Yale Psychiatry Grand Rounds: November 4, 2022

Transcript

• 00:00Epidemic of fentanyl and
• 00:03stimulated addiction overdose.
• 00:05These are two areas where we are
• 00:08really in need of improved treatments
• 00:10and and we have underserved needs.
• 00:13So with this let me turn it over to Tom.
• 00:15Thank you. Thank you very much, Stephanie.
• 00:18I just wish my mother was still
• 00:20alive so that she could hear that
• 00:22wonderful introduction and say, oh,
• 00:24you finally made it as a doctor.
• 00:28Hello. I have to say her and
• 00:29my grandmother preferred that
• 00:30I would have become a minister,
• 00:32but she can't have everything in life.
• 00:34Closest I got with a psychiatrist.
• 00:37So again, let me move forward with this.
• 00:40I do have a fair amount of stuff I'm
• 00:42going to try to go over and but one of
• 00:44those things I've learned over time
• 00:46is don't get too wedded to your slides
• 00:48that you need to present all of them.
• 00:50So I'll still be mindful of what time it is.
• 00:54This is just a little overview of
• 00:56what I'm going to be talking about
• 00:58today about fentanyl in particular.
• 01:00Uh, these are the disclosures, which,
• 01:03uh, I think the bottom line is that,
• 01:05you know,
• 01:06none of these are have anything to do
• 01:08with vaccines or what I'm talking about.
• 01:10The the people who make a lot of money
• 01:13generally aren't interested in addictions.
• 01:15So that that has been a an advantage
• 01:18and a disadvantage.
• 01:20One of the goals that I'm going
• 01:21to try to do today,
• 01:22I'm going to try to do well
• 01:25before I just get.
• 01:26I mean thank you very much for inviting me,
• 01:28Stephanie and John.
• 01:29I think that that was really a.
• 01:31A nice.
• 01:32I don't know.
• 01:33It always feels good to go back to your
• 01:36old homestead where I've been for,
• 01:38let's say, Stephanie, you asked 27 years,
• 01:40to be exact.
• 01:41I'm working on 16 now here in Texas.
• 01:44So, but I still don't say y'all my kids do,
• 01:47but I don't.
• 01:48As to the goals,
• 01:50we would like to try to describe the
• 01:52ways of the opiate overdose epidemic.
• 01:54There's certainly began with
• 01:56MD's overprescribing opiates.
• 01:58There was then a switch to heroin.
• 02:00There then was a switch.
• 02:01Fentanyl and what's happened most recently
• 02:03is a switch to fentanyl plus stimulants,
• 02:07which has been a significant
• 02:09problem in many ways.
• 02:10I'd like to be sure that we learn
• 02:12some new therapies for cocaine and
• 02:14stimulants including some little
• 02:16bit about pharmacogenetics and about
• 02:18vaccines and then learn why buprenorphine,
• 02:20which is our without a doubt
• 02:22our best treatment for opiates,
• 02:24why it fails to block fentanyl and how
• 02:27an anti fentanyl vaccine can in fact succeed.
• 02:32This is when the the thing started.
• 02:34This is wave one started about 20 years ago.
• 02:37And these are just some
• 02:39quotes from Barack Obama,
• 02:40which was when he was giving his sort of
• 02:44summary of it all ways into the epidemic.
• 02:47They were being described addiction
• 02:49to painkillers as the great threat,
• 02:51as terrorism, which is astounding.
• 02:55That they were seeing more
• 02:56people killed because of the
• 02:57opioid overdose than traffic accidents.
• 02:59They were going to make the government
• 03:02health insurance policies cover mental
• 03:04health and substance abuse on a par
• 03:06with treatment for physical illness.
• 03:08Well, they tried as to a grassroots approach.
• 03:13It was really needed to train physicians
• 03:15while they're still residents and how,
• 03:17when, why to prescribe opiates
• 03:19and and using buprenorphine for
• 03:21treatment of this addiction.
• 03:22So there was this,
• 03:23this is the history that's behind us.
• 03:26Which is summarized by this talk
• 03:29that Barack Obama gave back in 2016.
• 03:32It it did start with opiate over
• 03:36prescription from 1991 to 2013,
• 03:39it went from 76 to 207 million prescriptions.
• 03:43So it it really went up quite a bit.
• 03:46Um, back at around 2013,
• 03:49you were seeing 15 million opiate
• 03:52prescriptions just from primary care alone.
• 03:552,000,000 Americans had
• 03:57prescription opiate abuse in 2013.
• 03:59Physicians were being blamed for the
• 04:01epidemic of opiate addiction as much
• 04:03as individuals who abuse the opiates.
• 04:05Important keep that in mind
• 04:06because that can come up again.
• 04:08The FDA was talking about forbidding the
• 04:11marketing of opiates for chronic pain.
• 04:13Now that obviously never entirely happened,
• 04:15but there was a lot of movement.
• 04:16To do that,
• 04:17and the CDC was going to limit
• 04:19opiates to just three days for
• 04:21short term pain management.
• 04:22Once again,
• 04:23that did not entirely happen,
• 04:26but there was real guidelines for decreasing
• 04:30the amount of opiates being given out.
• 04:34Non medical pain reliever use at
• 04:35that point was 22 million people
• 04:37and you have you know a little over
• 04:39300 million in the United States.
• 04:41Gives you a little sense of how common
• 04:44this was 3,000,000 to use for the first
• 04:46time with the past 12 months that
• 04:48was at that point in aging in 2013
• 04:50you were looking 8000 new users per day.
• 04:54Most of these uh illicit drug users started
• 04:57now at that point with pain relievers.
• 05:00One would never believe that it
• 05:01over did you know marijuana as how
• 05:04people would start using drugs.
• 05:05I mean the the days of heroin were
• 05:08over by that time most of the abusers,
• 05:11which was more 56% of them were
• 05:13younger than 18 and were females.
• 05:15But once again a very different demographic
• 05:17than it had been with heroin use.
• 05:20This is just a little graph of that
• 05:22data that I was telling you about.
• 05:23This is back.
• 05:26From.
• 05:26205 and in fact it only got worse over time.
• 05:29But you can see pain relievers.
• 05:31Pain relievers were the more common
• 05:34initiates for drug abuse than was marijuana.
• 05:37And of course anything else that
• 05:39you can see on this list.
• 05:41And this continued on for a number of years
• 05:44and of course was blamed on many things.
• 05:47And the the Reaper has now hit
• 05:50many pharmaceutical companies where
• 05:51they're getting billions of dollars
• 05:54in settlements that they have to.
• 05:56Hand out.
• 05:57From 1999 to 2014,
• 06:00the opiate overdose deaths were
• 06:03quite profound on this was started
• 06:06with the MD over prescribing,
• 06:08but there was a fourfold increase.
• 06:10The Reds represent high areas of opiate
• 06:13overdoses, the blue relatively lower.
• 06:15Hopefully you can easily see there's
• 06:17a lot more red on the right than
• 06:19there is on the left, and you'll see
• 06:21that there are concentrations of it.
• 06:23The most important concentration that
• 06:25became of interest was in the Midwest.
• 06:28And in the Adirondack, I'm sorry,
• 06:30the Appalachian Mountain area where there
• 06:33was just tremendous amounts of overdoses
• 06:36and deaths from prescribed opiates,
• 06:38mercy, these were not urban areas
• 06:40where they were selling this stuff.
• 06:44All right, so by 2010, the prescription
• 06:47drug epidemic was plateauing 10 to 16.
