| 00:02 | This is lecture 21 of sally living science and its lecture four of |
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| 00:08 | Three. We covered a lot of E. G. Synchronization any g |
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| 00:16 | with um synchronizes simple protocol circus to the anatomy of some of the cortical |
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| 00:22 | cortical according to the alignment communication. look at epilepsy and incidence of epilepsy |
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| 00:30 | Little bit various causes of epilepsy and amongst us are unknown causes as |
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| 00:39 | We looked at channel open these and on mutations involved with created sodium channel |
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| 00:46 | talked about generalized epilepsy, febrile seizures severe my quality of infancy and |
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| 00:53 | S. And spasms. Um And talked about imbalance. And today we're |
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| 01:02 | look at how this imbalance maybe tweeted ecologically. We talked about how many |
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| 01:08 | the targets the pharmaceutical targets and dysfunctions epilepsy and imbalances. Excitation and inhibition |
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| 01:17 | treated with. Yeah but receptor We looked at how there is a |
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| 01:24 | scoliosis that forms and there is no of signaling through UR receptor. There's |
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| 01:31 | over the increased production of across the and uh that increases abnormally the production |
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| 01:39 | calcium causes abnormal movies have been made by stimulating a normal synchrony. We |
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| 01:48 | between generalized seizures versus partial seizures. partial this is complex. Partial talked |
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| 01:57 | neuro degeneration campus the aura stage and synchronization stage and generalized stage of seizure |
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| 02:05 | by E. G. Recall that lot of this repetitive behavior is being |
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| 02:12 | through the salama. Cortical circuit connected . Cortical circuit to discuss the mechanisms |
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| 02:18 | are pro the collective form which increase synchronization would lead to seizure activity and |
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| 02:28 | thought mechanisms that would be anti it would decrease epileptic form activity and |
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| 02:35 | collective form synchronization. We distinction between these, which is a genetic form |
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| 02:45 | epilepsy with acquired form of epilepsy such post traumatic couple of this autopsy and |
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| 02:55 | bullet of genesis and molecular circuitry organization follows, which is often bi |
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| 03:03 | Um There are circuits that decay and that grow to compensate for the decay |
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| 03:13 | . We discussed models of epilepsy. when you talk about models, you're |
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| 03:19 | talking about humans, you're talking about models of epilepsy. Different models to |
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| 03:26 | epilepsy to replicate epilepsy and seizures and replicate as much as possible. The |
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| 03:35 | conditions, for example, the genetic of severe mark, chronic epilepsy of |
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| 03:42 | . In the mouse model of transgenic model would contain a mutation and bulk |
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| 03:49 | sodium channel that would replicate many aspects severe metabolic epilepsy in infancy that can |
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| 03:55 | seen in humans in humans, temporal epilepsy is the most common form of |
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| 04:02 | in the location of hippocampus involvement of limbic system which carries the memory and |
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| 04:09 | emotional response and the susceptibility of every . Makes that area of temporal |
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| 04:17 | the hippocampus and the limbic system very area for this abnormal activity is not |
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| 04:26 | source of that activity in temporal lobe cortex can be the source if the |
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| 04:32 | doesn't always have to be the In any case it is very susceptible |
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| 04:37 | producing the blood perform activity o propagating blood perform activity and generalize synchronization happens |
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| 04:45 | the storm. A cortical circuits of involved other areas of the cortex and |
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| 04:52 | cortical salami. It's not important and about stimulus and synchronization that in this |
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| 05:00 | it's stimulus with actually in his So we talked about how there's an |
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| 05:06 | between excitatory cells and inhibitory cells and inhibitory cells can lead to the synchronization |
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| 05:14 | the excitatory networks. We're gonna look a model of seizure in a transgenic |
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| 05:22 | model. So in this case it's things that are being manipulated. First |
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| 05:27 | all, it's a transgenic mouse model it says heterocyclic speech E. |
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| 05:33 | It's a transgenic mouse model for severe capitalists of infancy. And so these |
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| 05:41 | contain mutations and mutation and replicate Investigated sodium channel replicate many aspects of |
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| 05:50 | human an epilepsy. Now we want study the cellular mechanisms the cellular neuroscience |
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| 05:59 | the seizures that you would see in seizures that you would see in whole |
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| 06:05 | . We go into a slice preparation is in vitro moments in the |
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| 06:12 | In vitro we have the capability to wholesale recordings, individual neurons as well |
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| 06:19 | extra cellular recordings or local field potential which are likened to E. |
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| 06:27 | Except that this electorate is actually sitting the tissue. This is a big |
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| 06:33 | and to induce the seizures because the may not exhibit in isolation, seizure |
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| 06:41 | activity to induce the seizure like activity the dish. We raise the temperature |
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| 06:49 | replicates federal seizure. Now, this important because in severe my chronic epilepsy |
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| 06:56 | infancy, Children are very susceptible to in temperature and they have a lot |
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| 07:05 | febrile seizures. They also have a of spontaneous seizures that we cannot determine |
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| 07:13 | causes for it. But these Children have severe my chronic epilepsy of infancy |
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| 07:20 | it's a development reform of activists to its catastrophic form of epilepsy because about |
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| 07:25 | of severe Micronics and posted instantly, die in their sleep and once the |
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| 07:32 | months hit in warm climates, there's increase in seizure activity which is correlated |
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| 07:39 | even the ambient outside temperature, let the body temperature, which may rise |
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| 07:45 | to infections and and colds and things that. So to replicate what the |
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| 07:55 | would experience and to see these mutated animals have anything different in the presence |
