 NEUSCI 404 Notes

Lecture 10 (4.21)

6.2) Evidence-Based drug development: Transformative therapeutic approach

 Reliable source of bioactive compound -> Delivery system -> Body distribution
pharmacokinetics -> Molecular mechanism -> Cell response -> Therapeutic index ->
Human clinical trials

6.3) Clinical trial : preclinical and human

 Preclinical trial: two small animals – in vivo efficacy, PK and toxicity; large animal:--
toxicity
 Phase I: small population healthy subjects (~10-20 people def under 100) for safety and
initial pharmacokinetic data. Usually male subjects. Occurs in hospital with constant ECG
and blood monitoring
 Phase II: small population of patients (100-300) for safety (aka not worsen the disease)
and initial drug efficacy data
 Phase III: large multi-center trial (1000+). Must gather enough data to prove to the FDA
the efficacious (statistical significance – i.e., drug is at least as safe and as efficacious as
other drugs currently available)
 Phase IV: drug is FDA approved and data acquired to capture quality of life and safety in
millions of pts

6.4) Clinical Trials: Challenges (recruiting and phase 0)

 Recruiting patients
 Considerations: placebo, side effects (grade 1-5), disease readout, overall
survival/disease free survival, tumor volume, age, etc.
 Phase 0: window of opportunity
o Surgical trials early during drug development
o Pts receive therapeutic agents for 1-2 weeks prior to surgery
o Tumor from both enhancing and non-enhancing areas obtained at surgery are
analyzed for drug concentrations and PD effects

6.5) Clinical trials: innovative optimization (changing designs and leverage personalize
medicine)
 waterfall (linear) -> agile
 De-risk (faster, cheaper), master protocol, infrastructure, regulatory, multiple
indication , biomarkers, strong control populations, rational combination therapies,
international regulatory alignment

6.6) Clinical trial : Innovative optimization (basket/umbrella/platform)

 Basket (multiple diseases -> common targets interventions)
 Umbrella (single disease -> multiple targeted interventions)
  Platform (see slide)
o Reduces number of placebos

6.7) Medical properties: in humans (expert committee of the national academic of sciences,
engineering and medicine)
 Nearly 100 conclusions related to the health effects of cannabis and cannabinoid use
o Therapeutic effects: antiemetic, chronic pain, MS
o Risk: cardiometabolic, cancer, respiratory disease, immunity, psychosocial,
mental health, abuse

6.8) THC Bioactivity: response occurs along continuum

See slide
6.9) CBD bioactivity: response occurs along continuum
See slide

6.10) Dynamic Therapeutic Index: age and vulnerability dependence

 THC more toxic for younger pop

6.11) Drug discovery and development: evidence based (example of anti-cancer drug)
 In vitro -> In vivo -> Preclinical trials (efficacy & toxicity, therapeutic index, manufacture)
-> Clinical trials (efficacy & safety, first in human)

6.12) drug discovery and development: drug failure

See slides

Lecture 11 (4/23)
6.13) vulnerable population: age and subpopulations (brain development vs medicinal
properties)
 Cannabis use by young adults
o Wide used “illegal drug”
o Concerns about new products
o High THC affect young brain development
o Consequence on adult cognitive function
6.14) Effect on brain development: embryonic and adolescents (evidence on the negative
impact of THC use)
 THC use by adolescents
o Neuronal connection impact
o See slides

6.15) Pregnancy and Young adulthood: Effect on brain development (evidence on the impact of
THC use)
  Need for well-controlled studies in human and preclinical models on THC as a
development neurotoxicant

6.16) THC impact on adolescent brain: Loss of Cb1R in VTA (voluntary oral consumption in
rodent preclinical models)
 Gelatin edibles containing YHC consumed during adolescence
o CB1R receptor and v GLUT loss in males
 THC use during adolescence impacts resulting adult brain anatomy

6.17) Impact of adolescence: Effect on decision making (measure of pavlovian reward-

predictive cue behavior in adult rats)
 Males -> inc. risk
 YHC in adolescence impacts decision-making in adult males

7.1) Dravet syndrome: from basic science to treatments (study and optimize the anti-seizure
properties of phyto-canabinoids)
 Genetic disease ion channels interneuronopathy
o Mutation in ion channel (usually Na)
o Majority impact inhibitory GABAergic neurons
 Spectrum of SCN1A disorders & therapeutics
o See slides
o Ca channel blockers etc.

7.2) Cannabinoids reduce seizures: from basic science to FDA approval (study and optimize the
anti-seizure properties of phyto-cannabinoids)
 Preclinical evidence that cannabinoid reduce seizures
 Cannabis use by epilepsy patients
 Cannabis clinical trials

7.3-5) clinical trial: CBD in DS

 Placebo effect big for the observational studies
7.6) CBD and Scn1a +/- mice: effects on seizures (thermal and spontaneous seizure behavior)
 Preclinical genetic mouse model of DS
 Efficacy on acute thermal seizures
 Efficacy on spontaneous seizures
7.7) CBD and Scn1a+/- mice: effect on Dentate Gyrus Excitability (Hippocampal slice
electrophysiology)
 Inhibitory interneuron downregulated in DG -> seizures
 DG recording: AP
o Number reduced
 DG recording: spont.
o IPSCs measures (increased)
 Dg recording: AP
 o Antagonize GPR 55 (how CBD reduces AP)
o CBD acts and an antagonist on GPR 55
 CID = also antagonist
 CID+ CBD together gives no other impact
7.8) CBD and Scn1a+/- mice: effect on Behavioral impairment (acute activity of CBD social
behavior)
 Reverse effect on autistic behavior
o Recover normal social behavior

7.9) CBD and other mouse models of epilepsy: therapeutic indication

 Chronic administration of cannabidiol modifies the overall spon seizure burden ratio and
seizure burden in the reduced intensity status epileptic (SE) –induced spontaneous
recurrent seizures rat model of chronic temporal lobe epilepsy
 Acute administration of subtherapeutic doses CBD attenuates maximum seizure severity
to a similar degree as subtherapeutic doses of the prototype antiseizure drug