• 06:50Wave two started of the opioid epidemic
• 06:54as doctors began prescribing less and less
• 06:58and the overdoses from heroin came back
• 07:01again as an issue that plateaued in 2016.
• 07:04And in 2014, wave three of the
• 07:07epidemic started with fentanyl.
• 07:09It rapidly escalate escalated to pass
• 07:11heroin and the prescription drugs.
• 07:14And this fentanyl epidemic continues.
• 07:17What's happened since 2016 is Wave 4,
• 07:19the epidemic and that started
• 07:21with cocaine and amphetamine,
• 07:23with fentanyl being mixed in with these
• 07:26white powders and therefore the combination
• 07:29becoming causes of drug overdose.
• 07:32And this is continued again and escalated
• 07:35and escalated in some rather surprising ways.
• 07:38So this is simply the same
• 07:40kinds of graphs again,
• 07:41the red line or orange.
• 07:44Depending on how color blind you
• 07:47are that's shown on the left is
• 07:49fentanyl going up through the roof.
• 07:51And what you can see on the right is the
• 07:53comparison from 2003 to 2017 and a map
• 07:57that has mostly just sort of Gray in it 2003.
• 08:01But by 2017,
• 08:03the fentanyl deaths have got red
• 08:06areas all over the Midwest being
• 08:08one of the more surprising areas.
• 08:10At least that because that was
• 08:12not from the big cities.
• 08:14Necessarily,
• 08:14these were in fact often rural
• 08:17areas that we're having this
• 08:19fentanyl epidemic of deaths.
• 08:21So what about fentanyl,
• 08:23which is again,
• 08:23this is wave 3 synthetic opiate,
• 08:2750 to 100 times more potent than morphine,
• 08:3030 to 50 times greater than heroin.
• 08:33A lethal dose of fentanyl can
• 08:34be as little as 2 milligrams.
• 08:36It just not take very much,
• 08:38which means that, you know,
• 08:40you can import tiny amounts of
• 08:42this and make plenty of money.
• 08:44Selling it fentanyl analogs range
• 08:45of potency from 15 times more
• 08:48potent than morphine to 10,000
• 08:49times more potent than morphine.
• 08:51That is carfentanyl.
• 08:53And this epidemic again starts
• 08:55at around 2014.
• 08:58So what did we have to treat this?
• 09:00Well,
• 09:00these are the FDA approved treatments.
• 09:02There's the naltrexone and particularly
• 09:04the long acting injectable naltrexone.
• 09:07There's buprenorphine or buprenorphine
• 09:09naloxone.
• 09:10At that point they were initially
• 09:14using the sublingual form that often
• 09:16with the film and then later on of
• 09:19course an injectable became available
• 09:22and methadone which is a full agonist.
• 09:24So this is the three mainstays
• 09:27buprenorphine came the closest to being.
• 09:29Essentially a way that you
• 09:32could combat fentanyl.
• 09:33Fentanyl easily overrides
• 09:35methadone for analgesia,
• 09:36so it was very unlikely to protect
• 09:39against a fentanyl overdose.
• 09:41Buprenorphine may protect against
• 09:42the fentanyl overdose,
• 09:43though clinically the buprenorphine
• 09:46blood level of five nanograms per
• 09:49milliliter was found to prevent
• 09:51respiratory distress from about
• 09:53.7 milligrams of fentanyl.
• 09:56This was in.
• 09:57It's twice the apnea dose
• 09:58in non tolerant patients,
• 10:01so this was this was done in an actual
• 10:03human study that got published however.
• 10:06You've been orphine blood levels
• 10:08at 24 hours after dosing.
• 10:10Assuming you're giving it once a day,
• 10:1216 milligrams of sublingual buprenorphine,
• 10:15which is the usual dose for addiction
• 10:18treatments, produces a level of
• 10:20.67 nanograms per milliliter.
• 10:22You'll notice that that's at least
• 10:2410 fold lower than what you're
• 10:26going to need to block fentanyl.
• 10:28If you give 44 milligrams of buprenorphine,
• 10:31which is above the 24 milligram
• 10:34milligram maximum FDA dose,
• 10:36you still only get up to 1.7.
• 10:38That agreements familiar,
• 10:39so you're still, you know,
• 10:41less than half of what you're going to need.
• 10:43If you give the 300 milligram Suboxone
• 10:46supplicate injectable dose though,
• 10:49you can attain a blood level of 6.54
• 10:52nanograms per milliliter and you could
• 10:54maintain that for about 30 days.
• 10:56This is giving the 300 milligram dose,
• 10:58which is not typical to give
• 11:00that every month, but if you do,
• 11:02you can in fact get close to a level
• 11:04at which you're going to at least
• 11:06block any respiratory distress.
• 11:08From the usual,
• 11:10let's call it therapeutic dose of fentanyl,
• 11:12obviously overdoses are using dosages
• 11:15that are not the therapeutic dose of .7,
• 11:18but are usually twice or three
• 11:21times that dose.
• 11:22So it's still not perfect,
• 11:24but it if you want to get buprenorphine
• 11:26to work the best for fentanyl,
• 11:28this is probably as good as you can hope for.
• 11:31So as the epidemic moves along
• 11:35and wave 42016 which is when the
• 11:38opiates and stimulants.
• 11:39Umm, the red line that I have,
• 11:42as you can see on this graph at the bottom,
• 11:44that's starting to rise and around 2015,
• 11:46that's wave four and wave 4
• 11:49psychostimulants combined with the
• 11:51opiates and that has gone up and up and up.
• 11:54And this data obviously stops at 2019,
• 11:58but the data that comes through with
• 12:012021 with 2022 data not yet being
• 12:04available continues that upward trend.
• 12:09So I think some questions for
• 12:11the physicians to think about,
• 12:13which was something that we,
• 12:15you know, pressed physicians about
• 12:16for the last 15 or 20 years,
• 12:19is our physician prescribers on
• 12:21ethically contributing to the wave
• 12:24four of this ongoing lethal epidemic.
• 12:27They certainly contributed to the
• 12:28first phase of this opiate epidemic,
• 12:31but there's been a market increase in
• 12:34amphetamine prescribing specifically
• 12:35for adult ADHD patients in the past.
• 12:37Five years.
• 12:39The abuse of pharmaceutical
• 12:41amphetamine has become widespread
• 12:42in adolescents and young adults.
• 12:44I'll show you some of that data,
• 12:46and much is from physician prescribing.
• 12:49But recently there have been sales
• 12:51on the Internet and on the street
• 12:54of counterfeit Adderall pills that
• 12:55contain fentanyl at lethal dosages.
• 12:57And about 1/4 to 1/3 of the
• 12:59pills that are on the street,
• 13:01it's because they're it's not that the drug
• 13:04dealers want to have a lot of fentanyl.
• 13:06They want to have enough that you'd have
• 13:08a good time not necessarily to kill you.
• 13:10But their quality control
• 13:13is not exactly precise.
• 13:15This is the adolescent data
• 13:18from 2008 through 2011.
• 13:22The adolescents age 13 to 18,
• 13:25what you can see in 2011 is that
• 13:28the rate of of doctors giving out.
• 13:33Adolescence amphetamines
• 13:34has more than doubled,
• 13:37so that's what that red line is showing.
• 13:39The opiates haven't changed that much and
• 13:41the depressants haven't changed that much.
• 13:43They they're more,
• 13:43more or less flat lines,
• 13:44but going down somewhat.