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| 08:07 | temperature when we raise the temperature from 36 C to about 42 C. |
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| 08:18 | we see is that heterosexuals animals will seizures at much lower temperatures to the |
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| 08:25 | in the circuit. The transgenic mutation circuit in the ball castrated sodium |
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| 08:30 | Makes this circuit more susceptible to temperature a federal like seizure like events that's |
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| 08:42 | to the wild animals who has very incidents. So now you understand how |
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| 08:48 | have a mutation as a transgenic and you may have to use a model |
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| 08:54 | order to provoke that circuit. And you use the model to provoke that |
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| 08:59 | again, you want to somehow replicate humans might go such as rises and |
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| 09:05 | temperature and having these people all So the ability of having these intracellular |
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| 09:14 | and extra cellular recordings allow us to how different cell subtypes act during these |
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| 09:22 | like events to look at the granite cells in the hippocampus. Um This |
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| 09:29 | a different model in this case it's forming a period in model of |
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| 09:37 | We're forming a period ng is a for potassium channels and in addition there |
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| 09:46 | a reduced magnesium concentration in the solution is surrounding the cells that were recorded |
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| 09:54 | the reduced magnesium concentration. Makes the more susceptible to excitability because there is |
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| 10:03 | of the magnesium blocking and then being . So when we have this condition |
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| 10:10 | forming a period in blocking potassium channels we have over excitation of an |
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| 10:18 | D. A receptor. We can activity in two parameter cells with the |
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| 10:24 | sound and the specific subtype of inhibitory and see how this individual cellular activity |
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| 10:32 | to the network activity which is indicated this local field with artificial then we |
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| 10:39 | see for example how well are the synchronized between these two pyramidal cells that |
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| 10:45 | located some very close distance from each . How well are the spice in |
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| 10:52 | phenomenal cells synchronized? When does the occur compared to the start of the |
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| 10:58 | indicated here by this inverted triangle and us a really good understanding of what |
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| 11:05 | subtypes of cells are doing. As you know, hippocampus is complicated |
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| 11:11 | inside this area that we looked at this area see a wang we have |
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| 11:17 | lot of difference of types of inhibitory but in this case I targeted in |
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| 11:23 | other model. So don't confuse this and transgenic model you're gonna be on |
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| 11:30 | test action futbol seizures and transgenic mouse . This is chemically induced seizures and |
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| 11:38 | this case it's actually wildlife tissue. no genetic mutation in this tissue. |
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| 11:44 | provoking this issue with chemo convulsants. can in this case I decided to |
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| 11:51 | orients looking off from a local Aryanto all around into neurons and the location |
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| 11:57 | this into neurons in e here is by these stars where I patched and |
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| 12:05 | hope so recordings from these into So prior to inducing chemical seizure you |
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| 12:13 | want to measure and look at the what we call membrane properties of the |
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| 12:20 | . And as you know different cells produce different responses to the same electrical |
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| 12:27 | . So as we're recording from these , the phenomenal cells and the alarm |
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| 12:32 | inhibitor herself before the induction of the convulsive seizures. We test for the |
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| 12:39 | and we can see that this is classical prominent cell response and we inject |
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| 12:44 | same amount of current and stimulus into inhibitory cells. And we see that |
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| 12:49 | not quick response like you would expect oh himself to respond during the recording |
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| 12:57 | the pipe that we have a dye neuro biotin and that neuro biotin die |
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| 13:02 | the cells. And only after the we performed history, chemistry, immuno |
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| 13:09 | , chemistry or histology procedures that allow to recruit the precise morphology and anatomy |
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| 13:16 | these recorded neuro. So when we these inhibitory neurons, I'm excited |
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| 13:23 | So inhibiting around here because like oval , excited areas are pyramidal shape and |
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| 13:28 | did extra salary recorders which is C. When we saw this peculiar |
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| 13:34 | . And I saw it over and and over again and it's not just |
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| 13:38 | South saw many cells. And this a great representative example. The question |
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| 13:45 | we wanted to ask is not necessarily sells synchronized. Of course we wanted |
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| 13:52 | know is there synchrony between excited to . But one of the other key |
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| 13:59 | that we wanted to ask him to which cells become more active which sells |
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| 14:06 | synchronized before other cells. Is there particular subtype of cell was synchronized. |
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| 14:12 | really love these l alarm cells. there. Look they're shaped the way |
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| 14:18 | look in the microscope. So just level themselves. Honestly, that's that's |
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| 14:23 | best explanation why I just these sub of south. So when we zoomed |
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| 14:30 | on this would be an individual seizure approximately one minute or similar in |
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| 14:39 | We would see that prior and in in the chemo convulsive solution, it |
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| 14:47 | the inhibitory cells that were hyperactive almost and they would fire a lot of |
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| 14:54 | potentials that would drive themselves into the of what we call deep polarization |
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| 15:00 | And in this state you can see the number of potential like here can |
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| 15:05 | in this state, the number of is deep polarized but the action potentials |
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| 15:12 | blocked. There is no production of action potential. And in this state |
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| 15:17 | is basically a failure by the inhibitory to release the inhibitor americans mary |
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| 15:26 | When we look at the parameter they don't wait long As soon as |
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| 15:31 | a failure in this hyper excitable state the inhibitory cells to fire action potentials |
