Path Rules - Enabled Paths sometime are restricted

I have a problem where programs which are enabled via Path rules sometimes
will still be blocked. The paths are correct and work 80% of the time, but
sometimes you will click and receive the restricted message. Somtimes it
happens to IE, sometimes to an FTP program, sometimes something else. Doing
a GPUpdate/force/reboot solves the problem.... but it might crop up later.

I have seen this problem on both 16 bit and 32 bit applicatiosns. What
should I look for?

Thanks!
.