• 13:46If anything,
• 13:47when you look at the young adults 19 to 25.
• 13:50By 2014, you're seeing a significant
• 13:53divergence that's occurring between
• 13:55prescribing opiates to them and
• 13:57prescribing stimulants to them.
• 13:59It is again,
• 14:00it's reached a plateau again at about
• 14:03the same time as the younger adolescents,
• 14:06but the drop off in the opiate
• 14:09prescription has clearly had
• 14:10a much more traumatic effect.
• 14:12So doctors are prescribing a
• 14:15lot of stimulants and they're
• 14:17out there all over the place.
• 14:21So that's the epidemic stuff.
• 14:23I'm now going to start trying to
• 14:25cover a couple of other things that
• 14:27are I think are important in this.
• 14:29So what about using stimulants
• 14:31for a pharmacotherapy?
• 14:33What kind did you want to use?
• 14:34Well, slow onset and slow
• 14:36release long acting.
• 14:37That would be the qualities you'd like with
• 14:40that kind of a substitution type therapy.
• 14:42I'll then talk a little bit about
• 14:45single gene pharmacogenetics,
• 14:46again in specifics with DOXAZOSIN,
• 14:50which is A1 blocker and the dopamine
• 14:54beta hydroxylase polymorphism.
• 14:56And then finally I'll try to have some
• 14:57time to talk about immunotherapies.
• 14:59With the anti cocaine vaccine and
• 15:02then the anti fentanyl vaccine
• 15:04which we've developed as a.
• 15:07I guess you could say a daughter
• 15:09or a son of that cocaine vaccine.
• 15:11So what about the slow onset and
• 15:13fentanes for stimulant use disorder?
• 15:15Well is a Swedish registry study
• 15:17that was brought to my attention
• 15:19actually by Stephanie and this
• 15:21was in a recent presentation 2022.
• 15:25They did it with lots of patients,
• 15:27you know 14,000 patients that were
• 15:29they had a mean age at 3470% were men
• 15:32and it was during the period from 2006
• 15:34to 2018 and it was a within subjects.
• 15:37Comparing on versus off medications
• 15:41and lisdexamfetamine which is a form
• 15:44of amphetamine that is has to be
• 15:47metabolized before the amphetamine
• 15:49could have its effect.
• 15:50So you're not going to get immediate effect,
• 15:52it's going to be slow.
• 15:53But what they showed were positive
• 15:55outcomes and relative risk for the
• 15:58people who got list Essick phetamine
• 16:00versus those who were given any kind of
• 16:02stimulant and that and what they were
• 16:05looking at was on versus off the medications.
• 16:08What they found was that there was
• 16:11less hospitalization for substance use
• 16:12disorders when they were on the medication
• 16:15then when they were off the medication.
• 16:17Overall there was less of any type of
• 16:20hospitalization when they were on the
• 16:23medication versus off the medication
• 16:25and there was less all cause mortality
• 16:28from the periods when people were on
• 16:30the medication then periods when they
• 16:32were off the medication that that
• 16:35odds ratio obviously relatively large.
• 16:37So that's these are important.
• 16:39Considerations that these treatments
• 16:41can in fact be useful even in
• 16:44substance abusing populations if
• 16:46they're carefully done.
• 16:48What about the randomized
• 16:50clinical trials using stimulants?
• 16:51Have they shown some efficacy?
• 16:53Well,
• 16:54the because this other was of course
• 16:56an epidemiological study from Sweden.
• 16:58The clinical trials,
• 16:59there are reviews of them in 2019
• 17:02and other one in 2016.
• 17:03There are 26 different studies that
• 17:06have been done involving over.
• 17:082000 subjects and what those studies
• 17:12show is that the cocaine abstinence
• 17:16relative risk ratio was 1.36 which is good.
• 17:20I mean it's better than one.
• 17:22And then the necessary number
• 17:24to treat of patients,
• 17:25you treat 14 patients to expect
• 17:27to get one of them that might
• 17:29have a positive response to this.
• 17:31So if it's still that that's not a, you know,
• 17:33number needed to treat is not great,
• 17:35but it indicates that there can
• 17:37in fact be a role for these.
• 17:39Slow onset look much lower.
• 17:42Abuse liability stimulants,
• 17:44the short onset ones,
• 17:46which is what the patients want,
• 17:48not so good.
• 17:50So I've tried to cover a balanced view of,
• 17:53you know, how stimulants can be used,
• 17:55but they have to be used very carefully.
• 17:57They're clearly a very useful treatment
• 18:00for attention deficit disorder.
• 18:02But a lot of people with
• 18:04attention deficit disorder,
• 18:04when they develop it somehow at age 25,
• 18:07and they now want, you know,
• 18:09methamphetamine to or
• 18:10amphetamine to treat it,
• 18:12one should be a little suspicious.
• 18:15So now let's shift to a
• 18:17totally different thing,
• 18:18which is let's talk about pharmacogenetics.
• 18:20This is one of my interests.
• 18:23This will be with Doxazosin,
• 18:24which is an A1 blocker.
• 18:26And the polymorphism that I'm looking
• 18:28at is dopamine beta hydroxylase,
• 18:30which is a gene that converts
• 18:33dopamine to norepinephrine.
• 18:34This is just a little picture of that.
• 18:36So you're seeing dopamine and norepinephrine,
• 18:38and this is the enzyme that
• 18:42makes that conversion possible.
• 18:43And so if you have very
• 18:46little of that enzyme,
• 18:48you're going to have dopamine
• 18:50released from norepinephrine
• 18:51neurons instead of norepinephrine.
• 18:53And if you have a lot of that enzyme,
• 18:55you're going to convert a lot
• 18:57of things to norepinephrine.
• 18:58Now, clearly not out of the dopamine neurons,
• 19:00because the dopamine neurons
• 19:02themselves don't contain this enzyme.
• 19:04It's in the norepinephrine neurons.
• 19:07And norepinephrine, by the way,
• 19:09is part of a reinforcing system also,
• 19:12and it can, and it of course contributes to.
• 19:16Craving and stress induced reinstatement.
• 19:21So there's a genetic variant
• 19:23of this particular gene,
• 19:25and it's the location is
• 19:29in fact before the actual.
• 19:32Gene itself that codes for the protein,
• 19:35so it's a regulatory polymorphism.
• 19:38It's in the promoter region,
• 19:40it's critically involved in
• 19:41the activity of DBH.
• 19:43There's a total of about 6 mutations
• 19:45that have been found to cause this
• 19:48DBH deficiency and the normal,
• 19:50which is ATT,
• 19:52produces about 100 times more
• 19:54norepinephrine than if you have one of
• 19:57these polymorphisms and the the CC and
• 20:00this particular one is the one that.
• 20:02This is the lowest levels,
• 20:03but it's also the most common.
• 20:05And it's been linked to a range
• 20:08of psychiatric disorders,
• 20:09from psychosis to conduct disorders.
• 20:11It's one of the genetic polymorphisms
• 20:13that's probably been the most widely
• 20:16studied in psychiatry for 30 years.
• 20:18So we looked at a drug, doxazosin,
• 20:21for cocaine abuse and found
• 20:23that indeed that the placebo,
• 20:25which you can see in the solid line,
• 20:28if anything there, cocaine use is going up.
• 20:31And the people who got the ducks.
• 20:32Places in there, cocaine use is going down.
• 20:36This is a profound effect.
• 20:38Of course not.