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| 15:38 | remember we need action potentials, you the strong deep polarization and this is |
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| 15:43 | the terminal to keep releasing Gaba. soon as there is a break from |
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| 15:48 | Gaba excitatory cells become very active fire potentials to go into this very |
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| 15:56 | deep polarization block. But every time inhibitory cells here in the failed excitatory |
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| 16:02 | . Fire failed fire failed fire fail and it goes on and on and |
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| 16:09 | . So we call this activity and and excitatory interplay. And in reality |
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| 16:17 | addressed many different issues about the synchronization individual and inhibitory cells because I did |
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| 16:24 | between two inhibitory cells, inhibitory excitatory . Later I trained the students to |
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| 16:31 | triple recordings and we did triple recordings another setback will sell the basket cells |
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| 16:36 | parameter cells was tremendous actually. Um it answered some of the questions and |
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| 16:43 | a theory and that theory was that inhibitory neurons would be first active first |
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| 16:50 | that there's something about the inhibitory neurons least. And this chemo convulsive environment |
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| 16:55 | they would synchronize and they would synchronize become hyperactive and they would fail. |
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| 17:01 | the failure of this inhibition will allow the excited themselves now to synchronize and |
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| 17:08 | propagate or project that information and the of action potentials burst synchronized versus activity |
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| 17:17 | the adjacent cortical areas from c one the hippocampus and spread it through the |
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| 17:26 | . So I did the study as postdoctoral Saleh at johns Hopkins University was |
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| 17:38 | first postdoc where I studied spike timing plasticity. And so if you look |
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| 17:43 | some of my work in the dark spike timing dependent plasticity and then later |
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| 17:49 | pursued studies in epilepsy m was very about what are different cellular interactions |
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| 17:58 | how does epilepsy spread through the neuronal . Um what are the synchronization rules |
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| 18:08 | different cells. Okay, So in 15 I was invited to give a |
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| 18:21 | stock in my birth town uh from Lithuania. And I talked about two |
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| 18:30 | in that talk. Actually. One them was the theme that we were |
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| 18:35 | discussing now, synchronization of different cells seizures and trying to explain to broad |
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| 18:46 | , different things about neurons. So you imagine? I'm trying to explain |
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| 18:53 | to general audiences about neurons and inhibitory neurons, varieties of these different |
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| 19:02 | what they do. And I even the same Experiment in that Cadillac stock |
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| 19:10 | was published in 2006. Now It's a while 15, 16 years. |
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| 19:18 | nonetheless, I talked about the seer and explain them and I showed some |
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| 19:25 | my imaging work uh this hyper excitable waves of activity in the hippocampus. |
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| 19:36 | , I loaded this general audience with lot of information. I talked to |
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| 19:42 | about severe my chronic capital of CNN infant state which is also known as |
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| 19:51 | Drive A syndrome Dravet syndrome. So S. M. E. |
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| 19:58 | These are the Children and how mutations there. Ah sodium overeducated sodium channels |
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| 20:08 | a lot of them don't lend themselves traditional medications, Pharmaceutical medications over 30 |
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| 20:18 | Children cannot be treated with traditional pharmaceutical . And these are real kids with |
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| 20:27 | A syndrome that was on the driveway foundation website? Um some of them |
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| 20:34 | passed since about 20% of Goddess and own Children pass in their sleep from |
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| 20:41 | condition that is false, severe, , sudden unexpected death in epilepsy. |
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| 20:50 | we talked about talked about basically how trying to understand this activity in the |
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| 20:57 | and activity and the slices and I'm does this is this even relevant to |
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| 21:03 | ? What I see in the fly are you explain this step talk how |
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| 21:09 | it is similar behavior a few years was recorded in humans in human epileptic |
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| 21:18 | with the inhibitory cells being excited first leading into the 5% for new of |
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| 21:25 | and failure by the inhibition along for to take over. So we talked |
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| 21:33 | driving syndrome and then I talked about the cannabinoids and cannabinoid receptor. Some |
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| 21:38 | reason why I talked about that was I wanted for people to understand what |
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| 21:47 | happening. In fact, a little of an insight is when I first |
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| 21:51 | to stalk my talk and never ended this portion of madre de syndrome. |
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| 21:59 | after I finished presenting it to myself my wife, I felt unsatisfied and |
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| 22:09 | felt that my real passion at the was interest in novel therapies and normal |
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| 22:17 | including for Dravet syndrome and untreatable forms epilepsy and that led me to actually |
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| 22:26 | cannabinoids in a lot of us h even come up with a patent and |
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| 22:33 | a patent, the University of Houston combination of cannabinoids. So I was |
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| 22:39 | passionate about that, but in 2015 felt timid about expressing that openly, |
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| 22:49 | I felt like it was time to it. I had received my tenure |
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| 22:55 | I thought well the worst case you know, maybe I'll just be |
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| 23:00 | somehow. And you know what probably date is the first talk that talk |
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| 23:10 | general audiences that tries to explain the system since then has been have been |
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| 23:17 | and then we can have a system actually garnered a lot more views. |
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| 23:21 | if you look historically nobody has shown cannabinoids system to the people and talked |
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| 23:28 | it. They mentioned that they talked the story. I really tried to |
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| 23:31 | it. I tried to explain the and the Europeans and we'll talk about |
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| 23:35 | and why do they talk about I talked about it because I was |
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| 23:41 | interested in the fact that cannabinoids were these Children with Dr A syndrome and |
