Druggability (continued tail)

Correction for nonspecific binding both to brain tissue and plasma proteins Total Brain/Plasma Ratio (Kp) Cu, brain = unbound concentration in brain A molecule is commonly deemed “brain penetrant” if its brain-to-plasma concentration ratio (Cb:Cp) is >0.04
Solubility	(Charlie) Solubility: drug is considered highly soluble when the highest therapeutic dose is soluble in 250 mL or less of aqueous media within the pH range of 1- 6.8 at 37 ℃
Permeability (oral absorption)	A drug substance is considered highly permeable when the extent of absorption in humans is determined to be 90% or more of the administered dose based on amass-balance determination or in comparison to an intravenous dose.
MPO	>4.5 (CRL vervally said at 20230728 TRAP1 Meeting)
Solubility	{Lipinski, 2000 #1879}	acceptable criteria
lipohilicity		LogP?

DWI VS DTI

	DWI (Diffusion-weighted magnetic resonance imaging)	DTI
most applicable	when the tissue of interest is dominated by isotropic water movement (ie where the diffusion rate appears to be the same when measured along any axis)	A special kind of DWI when a tissue—such as the neural axons of white matter in the brain or muscle fibers in the heart—has an internal fibrous structure analogous to the anisotropy of some crystals. Water will then diffuse more rapidly in the direction aligned with the internal structure, and more slowly as it moves perpendicular to the preferred direction
Most applicable regions	grey matter in the cerebral cortex and major brain nuclei	White matter (tract)
parameter	diffusion coefficient, or more exactly the apparent diffusion coefficient (ADC).	diffusion anisotropy measures such as the fractional anisotropy (FA)
In PD		{Zhang, 2015 #1629} Relations between DTI variations of the nigrostriatal tracts in PD and motor deficits based on UPDRS part III scores (UPDRS-III) are illustrated in Figure 4, separately for FA, rD, and aD. A significant relationship was found for nigrostriatal FA and rD, but not for aD. There was a trend (p = 0.09 via likelihood ratio test) towards an interaction between UPDRS-III and ipsilateral/contralateral definition, with nigrostriatal FA decreasing more substantially for larger UPDRS-III on the contralateral side. Specifically, after controlling for age and gender, per unit increased in UPDRS-III corresponds with a 0.40% (CI95: 0.11% to 0.68%) decrease in contralateral FA and a 0.30% (CI95: −0.17%, 0.44%) decrease in ipsilateral FA. rD increased on average 1.05% (CI95: 0.47 to 1.64 %) as per UPDRS-III unit increase, without significant differences between the contralateral and ipsilateral side. aD was not significantly correlated with UPDRS-III (p = 0.2). {Zhang, 2020 #1630} systematic review:

Dyskinesia

타케시:

• Takeshi introduced the proposed mechanism of L-dopa induced dyskinesia: in advance stage DaN axon damage causes the reduced uptake of excessive dopamine, which links to the fluctuation of dopamine level. Questions exist on can we find pts at the early stage rather than advanced stage (DaT scan may be the tool to find the pts as it can detect axonal damage)? nature history of the pts from early stage to advance stage, movement scales, time frame? (Amount of levodopa dosage requirement will be helpful to see that change)

Disord. 1998; 13(6): 885-894
Neurobiol. 2015;132:96-168.
Mov Disord. 2019;12:161-165

Clinical presentation of Dyskinesia in PD

{Schrag, 1998 #1701} not yet full text	1998	25- 40% after 4-6 years of levodopa therapy After a disease duration of 10 years or less, only 5% of patients were experiencing falls and 30% freezing, but all patients had developed L-dopa-related fluctuations and dyskinesias.
{Bastide, 2015 #1703}	2015	up to 80% of patients having LID within 5 years of treatment Eighty to ninety per cent of PD patients suffer from LID after 10 years of DA replacement therapy
{Martini, 2019 #1704}	2019	peak-dose dyskinesia (involuntary movements that coincide with the peak-action of levodopa and thus period of best anti-parkinsonian action), : most common (70%), Peak-dose dyskinesia is seen at high plasma drug level (eg. beginning 80–90 min after levodopa) OFF period dystonia (=wearing-off dyskinesia): 30% , seen when the serum level of levodopa is least, They are commonly seen in early morning diphasic dyskinesia (involuntary movements that emerge just before the DA replacement therapy turns the patient ON and that reappear at the end of the therapeutic benefit) : least common (14%), seen when serum level of levodopa is going up or down coinciding with two peaks of abnormal movements, one present at the onset of drug effect and another present at the end of drug effect.[11]

MOA of Dyskinesia

Normal	In DA nerve terminas: there are autoregulatory mechanism i) DAT ii) D2 autoreceptors, so they can buffer when DA are in excess In Serotonergic neuron: s are a another source of dopamine release in striatal synapses (AADC convert L-DOPA into dopamine), but there is no autoregulatory/buffer process
In PD	DA n terminal 은 없어 buffer 없고, 더군다나 serotonergic n 늘이 보상석으로 더 DA release 하고 있는 상태인데, When L-DOPA is administered to PD patients, synaptic dopamine levels oscillate as serotonergic neurons metabolize L-DOPA to dopamine but fail to autoregulate in response to elevated dopamine levels → ↑ LID{Martini, 2019 #1704}
PD?	levodopa therapy may sensitize the nigrostriatal system but (it alone) does not induce dyskinesia in the setting of preserved dopaminergic circuit [3]. a lack of presynaptic dopamine storage capacity, increased extracellular levodopa and pulsatile stimulation of dopamine receptors [4,5,6]. [Hattori] Dyskinesia in PRKN-PD is dominant in the lower limb, so-called dancing-feet dyskinesia. His team is trying to elucidate its mechanism by electrophysiological approach by using Prkn KO rat. Flash result suggests D1 signal is associated with dyskinesia. Prog Neurobiol. 2015;132:96-168.

Uncertain Spans

location	transcription	uncertainty
Clinical presentation / 1998 row	first-column reference label appears truncated at the page edge; full label {Schrag, 1998 #1701} not yet full text confirmed via the next photo (20240722_182950).	left edge clip; not derived from this page alone.
MOA of Dyskinesia / row labels	left-edge clip shows nal and the In PD row label n PD truncated; full labels Normal and In PD confirmed via the next photo (20240722_182950).	left edge clip; not derived from this page alone.