• 20:39We we have very few medications in
• 20:41cocaine abuse that produce profound effects.
• 20:44But you're getting about a 25%
• 20:47difference between the placebo
• 20:49and the active medication,
• 20:51and it's fairly sustained after the 5th week.
• 20:55And let's see next one.
• 21:00So we then looked at these genetic
• 21:03polymorphisms, that is, you know,
• 21:04how much of the enzyme was actually
• 21:07there and did that have an effect?
• 21:09Well, what's shown at the top is the
• 21:12one the people that have the genetic
• 21:15polymorphism that in general would
• 21:17produce lower levels of norepinephrine.
• 21:20And what we found is with these lower levels,
• 21:23there really was no significant
• 21:25difference between the placebo
• 21:27and the active medication.
• 21:29On the other hand,
• 21:30shown in the bottom there,
• 21:31which is the people that had this
• 21:34polymorphism and therefore had a
• 21:36reduction in the amount of genetically
• 21:38produced norepinephrine that their
• 21:40cocaine use significantly dropped
• 21:43over the 12 weeks of the trial and
• 21:46was in fact showing drops as you
• 21:48can see beginning at about week five
• 21:51or six and continuing to go down
• 21:53while the placebo group really just
• 21:55bounced around and if anything,
• 21:57increasing their cocaine use.
• 21:59So that the positive urns
• 22:02are reduced about 40%.
• 22:04From the baseline in these people
• 22:06that had this genetic polymorphism,
• 22:08we then you know repeated this
• 22:10in a couple of other studies.
• 22:13So it looks like it's something there.
• 22:15I didn't bring the data along to show you,
• 22:17but we've also found that a polymorphism
• 22:20in the alpha noradrenergic receptor
• 22:22which leads to less sensitivity and
• 22:25or difference in sensitivity in that
• 22:28receptor that that's also associated with
• 22:30response to this blocker that that is.
• 22:34The AA1 blocker and those,
• 22:38the DBH and that other polymorphism
• 22:42in the receptor for norepinephrine
• 22:44that they do act together to have a an
• 22:48additive effect in reducing cocaine use.
• 22:50It's it's unfortunate.
• 22:52It's been hard to convince that the
• 22:55powers to be that Pharmacogenetics
• 22:57has any role for substance abuse,
• 23:00but we've found it with a variety of drugs.
• 23:02This is for cocaine.
• 23:04So there's a pharmacogenetic
• 23:06hypothesis that I hope is obvious
• 23:08from this that the DBH is converting
• 23:10dopamine to norepinephrine.
• 23:12And then with Doxazosin which is
• 23:15actually blocking the A1 receptor,
• 23:17that if there's less norepinephrine there
• 23:21that we find that in fact the block by
• 23:25doxazosin then has a more profound effect.
• 23:28And this is again I think.
• 23:32A function that makes at least some
• 23:35sense that the doxazosin would work
• 23:38better in the cocaine use puppet patients
• 23:42that have this polymorphism that they're.
• 23:45Norepinephrine levels are
• 23:46in fact it says higher GPH.
• 23:49That's that that's not true.
• 23:52Lower TBH and it's and they're norepinephrine
• 23:54levels would be therefore lower,
• 23:56and therefore blocking it with Doxazosin
• 23:58would probably be much more effective.
• 24:03All right. I'll see if I can manage
• 24:04to have a couple of other slides
• 24:06where I write the stuff correctly
• 24:07and that is we're now going to talk
• 24:09about the immunotherapies which is
• 24:11the anti drug vaccines to protect.
• 24:14Really to prevent overdose is what
• 24:15we're thinking about and how that
• 24:17mechanism of action might work.
• 24:19And we're going to start with the
• 24:21cocaine because we've done a lot of work
• 24:23with the cocaine vaccine in general.
• 24:26We've been using a variety of different
• 24:29proteins as carriers because the drugs
• 24:32of abuse are too small to induce
• 24:34a an action of making an antibody.
• 24:37So that we've been recently using
• 24:41cream which is derived from.
• 24:44Let's see, diphtheria toxoid,
• 24:45but we've also used cholera toxoid,
• 24:47tetanus toxoid.
• 24:48And this cram is one that's been
• 24:51used in vaccines by Pfizer and GSK.
• 24:54So it's got a lot of safety data on it.
• 24:57And the fentanyl can be attached
• 24:59to the code by either succinyl
• 25:01linkages or glycerol linkages.
• 25:03And it attaches to what are the
• 25:0512 lysine amino acids on the
• 25:08outside of the creme protein.
• 25:10With tetanus,
• 25:10there's many more lysines on the outside.
• 25:13Tetanus is a much bigger protein.
• 25:15But Cream is a much cheaper protein
• 25:18in terms of using it as a carrier.
• 25:21So we're looking to make
• 25:23inexpensive versions of vaccines,
• 25:25and this is how they work.
• 25:27If you give the drug ordinarily,
• 25:29you take your drug of abuse,
• 25:30it concentrates in the brain because
• 25:31there are receptors in the brain
• 25:33for it to bind to give the vaccine.
• 25:35The vaccine makes these antibodies
• 25:36that stay in the bloodstream.
• 25:38They don't go into the brain.
• 25:40And so when you then take the
• 25:41drug plus you have the vaccine
• 25:44there already with the antibodies.
• 25:45You keep the drug in the bloodstream.
• 25:48Some of it gets into the brain,
• 25:50but in fact if you had a higher
• 25:52concentration in the brain,
• 25:53the antibodies would pull the drug
• 25:55out of the brain and into and onto the
• 25:58antibodies where they then circulate.
• 26:00And the cocaine or whatever the drug is,
• 26:04is eliminated through liver
• 26:06metabolism and also in the urine.
• 26:10You didn't like that particular picture,
• 26:12how it's working.
• 26:13Here's another picture of how it might work.
• 26:15And this is particularly
• 26:18relevant to monoclonals.
• 26:20For a monoclonal against fentanyl
• 26:25or against cocaine or whatever,
• 26:26they would actually pull the
• 26:28drug out of the brain.
• 26:29And so this could be a very
• 26:33rapid overdose treatment.
• 26:34And by injecting,
• 26:35but you'd have to inject the
• 26:37monoclonal into the person,
• 26:39there are some monoclonals.
• 26:41That can be given subcutaneously.
• 26:43That have been developed for Alzheimer's
• 26:45disease and they're ones that even
• 26:47look like you can give them orally,
• 26:49but obviously if someone's passed
• 26:52out you would probably give them
• 26:55by injection and subq as possible.
• 26:57So these are competitive antagonists.
• 27:00So can someone smoke enough
• 27:01to overcome these vaccines?
• 27:03Well, yes, they can,
• 27:04but it would take some effort.
• 27:06This is not someone who's taking the vaccine,
• 27:09obviously, but someone with a stunt.
• 27:11You'd have to,
• 27:12you'd have to take a lot of cocaine in,
• 27:14and in particular fentanyl,
• 27:16which we're going to get to.
• 27:17You really have to take
• 27:19massive amounts of fentanyl,
• 27:20which is not going to happen.
• 27:22So that's why with cocaine,
• 27:24we never could get it to work that well.
• 27:26And I'll show you some of those.
• 27:27Data because people take in so
• 27:30much cocaine compared to the
• 27:32amount that's taken in a fentanyl.
• 27:35So what are the?
