BUENOS AIRES (Reuters Health) Aug 28 - Treatment with the protease inhibitor ritonavir has resulted in a clinical response in animal models of multiple sclerosis (MS), according to a report by French researchers published in the August 30th issue of the Journal of Neuroimmunology.
Author Dr. Marc Peschanski, of the Inserm U421, in Créteil Cedex, told Reuters Health that ritonavir, or other HIV protease inhibitors, might eventually improve the efficacy of conventional treatments against neurological conditions such as MS, but this hypothesis needs to be tested first in more complex animal models and in clinical trials.
Researchers targeted the proteasome enzyme thought to be involved in the pathogenesis of multiple sclerosis. Although the mechanism is not fully understood, it is known that the proteasome plays a role in activation of lymphocytes, which attack the protective central nervous system myelin sheaths in some autoimmune disorders, Dr. Peschanski said.
Ritonavir has recently been shown have some modulating activity on proteasomes. "So we undertook a study to test in rats the capacity of ritonavir to block the development of experimental autoimmune encephalomyelitis (EAE), a classical animal model of MS," Dr. Peschanski explained.
The results of the study were encouraging, the French researcher reported. Daily administration of ritonavir prevented clinical symptoms of EAE in a dose- and time-dependent manner, suggesting that the drug might have a protective effect when given during the earlier phases of MS. Other protease inhibitors such as saquinavir, nelfinavir and indinavir did not seem to share the same degree of activity.
Dr. Peschanski prefers to be cautious, however. "Total suppression of the disease was obtained at a dose that is higher than that used for HIV-infected patients (20 mg/kg per day). It would be very difficult to propose a treatment with well-proven major side effects, such as lipodystrophy," Dr. Peschanski said.
The researchers are planning to test a combination of lower doses of ritonavir and interferon-beta in another animal model of MS.
Another limitation of long-term use of ritonavir is related to its pleiotropic effect; the drug interferes with various molecules whose activities are not known yet, but may have important biological functions. According to Dr. Peschanski, researchers now must identify the part of the ritonavir molecule involved in the proteasome-modulating activity, in order to design a more selective compound.
Although many HIV-infected patients with multiple sclerosis may already be receiving ritonavir as part of combination antiretroviral therapy, Dr. Peschanski says that researchers will need 1000 patients to demonstrate a direct effect of ritonavir on MS.
J Neuroimmunol 2001;118:233-244.
Copyright © 2001 Reuters Ltd
Copyright © 2001 Reuters Ltd