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| 23:52 | medications that they were taking pharmaceutical We're not helping them. I was |
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| 23:59 | pharmaceutical synthetic preparations of phenomenon in I see a whole story of murder |
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| 24:07 | the market of natural treatment with cannabis promenades, you should really intrigued |
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| 24:15 | So it's trying to deliver these news a scientist and as there was a |
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| 24:23 | basis behind it of course in clinical too and talking about the differences between |
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| 24:31 | and CBD. If you were to the talk, I say that CBD |
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| 24:35 | bind to CB one receptors. It has low binding affinities, the CB |
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| 24:40 | receptors, but it acts primarily through system through serotonin receptors. CBD cannabidiol |
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| 24:47 | to that sector. So really cool is you know at the end of |
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| 24:52 | talk I have this recording of and is a private all song. This |
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| 25:02 | uh inhibitory interneuron, a different type inhibitory interneuron but you can see this |
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| 25:07 | of interplay activity going on here. had two extra cellular recordings network on |
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| 25:14 | network to This is about three minutes electrical traces of. All right using |
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| 25:23 | wholesale and extra selling in accordance. so I invited a friend and colleague |
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| 25:28 | mine uh in Lithuania, very talented profession ist I thought he got this |
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| 25:36 | , he's sitting here at the drums outside. You know what I caught |
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| 25:40 | . And I said you're gonna play cedar. He says, what do |
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| 25:44 | mean? I'm going to play a . I'm not a neurologist and understand |
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| 25:48 | . And I said perfect and says do we need to do is just |
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| 25:53 | your drum set and some professional instruments I'll send you an image for sentiment |
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| 26:03 | the brothers Jonathan percussion. So and before. And um you didn't do |
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| 26:12 | actually. You didn't we didn't rehearse him. He just wanted to talk |
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| 26:17 | me for 10 minutes. He well what is this? You |
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| 26:20 | like he says I couldn't print it I don't remember what damage looks |
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| 26:23 | Okay, so basically the same day few hours before I said, look |
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| 26:29 | is the image of breaking him, copy and this is seizure. |
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| 26:33 | it's like it's not good. I no it's not good. He says |
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| 26:39 | . And he says what else? said like look this is your your |
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| 26:44 | of senior, you're a drummer, are a precaution, you're not a |
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| 26:50 | . That's my exact point is that is very high level scientific data and |
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| 26:56 | just tried to translate and explain that high level scientific data using my tongue |
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| 27:03 | slides and examples and stories and some and a lot of energy. But |
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| 27:14 | however different interpretations as a lay as a lay person with respect to |
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| 27:22 | selected physiological seizure recordings and you are expert on percussion and rhythm. I |
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| 27:31 | you to play it out how you these traces that you're looking at your |
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| 27:38 | 1212, how they play out. so he did this performance. And |
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| 27:45 | you look at the commentaries under the X talk as people are commenting a |
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| 27:50 | on the music part and there is a few comments that state that this |
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| 27:57 | really hard to kind of handle. believe there is even an epileptic one |
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| 28:03 | two people saying this is really but it kind of represents how I |
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| 28:08 | another person saying I had to turn off because it was just bringing that |
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| 28:15 | within me or feelings this is And so, well, I'll leave |
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| 28:21 | up to you to see what kind emotions that brings it up to |
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| 28:27 | But it would be good as he watch the aesthetics talk. They may |
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| 28:34 | a question for you from the Cdx , you can just look up my |
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| 28:39 | name and Ted X and it will up and if you like it uh |
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| 28:46 | it or share it uh with your or with your peers. I think |
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| 28:58 | it's really cool. Um, it a very interesting experience. It was |
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| 29:03 | experience of growth for me personally, go through, just had ex |
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| 29:08 | I worked with creators of Ted X Francisco and today is illness together in |
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| 29:16 | . And they really pushed me, pushed me and asked me to run |
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| 29:20 | and wave my hands and I why aren't you asking this other guy |
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| 29:24 | me to do the same thing. then you interrupted the afternoon one minute |
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| 29:27 | you said you're good. So I even run through my whole talk, |
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| 29:30 | is what, 19 or 18 He goes, you're good. I |
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| 29:35 | , but you're not asking this other to run around and waved his hands |
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| 29:39 | because he can't you tricked me. it's a big you know the uh |
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| 29:48 | the energetic person here feels like well really complicated material. You have to |
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| 29:53 | people engaged. So there were a of lessons that I've learned from or |
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| 29:59 | lessons presentation lessons I have learned in experience. Working with international coup. |
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| 30:07 | hmm. And I would love love to do another Ted talk or a |
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| 30:13 | of stock on a different theme. so the more you guys watch this |
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| 30:20 | , I contacted Ted and I said know I'd like to do another talk |
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| 30:25 | the Ted talk, contacted their managerial oh well you know your talk is |
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| 30:31 | great but apparently they want more views my talk and then they may nominate |
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| 30:38 | for ted talk general anyway so it be an honor. There was a |
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| 30:44 | of fun, great learning experience. really learned a lot and banned myself |
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| 30:52 | of kind of a comfort zone and grateful for that because I'd say that |
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| 30:57 | talk coming out of the comfort zone me to certain certain athletes of my |
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| 31:05 | and especially entrepreneurship in my life that didn't foresee as strongly at the |
