The Effects of Tiopronin on 3-Aminopropanal Level & Neurologic Outcome After Aneurysmal Subarachnoid Hemorrhage

The annual rate of aSAH in United States is approximately 18 to 24 thousand cases each year.
Mortality rates following aSAH range from 30-70% with 10-20% of survivors experiencing severe
neurological disability. Following aSAH, a major cause of morbidity and mortality is
vasospasm, which causes delayed ischemic neurologic deterioration. There is currently no
effective treatment for preventing or ameliorating the damage that occurs following cerebral
ischemia. A myriad of neuro-toxins are produced in the ischemic brain resulting in a vicious
cycle of cellular death and destruction. The polyamines spermine and spermidine are
metabolized by polyamine oxidase (PAO) into putrescine and 3-aminopropanal (3AP).

Tiopronin (Thiola) is an FDA approved drug used for the treatment of cystine stones in
patients with cystinuria in the U.S. In Europe, it is also used for the treatment of
rheumatoid arthritis and bronchial hypersecretion. In previous animal studies, we
demonstrated that tiopronin is able to bind and neutralize the toxic effects of 3AP. We have
shown in previous studies that aSAH patients have elevated 3AP levels, and higher levels
correlate to a poor neurologic outcome.

The goals of this phase II multicenter, randomized, double-blinded safety and efficacy trial
are to (1) further evaluate the safety of the drug in our patient population at the dose
established in phase I; (2) demonstrate that tiopronin crosses the blood-brain barrier; (3)
show that both serum and CSF 3AP levels are reduced by administration of tiopronin; and (4)
demonstrate that a reduction in 3AP levels is associated with improved neurologic outcome in
aSAH patients.

Inclusion Criteria:

- Admitted to a recruiting center with aneurysmal subarachnoid hemorrhage

- Ability to initiate study drug treatment within 96 hours of aSAH onset.

- Ability to provide either informed or surrogate consent

Exclusion Criteria:

- Hypersensitivity to penicillamine

- Creatinine level greater than 1.5/mm^3 on admission

- Platelet count of less than 100,000/mm^3 on admission

- White blood cell count of less than 3.5/mm^3 on admission

- AST or ALT of greater than 60/L on admission or history of liver failure

- Pregnancy

- History of lupus, Goodpasture's syndrome, myasthenia gravis, pemphigus, nephrotic
syndrome, glomerulonephritis, or renal failure

- Patients considered unable to comply with the protocol