• 27:36These cocaine vaccines look like,
• 27:39well pharmacologically they looked
• 27:40sensible and that if you had
• 27:42a high antibody which we could
• 27:44develop by giving a larger dose
• 27:46of the vaccine or low antibodies
• 27:48from a lower dose of the vaccine.
• 27:51You would find that the blockage,
• 27:53which of the cocaine and then
• 27:55we gave either 25 milligrams
• 27:57or 50 milligrams of cocaine.
• 27:59This was smoked cocaine.
• 28:01And you could get an 80% blockage.
• 28:04So what is the the purple
• 28:06versus the Gray or not Gray?
• 28:08I guess brown blocks or bars there
• 28:11illustrate how much of a high you got
• 28:14or a whole different set of ratings,
• 28:16good drug effect.
• 28:17In this particular case,
• 28:19you get an 80% reduction.
• 28:20So the the purple was that week
• 28:23three before we had vaccinated,
• 28:25week 13 was after we had put in
• 28:27three vaccinations into the people.
• 28:29If you then doubled the dose of cocaine,
• 28:31which is shown again.
• 28:32On this left side, you get a 50% reduction.
• 28:35If you had a low level of antibodies,
• 28:37you only got a 23% reduction with
• 28:39the 25 milligram dose of cocaine,
• 28:42and if you doubled the dose of cocaine,
• 28:43you only got a 13% reduction.
• 28:45Neither of those were statistically
• 28:48significant.
• 28:48Both of them were significant
• 28:50though at the high antibody levels,
• 28:52which simply meant giving a
• 28:54high dosage of the vaccine.
• 28:56So this was good pharmacological
• 28:59demonstration of dose response effect.
• 29:02So how did this turn out when we did the
• 29:05randomized controls outpatient trials,
• 29:07I'm not going to review
• 29:08these studies in any detail,
• 29:10but these are double-blind
• 29:12placebo-controlled.
• 29:12We vaccinated without actually 5 dosages
• 29:14of the vaccine over a 12 week period.
• 29:17We did urine toxicology.
• 29:18We measured antibody levels and
• 29:21we had calculated that a single
• 29:23cocaine dose could probably be
• 29:25blocked by 20 micro 20 micrograms per
• 29:28milliliter of antibody and we could
• 29:31block probably 3 doses of cocaine.
• 29:33Um, with 42 or more,
• 29:35because that was blinding about
• 29:3780% of cocaine by our calculations.
• 29:42Well,
• 29:42what happened was only a third of the
• 29:44people reached our threshold of 43
• 29:47and that's what's shown in blue here.
• 29:49And what you can see is as we
• 29:52repeatedly immunized them over
• 29:53the first looks like 16 weeks
• 29:55but was actually only 12 weeks.
• 29:57The antibody levels steadily rose
• 29:59and then the antibody levels
• 30:01steadily go back down again but
• 30:03for the people in the high.
• 30:06Antibody group,
• 30:07their average antibody levels
• 30:09by week eight were in fact up
• 30:12above 40 and they stayed up
• 30:14above 40 out to week 24,
• 30:15which would be six months,
• 30:17which meant about three months of
• 30:19protection you could get and then
• 30:21you'd have to give a booster and we
• 30:23did give boosters to a number of
• 30:25these patients and a single booster
• 30:27would push their antibody levels back
• 30:28up to the peak that they had before.
• 30:31So you'd probably be with this vaccine
• 30:33be giving it to responders about.
• 30:36Every three to four months,
• 30:37the newer vaccines we've got now,
• 30:39it looks like we can go six
• 30:42months between vaccinations.
• 30:43But you can see you're looking
• 30:45at 2/3 of them.
• 30:45That didn't make it at all
• 30:48as far as what you needed.
• 30:50So we then looked at these three groups,
• 30:52the people who got the placebo,
• 30:53the people who had the low levels
• 30:55of antibodies and the people
• 30:56that had the high levels of the
• 30:57levels that we thought you need.
• 30:59And what we found is the proportion
• 31:01of drug free urones during the period
• 31:04of weeks 9 to 17 versus the baseline
• 31:06period that there was a 2 1/2 fold
• 31:09reduction in cocaine use for the
• 31:11people that had attained our levels.
• 31:13For those that didn't attain them,
• 31:15which was you know, 60% of the vaccinated,
• 31:18they got some reduction.
• 31:201 1/2 or so,
• 31:2150% reduction and the placebo
• 31:23really didn't show any change
• 31:24from what the baseline was.
• 31:26So this was a nice gun stair
• 31:27step dose response kind of thing.
• 31:29Also not enough to convince the
• 31:31FDA that this was useful,
• 31:33but enough to give us money
• 31:35for another study.
• 31:36And this was looking at all the
• 31:39different levels of antibody
• 31:40that we had in the study versus
• 31:43the percent of cocaine urones.
• 31:45And we found you could reach a
• 31:47level of antibody at which people
• 31:50just simply stopped.
• 31:51Using cocaine altogether because it wasn't.
• 31:53They didn't have enough money
• 31:55or it just wasn't worth it.
• 31:56When we asked them why did they stop,
• 31:58they said, well,
• 31:58they just couldn't find a good enough dealer,
• 32:00so nobody seemed to believe
• 32:02that the vaccine did anything,
• 32:04even though when we asked them
• 32:06who thought they got the vaccine,
• 32:0880% of the people thought they
• 32:10got the active vaccine,
• 32:11even though only 50% actually did.
• 32:14I think that was because our
• 32:16placebo had some alum in it and
• 32:18the alumnae your arm hurt,
• 32:19so they assumed that was the real thing.
• 32:23So what do we conclude?
• 32:24That the vaccine was better than a placebo,
• 32:27that the cocaine free Urnes increased
• 32:29as the antibody levels increased.
• 32:3140% of the patients had
• 32:33effective antibody response.
• 32:34That's 40% of vaccinated.
• 32:36It was medically safe.
• 32:37There was increases in cocaine
• 32:39use above baseline levels that we
• 32:42could find intermittently in their.
• 32:44There are benzoylecgonine,
• 32:45well urine levels where we found
• 32:47a number of people that had urine
• 32:50benzoylecgonine levels that if
• 32:51they would not been vaccinated
• 32:53they probably would be dead from
• 32:55an overdose at least would have
• 32:58been seriously damaged by it.
• 32:59But they in fact describe
• 33:01really no effects at all.
• 33:03A few people described that their heart
• 33:05went pitter patter a bit but very
• 33:07unimpressive as far as they were concerned.
• 33:10So this LED us to a multi
• 33:12site cocaine study it was.
• 33:14National study.
• 33:17OK.
• 33:17Basically the same dosage of the vaccine,
• 33:20the urine toxicology was 300
• 33:22outpatients and we measured
• 33:23the same kind of outcomes and
• 33:25unfortunately got the same kind
• 33:27of outcome from the vaccine,
• 33:29which is if you're looking at 40,
• 33:31we at best did that.
• 33:33We got maybe half of them,
• 33:34but some of them now because
• 33:37we rejuvenated the vaccine,
• 33:39we we made new batch of it got up
• 33:42to antibody levels of over 250,
• 33:44which is astounding so that there's quite a.
• 33:48Quite a amount of antibody that
• 33:50can be produced in some people,
• 33:52and the trick of course is to either
• 33:54get everybody to move up there or
• 33:56to be able to select ahead of time
• 33:58which people are not going to respond.
• 34:02Well, what we did find is, again,
• 34:03this is just the average data from the study.
• 34:07And 59 was our average of
• 34:10peak effect at week 16,
• 34:12which was better than in the other study.