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| 31:13 | And I have learned since that have in the in the entrepreneurial world too |
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| 31:19 | any case. So we talked about incidents were talking about synchronization E. |
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| 31:35 | rhythms, epilepsy, epileptic rhythms, mechanisms and epilepsy now we have to |
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| 31:44 | a little bit about treating epilepsy and as much from neurological perspective though the |
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| 31:51 | has these symptoms that I can read E. G. And this is |
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| 31:55 | rhythm. So this is this is , mm hmm. Years of working |
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| 32:04 | in the clinical level. What clinicians is the most important staff on addressing |
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| 32:12 | has confirmed that the bonafide seizure it occurred. Often multiple seizures once they |
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| 32:23 | the diagnostic criteria for epilepsy or status the left anti epileptic drug treatment should |
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| 32:30 | initiated. So primary pharmacological treatment strategy epilepsy is a monotherapy meaning giving person |
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| 32:40 | drug. The ready made treatment strategy be prepared for status of properties and |
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| 32:49 | using a team based approach. So often the neurologist working with other decisions |
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| 32:58 | our first and even anesthesiologists in case person needs to be placed in a |
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| 33:07 | medical coma if the status of a because they're very severe. So your |
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| 33:12 | be stopped. Yeah. The primary of anti epileptic drugs. Don't notice |
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| 33:18 | most of the drugs and most of things that we call here E. |
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| 33:22 | . Anti epileptic drugs that really is epileptic drugs, correct terms anticonvulsant |
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| 33:29 | Anticonvulsant treatments for epilepsy is lasting remission significant adversity. Bye adverse effects of |
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| 33:37 | drugs themselves should be addressed by the and patient together. We'll look at |
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| 33:41 | of the very common adverse effects. common and collecting trucks in the light |
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| 33:47 | the concept, the resolved epilepsy. there's no more seizures. We recommend |
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| 33:52 | for a seizure free period of at five years before considering a drug withdrawal |
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| 33:57 | the drug withdrawal. That's a very time. Okay, But why Wait |
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| 34:02 | years? It's because, well the take time to to rebuild themselves. |
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| 34:09 | change to rebalance themselves and sometimes the secretary physiology may still be lurking in |
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| 34:19 | background. Um sometimes can wear its head. Years afternoon stopped having any |
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| 34:28 | , especially if you stop taking them . Elliptic taking some drugs. So |
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| 34:36 | dealing with that, when dealing with our logic treatment, what the physician |
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| 34:46 | to do is set the optimal deficits the ongoing drugs avoid drives a similar |
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| 34:54 | mechanisms. It's monetarily doesn't work a of times. You have to go |
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| 35:02 | Polly therapy which is multiple therapies Maybe two medications together. Those doesn't |
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| 35:09 | . Sometimes it's a popular three or medications together. But if they act |
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| 35:14 | a similar mechanism, you have to relevant if they get metabolized by the |
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| 35:20 | enzyme in the liver, you have be aware of it because it will |
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| 35:23 | significant side effects from these drugs, increasing the number of prescribed drugs. |
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| 35:32 | the change in dosage is needed, to taper off slowly. So at |
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| 35:39 | end of these let's say 23 The person should start slowly decreasing the |
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| 35:48 | of the drug that they're taking tapering . If you need to increase, |
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| 35:54 | have to titrate in very slowly increase record the increases the dozers and you |
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| 35:59 | do it just day by day Typically have to let the system of |
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| 36:04 | body and the brain accommodate for about weeks before changing anything in the |
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| 36:12 | typically a few months before adding or anything in the monopoly therapy regime. |
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| 36:19 | the drug treatment have to consider drug drug interactions. Drug and drug interactions |
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| 36:25 | through the same mechanism or through the . They're getting metabolized and they're overloading |
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| 36:33 | liver, overworking the liver because they overworking the same enzymes in the |
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| 36:40 | So you want to achieve synergy and adverse effects. New anti epileptic treatment |
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| 36:47 | suboptimal, replace it with another. new drug is effective, you can |
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| 36:54 | to slowly taper off the previous These are some of the most common |
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| 37:04 | epileptic drugs. Oh my God, I need to know who this |
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| 37:09 | No, but you should remember some the things. carBAMazepine peon um just |
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| 37:17 | a general understanding, recognize and police names as an epileptic drugs. Pentobarbital |
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| 37:23 | Owen very common drugs. Val provoke . What else is here? Initial |
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| 37:31 | versus maximum maintenance dosage. So if talking about studying a person or the |
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| 37:39 | you want to achieve what is called last act that does and the fact |
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| 37:42 | those will be seizure control. So you're starting with something like garba |
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| 37:51 | You're doing about 100 mg. You're with 100 mg but that may not |
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| 38:01 | the seizures. So you go to the dose whatever the doctor recommends based |
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| 38:07 | the medical history and all of the observations of E. G. And |
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| 38:11 | of the stuff Let's say 500 And then maybe the maximum dose of |
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| 38:19 | person. So he still has seizures the maximum 2400 mg. So long |
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| 38:30 | harassing time starts at 250 mg goes the way up to $3,000. Why |
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| 38:39 | say whoa. It's because it's three . You know what three g of |
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| 38:43 | look like three big cubes of Okay that's three g of sugar. |
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| 38:51 | not exactly actually. Like you know white tubes of the I think I |
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| 38:56 | maybe they're about two g or something that. So imagine just one of |
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| 39:00 | cubes. Well here you're talking about of those cubes that will have a |
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| 39:08 | medication. So these are pharmaceutical chemical , all of these that you're seeing |
