopronin in the aSAH population. If this study is successful, a Phase 3 drug trial will further analyze the clinical effects of tiopronin in aSAH. This would spark further study that could further explore neuroprotective pre-treatment of cerebral ischemia, and thus help neutralize a major source of morbidity and mortality in this disease process.

Public Health Relevance

Because of the different approach of pre-dosing drug before a patient is at risk for ischemia after aSAH, this study may establish tiopronin as the first successful treatment of the neurotoxicity that follows cerebral ischemia. This would spark further study that could further improve neuroprotective treatment of cerebral ischemia, and thus help neutralize a major source of morbidity and mortality in this disease process.

National Institute of Health (NIH)
Food and Drug Administration (FDA)
Research Project (R01)
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Special Emphasis Panel (ZFD1-OPD-N (01))
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Columbia University (N.Y.)
Schools of Medicine
New York
United States
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Kellner, Christopher P; Connolly Jr, E Sander (2010) Neuroprotective strategies for intracerebral hemorrhage: trials and translation. Stroke 41:S99-102