• 34:14There was no simple correlation
• 34:16this time with the antibody
• 34:18levels with cocaine for urones,
• 34:19although we just published a paper
• 34:22that this was looking at IG levels
• 34:25and we had a paper in nature vaccines
• 34:28at the beginning of this year showing
• 34:30that it looks like it's IGA, not IG.
• 34:33That's really important.
• 34:34And part of that is because IGA,
• 34:36that type of antibody,
• 34:38not only lines mucous membranes,
• 34:40it also lines the blood brain barrier.
• 34:44And so what's happening it looks
• 34:46like is that the cocaine or that
• 34:49we don't have it for fentanyl.
• 34:50Yeah, actually we do in the
• 34:52animals for fentanyl,
• 34:52it's it's binding to the drug as
• 34:54it's trying to get into the brain,
• 34:57which is fantastic because now
• 34:59what we've been chasing after is
• 35:01adjuvants that will increase the
• 35:02amount of IGA being produced.
• 35:04And we so we duplicated this,
• 35:07started the,
• 35:07the mouse finding that was in nature.
• 35:10We then just duplicated it in a
• 35:12rat study and this was we went
• 35:14back and reanalyzed this study.
• 35:16I found the same thing was true in humans.
• 35:19So this is very encouraging and an
• 35:22exciting discovery that IGA is in
• 35:24fact maybe the way this is working
• 35:26and there are some adjuvants,
• 35:28particularly some that could be
• 35:30given intranasally or orally that
• 35:33will markedly increase mucosal IGA.
• 35:35They're,
• 35:36they're being developed for COVID
• 35:38vaccines at the moment and that's,
• 35:41you know, as if I have nothing else to do.
• 35:43We actually have a COVID vaccine
• 35:45that we've come up with too.
• 35:46That's some.
• 35:47Again,
• 35:47focuses on this kind of IGA idea anyway.
• 35:51So what did we find in it?
• 35:53There was better treatment retention
• 35:55if you got these higher antibody levels.
• 35:57Three times more participants had
• 35:59at least two weeks of abstinence
• 36:00if they had these higher levels
• 36:02than either the placebo or the low.
• 36:04And there were more cocaine for
• 36:06urones compared to baseline.
• 36:08But neither are investors nor the
• 36:10FDA were impressed with these data.
• 36:12They said, you know,
• 36:14everybody you vaccinate has to
• 36:15show a good response or it's a.
• 36:17Lousy vaccine that led to all of the
• 36:22major pharmaceutical companies who
• 36:23got similar results with nicotine
• 36:25from dropping out from the field.
• 36:27And this is a while ago.
• 36:29So did we learn something from these studies?
• 36:32Yeah,
• 36:32we changed our protein carrier from
• 36:34cholera B to a better protein.
• 36:36We got a better agent.
• 36:38We started using a TLR four and
• 36:41five adjuvants.
• 36:41These are toll like receptor
• 36:44type adjuvants and agonists that
• 36:47push these systems.
• 36:48And that we really needed to get
• 36:50more patients who attain these
• 36:52higher antibody levels and it
• 36:54would be better to get patients
• 36:56who at least can become abstinent
• 36:58before we start trying to vaccinate
• 37:00them so they have a
• 37:01little motivation to want
• 37:03to become abstinent.
• 37:04And again, with fentanyl,
• 37:06we need much less antibody.
• 37:08So what's happening?
• 37:10Why is the fentanyl epidemic turned into?
• 37:14Stimulant epidemic well,
• 37:15stimulants have limited
• 37:17lethality compared to fentanyl.
• 37:19I mean, it's hard to die.
• 37:21I don't shouldn't say hard,
• 37:22but deaths from just cocaine
• 37:25or methamphetamine are not that
• 37:28common compared to fentanyl.
• 37:30The abusers had returned to stimulants,
• 37:33including amphetamines that were
• 37:35obtained from prescribers and in
• 37:37cocaine bought from the street.
• 37:39Because people were recognizing
• 37:40that taking opiates you were taking
• 37:43a big risk with the fentanyl.
• 37:44That's almost always an opiates now.
• 37:47So the distributor started mixing
• 37:49fentanyl with the stimulants like
• 37:50cocaine powder and methamphetamine.
• 37:52Why did they do that?
• 37:54You could take very inexpensive,
• 37:56crappy cocaine and methamphetamine and
• 37:58put a little bit of fentanyl in it,
• 38:01and it feels like it's a great drug,
• 38:02apparently to the patient,
• 38:04so that they're not patients
• 38:05but people on the street.
• 38:06So that's the reason to put fentanyl in.
• 38:08And fentanyl, of course,
• 38:09a little bit of it goes a very long way,
• 38:12so your marketing becomes
• 38:14much more profitable.
• 38:16Then, early in 2021,
• 38:18counterfeit Adderall pills
• 38:19containing fentanyl began to appear.
• 38:22And this is a.
• 38:23Big problem.
• 38:24In March of 2021,
• 38:26the DEA had seized 600,000
• 38:28counterfeit pharmaceutical pills.
• 38:30They all contain fentanyl.
• 38:33All of those at that time
• 38:34were being sold as Adderall.
• 38:35But there's now also been evidence that
• 38:38it's in Percocet and that it's also in Xanax.
• 38:41One in four of these pills had
• 38:44lethal fentanyl overdoses in them.
• 38:45Now that was not purposeful
• 38:47on the distributors part.
• 38:48There's no point in killing your
• 38:51customers but this new rising.
• 38:54Mortality from stimulants is due
• 38:55to the fentanyl disguised as a
• 38:57stimulant or mixed with the stimulant.
• 39:00The stimulant mortality rate with
• 39:02this is now rising at twice the
• 39:04opiate mortality rate due to just
• 39:06the fentanyl adulteration of heroin.
• 39:09Amphetamines fourfold mortality
• 39:10rise only required five years
• 39:13versus for the opiates.
• 39:15With fentanyl it took ten years
• 39:17to get this fourfold increase.
• 39:18So the the the path of the epidemic
• 39:21is now much more much steeper.
• 39:24And much more dangerous.
• 39:28This is what the counterfeit pills look like.
• 39:31The authentic oxycodone,
• 39:33the counterfeit one on the bottom
• 39:36in the middle is the Adderall.
• 39:39Adderall is the the real thing on the
• 39:42top and the counterfeits on the bottom.
• 39:45If anything, the counterfeit pill
• 39:46looks like it's cleaner and nicer and,
• 39:48you know, Oh yeah, I'd rather have that more.
• 39:51And it's got a 30 on instead of 20,
• 39:53so it must be a more potent pill.
• 39:55Xanax, the same thing.
• 39:57That's the other counterfeit
• 39:58and the real one that.
• 40:00These are being, you know,
• 40:02distributed on the streets
• 40:04and on the Internet sites,
• 40:07virtually on the Internet sites,
• 40:09any of the the dark Internet
• 40:11for Adderall at least,
• 40:12is Adderall with fentanyl.
• 40:13Virtually none of them now,
• 40:15or just really Adderall.
• 40:17So this has become extremely big
• 40:20problem. And what's the problem
• 40:21is that if we as doctors are
• 40:24prescribing Adderall, you know,
• 40:25like water and that is happening with kids,
• 40:29this is going to be a problem.
• 40:30Because when you take the drug and you
• 40:33take it and then a way to get high,
• 40:35you're going to have to take escalating
• 40:37dosages and those escalating dosages.