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| 39:16 | . But the maximum dose is never you can see exceed 3000 mg for |
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| 39:27 | and that's a very heavy loads to regardless there is no pharmaceuticals that you've |
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| 39:33 | hundreds of grams I think basically the off is about three g of that |
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| 39:39 | and that drug you're taking now I'm exit out of presentation Marilyn alone. |
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| 39:48 | man yeah so for all of these and politics drugs you have adverse effects |
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| 39:56 | you have contra indications and adverse the that require E. D. |
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| 40:03 | Which means in some instances the counter or the side or the adverse effects |
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| 40:10 | so bad that the personal customers continue drive. So what are some of |
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| 40:17 | adverse effects again? We're gonna need know all of this where you start |
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| 40:24 | . But let's go through this neurological , lethargy dizziness. Somnolence dizziness. |
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| 40:31 | lethargy dizziness. Somnolence lethargy taxi business be dizziness, diplo pia taxes someone's |
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| 40:41 | business Chatterjee distance did you just let repeat it again? Somnolence lethargy dizziness |
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| 40:55 | attacks him. These are the most basically adverse side effects. Being lethargic |
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| 41:04 | being dizzy and being very slow and . Almost like drunk like back from |
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| 41:11 | lot of these chemical therapies especially in concentration. What are some of the |
|
| 41:23 | ? They're very different for gabba Pancreatitis and absolute season. So all |
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| 41:29 | a sudden you have an absence like . Your pancreatic enzyme levels change |
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| 41:36 | They have to stop the avocado To on 11th aerosol. Tom if you |
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| 41:41 | doing suicidal thoughts. Having suicidal thoughts withdraw again against the suicidal was repeating |
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| 41:49 | on the side of ideation. Killing else who anyways. So most common |
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| 41:58 | can see scientific facts. Uh some them contrary indications but the most important |
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| 42:07 | us and then this course is really understand some of the mechanisms cellular mechanisms |
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| 42:15 | action of these drugs. And so have actually two diagrams. One is |
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| 42:20 | one and this one is we were slightly and large. Well basically what |
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| 42:27 | looking at here, you're looking at inhibitors and have some exciting tourism |
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| 42:33 | And here you have the president after all sort of a divided country. |
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| 42:39 | doesn't happen but it's just kind of in one synapse here. It's a |
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| 42:44 | medium gather. So you can see a lot of the drugs that you |
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| 42:50 | saw of operate Gabba eternal or bigger and Gaba uh transporter decrease. So |
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| 43:04 | targeting a molecule itself does it as means of perpetuating reverse syrup until we |
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| 43:09 | Gabba receptor. Arrow here indicates agonist been inhibits litum it transporter. The |
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| 43:24 | transporter sorry ingredient. And nervous. it allows for gather to linger around |
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| 43:34 | the synoptic last long. So these strategies here. Benzos barbiturates still stupor |
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| 43:46 | control, operating to Britain. There's inside the synapse and tag them now |
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| 43:54 | the present appliques size. These benzos mostly affecting the possum after gathering. |
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| 44:01 | when you're thinking about the cellular mechanisms strategies for treating and then balance and |
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| 44:07 | in the division. Like I you're gonna want to manipulate different aspects |
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| 44:12 | the either excitatory or inhibitory neural transmission their Attackers. So Gabba Panton and |
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| 44:23 | Goblin they will block calcium channel pre up the calcium channels by blocking calcium |
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| 44:33 | . There is not enough influx of . Okay so these are blockers of |
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| 44:41 | channel and they control gather release in case ready to bend will open the |
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| 44:51 | tradition channels and will cause hyper So most of the instances you can |
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| 45:00 | you're targeting the increase in Gaba and some instances you're targeting the release of |
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| 45:07 | . In this case you're blocking This is a blocking sign and this |
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| 45:13 | is reactivating your sent out the potassium to reduce the polarization and to decrease |
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| 45:20 | release. This targets Ghabra in a a different way of origin synapses. |
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| 45:28 | look here on the right you have it'll and carbon mustard and outstanding thomas |
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| 45:42 | drugs that target voltage gated sodium channels block us from walter treated sodium |
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| 45:50 | So you will say well wait a but if you block both educated sodium |
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| 45:54 | . Yeah um excitatory factors then you excitation. But if you block the |
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| 46:00 | of sodium equalization inhibitory factor, you inhibition. Exactly and that's exactly the |
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| 46:10 | with so many drugs they are non and the same voltage gated sodium |
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| 46:18 | Okay so you will say that it ubiquitously expressed where it is dominating. |
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| 46:25 | can be found and all of the so but it can only be defined |
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| 46:32 | certainly that helps you a lot if find a subtype of bolt educated sodium |
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| 46:43 | that is specific to Justinian the third . We're just excited to herself. |
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| 46:52 | been discovered. There's usually a co of the smoke educated sodium channels. |
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| 46:59 | and inhibitory cells express mint. So just to what extent to what degree |
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| 47:06 | subtypes may be expressed along the excitatory , inhibitory power. The same goes |
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| 47:16 | the calcium channel control too. Block pre synaptic aly on the inhibitor yourselves |
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| 47:23 | releasing, reducing the release of an but I'm excited for ourselves reducing the |
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| 47:30 | of excitation. Now this is an one SV. 2 a. We're |
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| 47:38 | to look a little bit into the SV. two a. But not |
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| 47:43 | as much as just the fact that it targets the loading and the vesicular |
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| 47:52 | . We live at the acetone and . Rosita. It's a cellular mechanism |
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| 47:57 | this particular release including me. So don't get as much glutamate. So |
