Retinitis Pigmentosa (RP) is a devastating eye disease and at present there are no known
treatment options that can alter the rate of vision loss and eventual blindness. In a series
of studies in animal models, the effects of exposing cones in the periphery of the retina to
a large excess of oxygen results in progressive oxidative damage to cone photoreceptors and
cone cell death. Cone cell death gradually spreads from the periphery of the retina toward
its center, narrowing the visual field and eventually resulting in tunnel vision. Compared to
control patients, those with RP showed significant reduction in the reduced to oxidized
glutathione ratio (GSH/GSSG) in aqueous humor and a significant increase in protein carbonyl
content. This demonstration of oxidative stress and oxidative damage in the eyes of patients
with RP, suggests that oxidative damage-induced cone cell death in animal models of RP may
translate to humans with RP and support the hypotheses that (1) potent antioxidants will
promote cone survival and function in patients with RP and (2) aqueous GSH/GSSG ratio and
carbonyl content on proteins provide useful biomarkers of disease activity in this patient
population. Orally administered N-acetylcysteine (NAC) has been found to be a particularly
effective antioxidant that promotes prolonged cone survival and maintenance of cone function
in a mouse model of RP. Since oral and/or topical administration of NAC is feasible for
long-term treatment in humans, and NAC has a good safety profile, there is good rationale to
test the effect of NAC in patients with RP.
Oxidative damage has been implicated in several diseases including cystic fibrosis, chronic
obstructive pulmonary disease (COPD), and Idiopathic Pulmonary Fibrosis. The effect of oral
NAC has been tested in these indications in several clinical trials providing extensive
safety data. In COPD, NAC 600mg bid improves airway function and reduces the frequency of
acute exacerbations. Doses of up to 1800mg/day have been well-tolerated in the treatment of
Idiopathic Pulmonary Fibrosis. Paracetamol (acetaminophen) toxicity is treated with a loading
dose of 140 mg/kg NAC followed by 70 mg/kg every 4 hours for 17 doses. Normal volunteers
tolerated a dose of 11.2 grams NAC/day for three months without any serious undesirable
effects and in another study a dose of 500mg/kg/day was tolerated. The most frequent adverse
events associated with the oral administration of NAC are gastrointestinal in nature and
include vomiting, diarrhea, stomatitis, abdominal pain and nausea (incidence rate >1/1000 to
<1/100). Hypersensitivity reactions including anaphylactic shock and
anaphylactic/anaphylactoid reaction (incidence rate <1/10,000), dyspnea, bronchospasm
(incidence rate >1/10,000 to <1/1000), angioedema, tachycardia, urticaria, rash and pruritus
(incidence rate >1/1000 to <1/100) have been reported less frequently. Finally, reports of
headache, tinnitus, pyrexia, blood pressure decreased (incidence rate >1/1000 to <1/100),
face edema and hemorrhage have also been collected with oral NAC.
In the FIGHT-RP 1 Study, the investigators used escalating doses of NAC effervescent tablets
(from 600 mg in Cohort 1 to 1800 mg in Cohort 3). The maximum tolerated dose was 1800 mg
twice a day which will be continued in this study.