• 40:39Sooner or later the doctor is going to say,
• 40:42no, I'm not going to give
• 40:43this to you anymore.
• 40:44The doctor shopping may work or may not work,
• 40:46which means you go to several different.
• 40:48Not just to get it,
• 40:49but sooner or later you're going to turn
• 40:50to either the Internet or the street
• 40:52and you're going to be getting you.
• 40:54I say you in a very general sense that the
• 40:56abuser is going to be getting Adderall,
• 40:58it's got fentanyl in it and that
• 41:01fentanyl has got a one in four
• 41:03chance is going to be a lethal dose.
• 41:06So fentanyl vaccine that's
• 41:08in current development,
• 41:10we're trying to apply the
• 41:11discoveries from an improved cocaine
• 41:13vaccine to the fentanyl vaccine.
• 41:14We've been working on this for a
• 41:16few years now and this was from the
• 41:20paper that was in nature vaccines
• 41:23and this is a very complicated slide
• 41:25that's got much more information
• 41:27than you really need to know,
• 41:29but if you look at.
• 41:31The C&D,
• 41:33and you look at the one,
• 41:35the the bars that are purple and the
• 41:38bars that are dark blue all the way
• 41:40to the right on all of these four
• 41:42different graphs that are shown there.
• 41:44This is what's happening if you
• 41:47give fentanyl to mice that have
• 41:50been vaccinated or not vaccinated.
• 41:53The clear bar is the naive mice
• 41:55that have not been vaccinated,
• 41:57and the blue and the purple bars
• 42:00are to the mice.
• 42:01That have been vaccinated and given fentanyl.
• 42:05Now the fentanyl dose on the far left
• 42:08bottom which is the C part that's 30
• 42:11micrograms per kilogram that is a you
• 42:14might call a therapeutic dose of fentanyl.
• 42:17The 100 micrograms per kilogram which
• 42:19is the next set of bars over is in
• 42:22fact the lethal dose of fentanyl and
• 42:24what you can see is that the the
• 42:27blocking of of pain from that 100.
• 42:31Who is complete?
• 42:32When you have the naive mice that
• 42:36you just you, you can't get,
• 42:38you know, you don't feel any pain.
• 42:40I guess that's one way to put it
• 42:42before you die on the blue bar,
• 42:45blue and purple bars.
• 42:46Those are with the vaccination with.
• 42:49I'm not gonna go into the two different
• 42:52types of adjuvants that we have,
• 42:54the DLT and the LTA,
• 42:56only to tell you that the LTA 1 adjuvant
• 43:00is the one that produces much more IGA.
• 43:03And it's very clear from this making
• 43:06more IGA is what's the key to success.
• 43:10So the left,
• 43:11so the C's are the tail flick,
• 43:13the D's or the is the hot plate
• 43:15measure in these mice and it
• 43:17shows exactly the same sorts of
• 43:19things, the hot plate,
• 43:21perhaps more graphically,
• 43:23that the vaccines are really
• 43:25knocking down fentanyl's ability.
• 43:29To act as an analgesic
• 43:31and which is, you know,
• 43:32that's the simplest test one can do.
• 43:35So that's mostly what this
• 43:37slide shows in the mice.
• 43:39We then looked at the brain levels
• 43:41also and what you can see on the left
• 43:43or the brain levels of fentanyl,
• 43:44and on the right of the
• 43:46blood levels of fentanyl.
• 43:48The open bar is the one that's
• 43:51got the naive mouse, the dock,
• 43:54the blue and purple bars are the
• 43:57ones that have the vaccinated.
• 44:00And what you find is very little
• 44:03fentanyl is getting in the brain now,
• 44:06yet if you look in the bloodstream,
• 44:09a lot of fentanyl is getting in the brain.
• 44:11So it's going from about 10 nanograms per
• 44:15milliliter in the blood up to about 130,
• 44:18a 100 or I'm sorry about 170.
• 44:21So we have clearly gotten the fentanyl to
• 44:24stay in the blood and not go into the brain.
• 44:27The brain levels,
• 44:28I hope you can see are virtually 0.
• 44:31So this is a big success.
• 44:34We then also looked at the type of antibody
• 44:38and this is with the anti fentanyl, IGA.
• 44:43What's on the left is the brain levels.
• 44:45The brain levels of,
• 44:49of and of the.
• 44:52The IG let's see the brain levels of the
• 44:56fentanyl with the anti fentanyl vaccine.
• 44:59The bigger the concentration of
• 45:02that antibody is which is what's
• 45:05the the collection of diamonds and
• 45:08and triangles that are up in the
• 45:11left hand corner on the left side.
• 45:13That's the antibody there and
• 45:17you're looking at the.
• 45:20The anti fentanyl antibody and
• 45:22the amount of IGA as the brain.
• 45:25Fentanyl is it.
• 45:27As it is. Uh,
• 45:28those levels are going down of the antibody.
• 45:32The brain levels of fentanyl are going up.
• 45:35I said that that's all that
• 45:37that's this is trying to show.
• 45:38It's just it,
• 45:39it would be a,
• 45:40it would be a line except that
• 45:41we really just have two clusters.
• 45:43You either knock the fencing all out
• 45:45completely from getting into the brain
• 45:47or it completely gets into the brain.
• 45:48There's just you know nothing in between.
• 45:51We then looked at tail flick also and
• 45:53found the same association that when you
• 45:56have had these higher levels of the antibody,
• 45:59the anti fentanyl,
• 46:00IGA,
• 46:01the tail flick doesn't occur,
• 46:03although there there were a few exceptions.
• 46:05Of animals that we're still getting
• 46:08some tail flicker effect that is
• 46:10because the tail flick also involves
• 46:12spinal cord reflexes and we're not
• 46:14clear that this actually keeps fentanyl
• 46:17completely out of the spinal cord in some,
• 46:19some animals will, but.
• 46:23So this is brain levels and pain.
• 46:26This is a rat study.
• 46:28This in the RAT study is what we're
• 46:31looking at is will rats self administer.
• 46:35The fentanyl and what you can show is
• 46:38that on the far left with no vaccine,
• 46:41yes, the the rats will,
• 46:43you know,
• 46:44knock at the bar a million times to
• 46:46get the fentanyl and as you push the dose up,
• 46:49you know they get pushed the bar more.
• 46:53Once you vaccinate them though,
• 46:55you just completely knock out that ability.
• 46:59We also looked at it in combination
• 47:02with buprenorphine because we wanted
• 47:04to be sure that we weren't decreasing
• 47:06the efficacy of buprenorphine.
• 47:09And what we found is that no,
• 47:10we did not decrease the
• 47:12efficacy of buprenorphine.
• 47:13If anything, it's enhancing some
• 47:14of the efficacy of buprenorphine,
• 47:16which we're a little puzzled by,
• 47:18but you know that's OK.
• 47:21This is a high dose fentanyl and lethality,
• 47:24this is in the rats.
• 47:26Hopefully you can see that on
• 47:28the right side of this slide.
• 47:31That's not what a rat should look like
• 47:33that's that's rigor mortis in the rat.
• 47:34They are basically stiff.
• 47:36They are basically dead from that
• 47:39dose of fentanyl on the left or the
• 47:41mice that were vaccinated and given
• 47:43the same dose of fentanyl hopefully
• 47:46you can tell that they're you know
• 47:48they're they're walking around and
• 47:49they look fine and they are you
• 47:51would not be able to hold them stiff.