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| 48:05 | you can find the transporter remember the that transport glutamate and Gaba into the |
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| 48:12 | at the terminals are transporters that upload vesicles. So if you somehow can |
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| 48:19 | a transporter that's specific to the excitatory cannot be found. And then in |
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| 48:24 | third synopsis boom you have a winner that will control liniment release, reduce |
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| 48:33 | release, reduce excitation. These are an epic mechanism parson optically in excitatory |
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| 48:42 | . Since you can target hamper an . B. A. Can block |
|
| 48:50 | ? Mm hmm. You can target channel hyper polarized, excited dressing arts |
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| 48:57 | ethically. And you can block the calcium channels. As you can see |
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| 49:05 | different calcium channels of T. Type channel with the subsystem eyes. We |
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| 49:10 | block it and it can decrease the of calcium. Been excited to his |
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| 49:16 | which can turn on secondary messenger cascades the production of collagen a system of |
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| 49:25 | even potentially change the transcription like a all the way down in the nucleus |
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| 49:30 | the south. So pretty neat. question is Professor do I have to |
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| 49:37 | that we drug that's great receptor in and targets. The answer is |
|
| 49:45 | But I hope what you know from and I may ask you is these |
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| 49:55 | . And what are some of these means, what are some of the |
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| 50:00 | mechanisms for anticonvulsant drugs and anything that's this diagram would be a fair salaries |
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| 50:12 | McIntyre's pre synaptic aly, it's pretty potassium calcium particular transformer and the number |
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| 50:22 | transport. Post synaptic leave you on inhibitors a being excited to ample remember |
|
| 50:30 | . A also manipulative K channel and really cool. So these are the |
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| 50:40 | mechanisms you know we would have to a separate course or separate few hours |
|
| 50:47 | then neurologists tell us for example how they identify gabapentin versus free apple, |
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| 50:59 | versus terrible, determined a lot of that come into play sometimes that some |
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| 51:10 | in the medical history. Sometimes it's new studies of the drugs. Sometimes |
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| 51:17 | adverse effects to some drugs where you to choose an alternative. So all |
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| 51:26 | these are very, very important pharmaceutical . Interview thinking about any neuro pharmacological |
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| 51:34 | development, you know, anything along chemical neural transmission pathway. You |
|
| 51:40 | one thing you're not seeing is, example, manipulation of gap junctions or |
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| 51:45 | junctions inside the south. This is little bit about STD to a but |
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| 51:54 | as you know, there is a system of Exor site ass's release of |
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| 52:03 | neurotransmitter on and end this site Asus the vesicles and refilling of that bicycle |
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| 52:10 | neurotransmitter, the new york transmitter This is where the transporters would be |
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| 52:15 | to. And then you have the and if you manipulate SB two, |
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| 52:24 | is your this specialized steroidal membrane The traffic along the accent to the |
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| 52:32 | opportunities where they internalize and storms or as we remember and harvest Brodin. |
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| 52:40 | of them highly like oscillated Mhm. precise sorting was required for an efficient |
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| 52:49 | transmission. So then involved in the of the neurotransmitters that gets shuffled basically |
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| 52:56 | the synapse and they get less than pre synaptic terminal here. So the |
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| 53:02 | that target the steroid almost be too steroidal member instructors that involved in trafficking |
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| 53:11 | can control the glutamate release in the enough. This is why I also |
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| 53:25 | started looking at the endocannabinoid system and actions of the Canaveral I started learning |
|
| 53:35 | and they can have a non system can harmonize In about 2007 or |
|
| 53:46 | And because there is not much in textbooks and the cannabinoid system and activity |
|
| 53:53 | we understand the longer than the cannabinoid . It's fairly recent we're talking about |
|
| 53:59 | 30 years old but I think it a very significant and it's significant because |
|
| 54:10 | so the molecules get synthesized in euros they get released on demand when there |
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| 54:18 | a lot of pasta. Matic a lot of calcium then the can |
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| 54:23 | get released remember intelligible they will travel lee and pre synaptic lee. The |
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| 54:31 | that can bind to CB one receptors through G. Protein couple of the |
|
| 54:37 | they shut down these calcium channels. the same calcium channels that you're talking |
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| 54:44 | here, they can also be manipulated the endocannabinoid system and when there is |
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| 54:53 | calcium influx there's no release. And you think about releasing of legitimate we |
|
| 55:00 | control glutamate release And the cannabinoids and one we suffered through this program public |
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| 55:06 | will control both excitation and inhibition. somehow Navin noise under cannabinoids especially nationals |
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| 55:15 | to have a positive effect And balancing in the tradition potentially through the CB |
|
| 55:22 | receptor mechanism. Cannabinoids that are in the ones that are in human body |
|
| 55:31 | the brain are called endemic anonymous. as to A. E. |
|
| 55:38 | Anandamide to A G. Cannabinoids that hear about. Canada's and phenomenal cannabis |
|
| 55:48 | a plant. And Kanam Iran is molecules that are synthesizing Canada's plant to |
|
| 55:56 | the majority of them in the mostly female flowers of Canada's plants, |
|
| 56:03 | would be very densely populated by tri . These are these translucent mushrooms like |
|
| 56:11 | extrusions and bland repetitions to come out the lease. And they have a |
|
| 56:18 | bio synthetic machinery and the stock and head to produce cannabinoids. But to |
|
| 56:25 | aromatic champions to give Canada, does smell? So we've done it smell |
|
| 56:32 | cannabinoids, cannabinoids from the front. can only smell Turpin's with these turbines |
|
| 56:37 | volatile odor molecules that gets produced in hands of the Tribals. So let's |
|
| 56:44 | with some of the basic things, don't know if you know, but |
|
| 56:47 | you don't, I will tell you industrial home for low THC cannabis Which |
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| 56:54 | up to 0.3% THC in the United is considered illegal federally illegal crops. |
|
| 57:03 | these are very tall plants that can grown for stems and stock and leaves |
|
| 57:11 | industrial purposes. Or it can be for flowers to obtain cannabinoids and to |
|
| 57:18 | uh Turpin's from medicinal purposes. Mostly sativa also susceptible. Gladiolus uh in |
|
| 57:28 | the hemp lines are combinations or hybrids sativa indica and potentially limited. 0.3% |
|
| 57:39 | . And the plant, the final and the states that have low THC |
|
| 57:44 | program, federally legal hemp program that's to have products that contain 0.3% THC |
|
| 57:51 | below. That's gotta amount of 0.2% is the limit in Europe. |
|
| 57:58 | in some countries in europe, there their own limits. So italy would |
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| 58:03 | this limit of 0.6 Switzerland 1% And that's because the plant likes to |
