Pharmacology of the biological response modifier bropirimine (PNU-54461) on experimental autoimmune encephalomyelitis (EAE) in mice
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Published on: April 9, 2012
S M Vroegop1, D L Chapman, L A Galinet
1Discovery Technologies, Pharmacia & Upjohn Inc, Kalamazoo, MI 49007-4940, USA. stephen.e.buxser@am.pnu.com
Abstract:
In murine severe experimental autoimmune encephalomyelitis (EAE), an animal model for the human disease multiple sclerosis (MS), we tested the efficacy of a 5-halo-6-phenyl pyrimidinone compound, bropirimine (PNU-54461). We observed that the compound is active in suppressing EAE when administered orally, a significant pharmacological advantage compared to some current therapies for the treatment of MS. Furthermore, bropirimine was most efficacious when dosing was begun 5-10 days after injection of myelin basic protein, the protein isolated from the central nervous system and used for inducing EAE in our model. This is a period of time following the initial immunological events leading to the disease, when large-scale leukocyte infiltration into the central nervous system begins. Following oral dosing, bropirimine peaked in the blood within 3 h and was cleared to undetectable concentrations within 16-18 h. Despite the pharmacokinetics in the blood, bropirimine was fully efficacious when dosed orally every two or three days. Surprisingly, bropirimine treatment did not result in a statistically significant decrease in leukocyte infiltration into the lower spinal cord, unless the compound was dosed daily at a high concentration. We also observed the concentration and time course of alpha-interferon in blood following oral dosing of bropirimine. The kinetics of interferon in the blood are similar to, but clearly distinguishable from, the pharmacokinetics of bropirimine in the blood. It is not clear whether or not the induction of interferon plays a key role in the efficacy of bropirimine. Nevertheless, the results using bropirimine in EAE suggest that the compound may be useful for the treatment of multiple sclerosis.
Insights
Bropirimine effectively suppressed experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis (MS), when given orally. This compound shows promise for MS treatment, even with less frequent dosing.
Area of Science:
- Neuroimmunology
- Pharmacology
Background:
- Multiple Sclerosis (MS) is a chronic autoimmune disease affecting the central nervous system.
- Experimental Autoimmune Encephalomyelitis (EAE) serves as a key animal model for studying MS pathogenesis and therapeutic strategies.
- Current MS therapies often require specific administration routes or have limitations.
Purpose of the Study:
- To evaluate the efficacy of bropirimine, a novel pyrimidinone compound, in a murine model of MS (EAE).
- To assess the therapeutic potential of oral bropirimine administration for MS treatment.
Main Methods:
- Administration of bropirimine (PNU-54461) via oral gavage in a murine EAE model.
- Dosing initiated 5-10 days post-induction of EAE, coinciding with leukocyte infiltration.
- Pharmacokinetic analysis of bropirimine in blood and assessment of leukocyte infiltration in the spinal cord.
- Monitoring of alpha-interferon levels in blood following bropirimine treatment.
Main Results:
- Oral administration of bropirimine demonstrated significant suppression of EAE.
- Optimal efficacy was observed when bropirimine treatment commenced during the active phase of EAE.
- Bropirimine exhibited favorable pharmacokinetics with rapid absorption and clearance, yet maintained efficacy with alternate-day oral dosing.
- A significant reduction in spinal cord leukocyte infiltration was only achieved with daily high-dose bropirimine.
- Alpha-interferon induction was observed, but its direct role in bropirimine's efficacy remains unclear.
Conclusions:
- Bropirimine is an orally active compound with significant therapeutic potential in the EAE model.
- The drug's efficacy, even with intermittent oral dosing, offers a practical advantage for potential MS therapy.
- Further investigation is warranted to elucidate the mechanism of action and clinical utility of bropirimine for multiple sclerosis.
