We proposed to do it two different ways
One was to make the drug water soluble so that it does not pass easily into the brain. Most cannabinoids are fat soluble and so can go through fatty cell membranes and get easily into the brain. This idea was turned down by the granting agencies as being impossible because spasticity has to be controlled within the CNS......, forgetting that Dantrolene works in the muscles..Ugh.
The other idea was to take fat soluble drugs and target to a drug pump in the blood vessels of the brain, which can pump out fatty molecules. One such pump is called p-glycoprotein it stops certain drugs from getting in the brain, it is also upregulated on cancer cells and this is why some drugs don't work. This idea was turned down by the granting agencies as being impossible because spasticity has to be controlled in the CNS.....Doble Ugh
So what do you do...well we started making some drugs with this idea in mind...........and one of them goes first in man in about 2 weeks time!
However, this is a different story and I have to declare CoI for that as that is now company stuff and it turns out that that drug does not work by the mechanism shown here.
There were no known drugs at the time...well we went hunting in the patent data base and found some and got our friendly chemist to make them. We had also unknowingly tested one called CT3 (a cannabinoid without the high) in around 2001, when we we trying to get our idea funded and off the ground.
Having spent a year trying to get hold of the drug to test it for free,without success. The company who owned the drug came to us to do some contract testing.
This work was filed in a patent in 2003 (We are named inventors but we made no money from this and all rights were assigned to the company).
However, the patent was written on toilet paper, because the contents of the work had already been publicly disclosed by the Venture Capital company trying to sell on the rights to another company that filed the patent. This press release was made (unknown to us) in New York on the morning of 11 September 2001, which must be the worse day in history to make any news announcement, especially from New York!
If the information is in the public domain then you are hardly inventing something, so the patent was worthless.
Anyway we found some compounds in the patent literature and one compound SAD448 was reported to be water soluble and 98% excluded from the brain. This was found in the results of patent from one company, linking back to a patent of the chemical for another company. We also found SAB378.
We got compounds made and started to work with them and they both controlled limb stiffness
Anyway move on a few years from the early work and we see a paper from the company that first invented the CNS excluded drugs (SAB378, SAD448) who were reporting that CT3 bound to the cannabis receptor and was largely excluded from the brain and was controlling pain. However, there was a row between the inventor of CT3 and some USA academic scientist. The inventor was claiming that CT3 was a cannabinoid without the high, which was being used in humans to control pain, but the scientist was claiming it was a stimulator of the cannabinoid receptor and caused the adverse effects associated with cannabis entering the brain.
We knew that CT3 and SAB378 where like "brick dust" and would not dissolve in water and were very fat soluble and had a structure that would predict they get into the brain. So we thought they must be pumped out by a drug pump. So we got a drug pump blocker and showed this to be the case. When the drug gets into the brain the mice feel no pain, stop moving and they get cold,
Interestingly, we found that the drug got in the brain of some mice, such as those used by American Scientist but not in others indicating that there was a mutation in a drug pump that stopped the pump working.
Interesting we could track this back probably to the arrival of white lab mice in to the USA that came from Switzerland in 1926. The mutation may have been in one of the two males used for the breeding colony and this causes a loss of function of the normal normal drug pump. Unfortunately we also found that the strains used to make transgenic (129 & C57BL/6) mice also lack an effective drug pump. This solves the Feud about whether CT3 causes a high or not....both people were right.
However it adds a note of caution.
Ivermectin is a drug that kills parasites
and has been used by 40 million humans and 5 billion wildstock. This
drug is pumped out of the brain by a drug pump called p-glycoprotein.
However if it gets into the brains it kills nerves.
Had Ivermectin first been tested in CF1 mice (or Collie Dogs), which both lack p-glycoprotein, it would have killed them or caused neurological problems..then would Avermectin/Ivermectin become a useful drug?
Little white mice (e.g. CD-1, NIH) and transgenic mice are used by drug companies for drug screening and these lack an effective drug pump, which means drugs may have odd absorption and circulation properties.
Have other useful drugs failed the development process because they were tested in mouse strains that lack a drug pump?
Finding the genes that cause this drug pump failure was not the easy task that the genetics said it should be, but we mapped then in genome studies. One of them is called Multidrug resistance protein one or ATP binding cassette C1 (ABCC1) that is present on brain blood vessels.
This and other drug pumps also keep THC out of the brain. Our guess is that people have varying levels of these pumps on the blood vessels of their brains, due to genetics, and this will mean that someone may get very high from a puff of a cannabis cigarette (which we do not endorse), whilst others may not.
Anyway back to the drugs We showed that the three drugs CT3, SAB378 and SAD448 all could inhibit spasticity at much lower doses than caused the side effects (wide therapeutic window) and we showed that if we knocked out the cannabinoid receptor from peripheral nerves, the drugs stopped working so telling us our idea was not stupid and the grant reviewers were wrong.
So know you have cannabis-like drugs without the high (if used in moderation) but the benefit that the cannabinoid system has to offer.
Interestingly all of the drugs above have been used in humans and have passed safety studies, after all they will be safer than cannabis which has global cannabinoid receptor stimulation potential.
Trials could be initiated tomorrow if there was an interest but....they are sat on shelves rotting (their patent life ticking away...and maybe have ticked away....Companies are afraid of the word cannabinoid) as the companies do not want to develop them for MS.
Why so long for the data to surface...lack of funds and don't ask?
Maybe some other companies will take up the gauntlet or maybe a change of heart?
CoI. This work from TeamG