|
| 58:11 | and raise the THC level of something in the clients that the temperature is |
|
| 58:16 | than a little bit of stress. produce a little bit more THC that |
|
| 58:20 | it across. It is far beyond loud level, which for farmers that |
|
| 58:28 | and the result and destroying the crop um for medicinal purposes, maybe repurposing |
|
| 58:35 | for industrial purposes. Only when you about medical cannabis, when you talk |
|
| 58:41 | adult use of recreational cannabis, particularly levels of THC. These are usually |
|
| 58:48 | plants, most of them are sativa hybrids. The most amount of cannabinoids |
|
| 58:55 | these flower wind tops called Nicola Scan up to 36 Canaveral in total and |
|
| 59:04 | is rare to find a cannabinoid output delta nine THC. That's higher than |
|
| 59:11 | . I have seen testers almost 40 levels and plants as high as |
|
| 59:17 | But that's all the genetic material because plan has to do something else to |
|
| 59:21 | besides making capitalism therapy is it has survive. Mhm. Do things that |
|
| 59:28 | need to do to live. So a maximum cut off. His genetic |
|
| 59:34 | can produce. About 36% of total . We talked about synthetic marijuana or |
|
| 59:40 | cannabis. No one thing is they're cactus. Is this synthetic orange that |
|
| 59:45 | have seen. Is there a synthetic tree? Plastic? But synthetic is |
|
| 59:53 | ? Okay, synthetic does not come the plants. And when you hear |
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| 59:56 | synthetic phenomenons, they're dangerous addictive. can be inducing psychosis and neurological and |
|
| 60:04 | problems. Following one or two it's synthetic and fake and it's usually |
|
| 60:11 | some plant matter and called kush or to replicate some of the common marijuana |
|
| 60:16 | some of the common hemp strain names mythical strain names that these plans may |
|
| 60:24 | . So this is very different. dangerous and they're much more potent |
|
| 60:29 | About 1000 times more potent synthetic THC to natural milk and nine THC. |
|
| 60:36 | the plant the housing times more potent the CB one receptor. The consequences |
|
| 60:45 | by the unknown and dangerous for these . How I became interested in apple |
|
| 60:54 | and cannabis is when I was doing in my lab on driving syndrome. |
|
| 61:00 | my eyes. I was watching the of charlotte figi in this beautiful young |
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| 61:07 | who unfortunately passed last year Charles figure Edward ma training position he made a |
|
| 61:17 | for medical marijuana in treating her severe couple of Civ infancy the driver's |
|
| 61:25 | And so and this was happening in early 2000s. This publication came out |
|
| 61:31 | 2014, But medical cannabis was legalized California. Medical purposes in 1996, |
|
| 61:40 | history of medical Canada is being realized that people that were having HIV and |
|
| 61:47 | and also advanced stages of cancer, following treatment of chemotherapy. Those patients |
|
| 61:55 | go through wasting syndrome. We would appetite, would not want to eat |
|
| 62:00 | that would contribute to there faster rates mortality, shorter living span and hippies |
|
| 62:13 | the 70s, in Oregon, in , british Columbia. In Canada realized |
|
| 62:21 | started using candidates for recreational purposes. gave it to their friends that had |
|
| 62:28 | severe of immune uh disorder, AIDS wasting syndrome from cancer. And those |
|
| 62:41 | are like, hey, it makes makes us hungry, we're gonna eat |
|
| 62:47 | and it made them coke and deal with nausea from chemotherapy. So there |
|
| 62:55 | two positive effects that the community saw people that started using marijuana smoking |
|
| 63:02 | they started seeing positive effect of gaining and also reducing some of the negative |
|
| 63:09 | effects of chemotherapy. So in the is when the synthetic pharmaceutical drugs came |
|
| 63:16 | . But it was the hippies actually the 70's that discovered this through their |
|
| 63:21 | with their extracts from home, grows lot of them. unfortunately in that |
|
| 63:27 | being incarcerated, really paving the way the modern day industry of medical cannabis |
|
| 63:35 | medical phenomenons in general. Somewhere in 2000, 2000 and 10, |
|
| 63:41 | 13 14, all these mothers that Children with Dravet syndrome and severe my |
|
| 63:47 | efforts and then from the house passes generalize our policy with few procedures. |
|
| 63:55 | they were showing up to the legislators to the regulators and saying, hey |
|
| 64:00 | at this bag of medicines, I to give this to my child everyday |
|
| 64:05 | thousands of dollars to treat my And still after years I'm just seeing |
|
| 64:12 | being with him wasting away. In year's been a policy doesn't form and |
|
| 64:18 | mothers started asking him give us it was cannabis. Let us try |
|
| 64:24 | historical reasons for there is uh case for There's reports coming out of California |
|
| 64:31 | Colorado because these are the two liberal , more liberal states that we're legalizing |
|
| 64:38 | candidates early on in California 96 in , I believe a few years after |
|
| 64:45 | . And so the story of charlotte comes in this girl that is taking |
|
| 64:51 | of these prescription drugs and she's she's basically like drunk kind of |
|
| 64:57 | She's staggering, has a taxing and dizzy and Sanjay Gupta from CNN, |
|
| 65:06 | chief medical correspondent goes to interview the of charlotte figi who were ex military |
|
| 65:12 | they or against marijuana. They moved colorado. And they tried using extracts |
|
| 65:19 | charlotte figi and in particular extracts that CBD cannabidiol and had a very positive |
|
| 65:27 | reducing Sears and trial it who was hundreds hundreds of seizures sedan control |
|
| 65:35 | And that's what prompted their parents to states to gain access to cannabis in |
|
| 65:42 | , which at the time it was . Hundreds and thousands of stories of |
|
| 65:46 | Children or their parents doing all sorts concoctions followed, which really I think |
|
| 65:54 | to everybody to the lawmakers and Look we have to do something about |
|
| 65:59 | . There's something going on outside the system. It cannot be discarded as |
|
| 66:06 | anecdote anymore. Now we're dealing with of case studies, medical case studies |
|
| 66:12 | the world, you can no longer ignored. And so there's some changes |
|
| 66:17 | the society and changes and with the and came about historically, what you |
|
| 66:24 | to know is medical cannabis was never upon badly or frowned upon by a |
|
| 66:31 | doctor. It's just the last 40 years of medical school training and |
|
| 66:39 | marijuana. A schedule one most dangerous drug that has no medicinal use whatsoever |
|
| 66:47 | is still on schedule. one by D a can you do with him |
|
| 66:53 | on schedule for a while but it changing there's a talk about the |
|
| 66:59 | there's a talk about Regulating and you all of the state's 38 states having |
|
| 67:06 | sort of a medical cannabis program. to 50 states and one shape or |
|
| 67:11 | have something. I think maybe there's states that are abandoned. Everything. |
|
| 67:16 | of the states that wants to go Dakota, sorry, I fear from |
|
| 67:22 | been. So, I'd like to to the south For no particular reason |
|
| 67:26 | that there's two north and south. think south would be one of |
|
| 67:32 | So this reports that are coming out 14 report of a parent survey, |
|
| 67:39 | , in which cannabis, recent pediatric resistant epilepsy case for medical marijuana and |
|
| 67:44 | with dr martin page figure, which charlotte figures mother from that. There |
|
| 67:49 | a strain that was named after her was called charlotte's Web. And there |
|
| 67:54 | a whole commercial aspect that grew out that. And since then there's other |
|
| 67:59 | that were developed specifically high CBD strains contain high levels of CBD, such |
|
| 68:04 | catatonic. There was hope that the toll. Most of these strains have |
|
| 68:10 | to do with industrial hemp because industrial , typically the sativa strains have high |
|
| 68:16 | of CBD cannabidiol versus THC, delta THC perceived african, another dollar which |
|
| 68:23 | extract creating pediatric epilepsy, potential infantile and Levitz syndrome. This is all |
|
| 68:32 | in 2013, 2015, it's emerging a very formal story. It's emerging |
|
| 68:40 | a very old story that dates back of years ago. recorded in fact |
|
| 68:47 | 3000 years ago, and described here great detail, including with hydration of |
|
| 68:55 | active ingredients to treat ap sports and treat seizures In 1843, by one |
|
| 69:08 | the great inventors, great minds, positions, explorers, um William johnson |
|
| 69:21 | the, I can see that we're gonna finish talking about cannabis today, |
|
| 69:28 | I don't want to necessarily rush through because there are certain things that I'd |
|
| 69:32 | to explain, and I'd like to walk you through the story Of this |
|
| 69:37 | here that is being treated for infantile in 1843, and the approach that |
|
| 69:44 | Sean C takes and describes in detail in this case of infantile convulsions, |
|
| 69:52 | known as infantile spasms. So, we're leaving at this. Thank you |
|
| 69:59 | |
|