• 47:53The way you can on the right side picture,
• 47:55so this vaccine,
• 47:57we've also measured respirations in
• 47:59the rats and the the respirations
• 48:02basically go down to 0 if you
• 48:04don't have the vaccine and if you
• 48:06do they don't change at all.
• 48:10So who should take the fentanyl vaccine?
• 48:13What's the target patient population?
• 48:15Well certainly treatment seeking
• 48:17opioid who are inevitably fentanyl
• 48:20users maintained on buprenorphine,
• 48:22they clearly want treatment because but
• 48:25people morphine doesn't block fentanyl and
• 48:28so they all of them should be vaccinated.
• 48:31What about stimulant and benzodiazepine
• 48:33users because of this adulteration
• 48:36with fentanyl which is driven
• 48:38by St rebranding of fentanyl?
• 48:39Is a dangerous drug so that you know
• 48:42people don't want to take fentanyl
• 48:43and there's been an increased use
• 48:45in stimulants and the much lower
• 48:47production and shipping cost of fentanyl.
• 48:49We think the stimulant and benzodiazepine
• 48:52abusers ought to be given some,
• 48:53particularly the stimulant users
• 48:55vaccinations for anti fentanyl
• 48:57because they're going to die from it.
• 49:00So we think there's a broad need for
• 49:02this overdose and relapse prevention
• 49:04vaccine beyond opioid users and
• 49:06whether it's going to extend into
• 49:08benzodiazepine abusers and virtually.
• 49:10Anything else will depend upon
• 49:11how the marketing goes with the,
• 49:14you know,
• 49:14the cartels in Mexico and the producers
• 49:17in China who are sending it here.
• 49:21Just a quick little summary of
• 49:23what I've tried to go over that
• 49:25the opioid overdose epidemic,
• 49:27it started with I think what I would
• 49:30consider unethical prescribing of opiates,
• 49:32the MD's are over prescribing opiates
• 49:34that led to the illicit fentanyl.
• 49:36It was something driven by a
• 49:38lot of pharmaceutical companies.
• 49:39There are pharmaceutical companies,
• 49:41I can tell you that are driving people
• 49:44to prescribe much more stimulants
• 49:45than they used to prescribe.
• 49:47Why? They're saying it's great
• 49:49for ADHD and adults.
• 49:51Even adults that didn't seem to
• 49:53have it as kids that it's in,
• 49:55kids that the diagnosis has
• 49:57been markedly increased,
• 49:59and there the kids are given.
• 50:02As I showed you from the data,
• 50:04you know early on these early adolescents
• 50:06are being given more substantial four
• 50:09times the amount of amphetamine or
• 50:11what they than they used to be given.
• 50:14So this is.
• 50:14And this is wave four and I think we
• 50:17have to be very careful as physicians
• 50:19that we don't get somehow blamed for
• 50:22this epidemic that this is our doing.
• 50:24And I'm afraid it's it's not
• 50:26necessarily coming from psychiatrist
• 50:28it's coming from pediatricians and
• 50:30it's coming from internists who are
• 50:32or or general practice doctors who
• 50:34I see in Texas all the time that
• 50:36are thinking that they see ADHD
• 50:38in adults and they say Oh yeah,
• 50:41this is and when they ask for a
• 50:43stimulant they give them Adderall,
• 50:45that's the the one to give them.
• 50:47And the company that makes it
• 50:49obviously is not discouraging that.
• 50:51So what about amphetamine for treating
• 50:53stimulant use 30 yes there can be
• 50:55and it needs to be particular ones
• 50:56though lisdexamphetamine would be 1
• 50:58to think about others would be long
• 51:01acting slow onset genetic matching.
• 51:03I I think there's a real role for this.
• 51:05I only showed it for doxazosin and
• 51:08the DBH polymorphism but there's
• 51:10in fact others that that are coming
• 51:13out including for the the use
• 51:15of buprenorphine to treat.
• 51:16For pain abuse,
• 51:17it ends up Dave Nielsen and I
• 51:21published a paper recently showing
• 51:23how a polymorphism in the the Kappa.
• 51:27System.
• 51:28It's in the actually dynorphin,
• 51:30dynorphin polymorphism that produced
• 51:32that predicts treatment response.
• 51:34And then there's the vaccines.
• 51:35I didn't have time to talk
• 51:37about cholinesterase enzymes.
• 51:38These have been around now for a while.
• 51:40These are high activity colon esterases.
• 51:43We published a paper now it's about 810
• 51:46years ago where we took our vaccine.
• 51:48Even our crappy vaccine combined
• 51:50it with the Colonel,
• 51:52one of the Colonel esterases,
• 51:53and it was phenomenal in
• 51:55that it completely blocked.
• 51:57McCain use and the animals,
• 51:59he just could not override it at all,
• 52:01even though they could override
• 52:03the vaccine and they could
• 52:04override the colon esterase,
• 52:05because the colony esterase
• 52:07is relatively slow,
• 52:08but when you put the two things together,
• 52:10it's unstoppable.
• 52:14And buprenorphine doesn't
• 52:15block fentanyl abuse,
• 52:16you know,
• 52:17sorry,
• 52:17but and a vaccine can block the
• 52:20fentanyl abuse and the overdose
• 52:22and the human fentanyl vaccine
• 52:24we've just started
• 52:26manufacturing as of this month.
• 52:28We're hoping to get it
• 52:29into people within a year.
• 52:31Depends on the FDA,
• 52:32but they've accelerated for COVID
• 52:34obviously the approval process
• 52:35and we're hoping to convince them
• 52:37that they should be doing the same
• 52:39thing for an anti fentanyl vaccine.
• 52:41We're not the only one working
• 52:43on this vaccine.
• 52:44But we're about at least probably
• 52:45two to three years ahead of
• 52:47the other three groups working
• 52:49on this around the country.
• 52:50It's not like we're we're competing
• 52:54with them in any real way.
• 52:56We're collaborating with them.
• 52:57We're trying to work together.
• 52:59There's a group at Harvard that
• 53:00we're working with another one
• 53:01out at University of Washington,
• 53:03another one and University of
• 53:05Maryland and then together plus with
• 53:08of course Niad and night etcetera
• 53:10together we think that would come
• 53:12up with this but our particular.
• 53:14Group is is rather aggressive I guess
• 53:16because I know how to do these kind
• 53:19of clinical studies and nobody else involved.
• 53:21It's done clinical studies
• 53:23with vaccines in addiction.
• 53:24So I think that is what's giving
• 53:26us an advantage, alright, so.
• 53:31It's always nice to say,
• 53:32you know,
• 53:33this is not everybody who's
• 53:34worked with me over time,
• 53:35including, uh,
• 53:36very few of the Yale people who worked
• 53:39with me on these vaccines are listed here.
• 53:42But, you know, there are some.
• 53:46And anyone who sees my wife in the
• 53:48young the next few months or whatever,
• 53:50you know,
• 53:50tell her to make sure that I did say,
• 53:52you know, thank you to my wife, Terry.
• 53:54Costume and the collaborators are,
• 53:57of course,
• 53:57a bunch of different companies who've
• 54:00worked with us and making these things.
• 54:02And and the National Institute of
• 54:05Health was both naida and the NIH NIAD,
• 54:09the Allergy infectious
• 54:11disease fouchy's group.
• 54:12With that,
• 54:13I think I've managed to burn
• 54:15up as much time as I'm allowed
• 54:17and I'm happy to address any
• 54:19questions that people have.
• 54:21So thank you very much.