Figure 4. Examples of D₁ (A) and D₂ (C) DAR binding autoradiographs at the caudal level of the striatum. The horizontal line under each example indicates the mean percentage of DAR binding. Nonspecific binding is shown on the bottom left corner of each panel. Below each of these examples, a scatter plot shows the mean binding data (open circles) of, respectively, D₁ (B) and D₂ (D) ligands, measured in the putamen at the caudal level, all quadrants of all animals being plotted (dark circles, n = 20 in D0, D12, D15, and D25 groups and n = 16 in D6 group). Data are in femtomoles per milligram of tissue equivalent. D, Dark line interpolates the mean binding data of D₂ ligand to underline the biphasic changes.
js: not informative tool, as shown above, not correlated at all with nigral neuronal loss
Druggability
| Lipophilicity | (Agoni et al. 2020, PMID): molecular weight of 200 and lipophilicity of − 2 < logD7.4 < 5, and a triangle apex, molecular weight of 450 and logD7.4 = 1.0–2.0. | ||||||||||||||||||||||||
| CNS penetration |
fu,b: unbound fraction in brain? Kp = AUCtotal,brain/AUCtotal,plasma = Total Brain/Plasma Ratio 그래서 이건 단위가 없구나 (%로 표현되지 않음) Kp=1 의 의미는 뇌와 blood 에 동등한 농도이다 ! | ||||||||||||||||||||||||
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Below {Summerfield, 2016 #1987} Kp,uu values were derived from steady-state intravenous CNS penetration studies in rodents Example : paracetamol Kp,uu ≈ 1
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Fig. 1. Bar graph showing steady-state Kp,uu values for CNS drugs, ordered along the x-axis in terms of increasing in situ BBB permeability (reference data reported in Summerfield et al., 2008). Kp,uu = Kp * (fu,brain / fu,plasma) Kp,uu = AUCu,brain/AUCu,plasma Kp,uu = (AUCtot,brain / AUCtot,plasma) * (fu,brain / fu,plasma) Kp,uu = Kp(in vivo) / Kp(in vitro) 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 | |||||||||||||||||||||||
| Lipophilicity | 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). |
Uncertain Spans
| location | transcription | uncertainty |
|---|---|---|
Druggability / NLRP3 inhibitor TR06673219 / Method | Free (잤지 ?) plasma AUC (nM*h) | the parenthetical Korean annotation is small and partially blurred; the question mark is the author’s own uncertainty marker. |
Druggability / Solubility / Charlie | pH range of 1- 6.8 at 37 ℃ | trailing degree-Celsius glyph appears as 1 in some OCR; visual confirms ℃. |
Druggability / Solubility (lower row) | row label Lipophilicity paired with value LogP? | the property label in the lower-row left column is faded; Lipophilicity is the most consistent reading from the figure-caption neighborhood. |