Compassionate use of quinacrine in Creutzfeldt–Jakob disease fails to show significant effects

We thank Dr. Benito-León for his comments. In vitro models of prion infection contributed to identify antiprion molecules. One of them, quinacrine, a drug largely used in humans as an antimalarial, has been proposed as an immediately applicable treatment for Creutzfeldt-Jakob disease and other human prion diseases. This led some countries to treat patients with quinacrine through open compassionate procedures.

In our report of 32 cases of CJD, we did not find any beneficial effect of quinacrine treatment on clinical evolution. [1] The observations reported by Benito-León of two cases with FFI that were treated using quinacrine [2] are in accordance with our results.

However, as we mentioned previously, [1] it must be clearly stressed that such studies as part of compassionate procedures are not controlled double blinded clinical trials and are not expected to detect slight effects of a molecule. In addition, we observed that the delay between disease onset and the initiation of treatment was long. We cannot rule out the possibility that an earlier onset of treatment cannot improve patient survival.

We believe that, while recent reports did not provide evidence of any beneficial effect of quinacrine on patients condition and in experimental models of the disease, [1,2,4,5] results from controlled trials have to be considered before eliminating quinacrine treatment for human prion diseases.

Haïk et al. [1] reported a series of 32 patients with Creutzfeldt–Jakob disease (CJD) whose overall condition worsened despite quinacrine treatment. I described my experience with quinacrine and chlorpromazine in two fatal familial insomnia (FFI) patients, an autosomal dominant prion disease, who received this therapy as part of a compassionate procedure. [2]

In an earlier report, quinacrine and chlorpromazine were suggested as treatments for prion diseases. [3] The first patient was a 43-year-old female. At the onset of therapy, her Rankin Scale score was 4 (moderately severe disability). Molecular analysis of prion protein gene revealed the codon 178 point mutation and Methionine homozygosity at position 129. Treatment with quinacrine (200 mg three times daily for five days, followed by 100 mg three times daily) and chlorpromazine (75 mg three times daily, increasing to 600 mg daily) was initiated on September 6, 2001. She was treated with a high initial dose of quinacrine at the beginning, because of the rapid clinical deterioration in the previous weeks. Eight days later, she developed decrease in psychomotor activity and orthostatic hypotension. Quinacrine was then discontinued and chlorpromazine reduced to 50 mg per day. Four days later, the patient recovered the level of consciousness. Chlorpromazine was finally withdrawn because of orthostatic hypotension. In September 25, quinacrine 100 mg daily was restarted.

However, from October 1, her condition worsened and quinacrine was withdrawn. She died 27 days later and the necropsy confirmed typical FFI findings. Blood analysis and electrocardiogram remained normal under therapy.

The second patient was a 52-year-old male. Molecular analysis revealed the codon 178 point mutation and heterozigosity Methionine/Valine at position 129. Therapy with quinacrine (100 mg three times daily) and chlorpromazine (75 mg three times daily) was begun in November 15, 2001. At the onset of the treatment the patient had a Rankin Scale score of 2 (slight disability). Over the next five months, the patient condition worsened and his Rankin Scale score increased to 4. In February 2002, quinacrine and chlorpromazine were withdrawn. Blood cell count and transaminase level were always normal. Finally, he died. At necropsy, typical neuropathologic findings of FFI were observed.

These observations in humans are in agreement with recent reports on the failure of quinacrine and chlorpromazine in prion disease murine models. [4,5] In my opinion, sufficient data are now available to eliminate this therapy for prion diseases.

References

1. Haik S, Brandel JP, Salomon D, et al. Compassionate use of quinacrine in Creutzfeldt-Jakob disease fails to showsignificant effects. Neurology 2004;63:2413-2415.

2. Benito-León J. Combined quinacrine and chlorpromazine therapy in fatal familial insomnia. Clin Neuropharmacol 2004;27:201-203.

3. Korth C, May BC, Cohen FE, Prusiner SB. Acridine and phenothiazine derivatives as pharmacotherapeutics for prion disease. Proc Natl Acad Sci 2001;98: 9836-9841.

4. Collins SJ, Lewis V, Brazier M, et al. Quinacrine does not prolong survival in a murine Creutzfeldt-Jakob disease model. Ann Neurol 2002;52:503-506.

5. Barret A, Tagliavini F, Forloni G, et al. Evaluation of quinacrine treatment for prion diseases. J Virol 2003;77:8462-8469.