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Saturday, May 2, 2015

10 Rules for Assessing the Value of NeuroPharmacological Studies; How a Substance will Affect You & Why


HOW TO DETERMINE HOW A DRUG, CHEMICAL, OR NATURAL COMPOUND WILL AFFECT A LIVING HUMAN SUBJECT BASED ON A PUBMED STUDY OR REFERENCE & WHY


1.) Identify what is MISSING in the study before you register what is there.

  • In other words , analyze unaccounted for parameter's or factors such as age, body weight, receptor integration etc.
  • Look for determining cues of result fluctuation, or possible other reasons that could substitute or mimic the effect of the substance of question. Is it a significant difference than placebo and how many regions do the compounds effect?

2.) Determine whether the effects of a substance are primarily due to indirect 'shifting of receptor activity, or whether a direct effect of signal transduction modulation at the direct level. 

  • Say you are talking about a 5-HT6 serotonin antagonist, and the study of it's pro cognitive effects. The receptor is positively coupled to adenylate cyclase. Therefore, does blocking it improve cognition because of the reduction of that enzyme or because the remainder of endogenous serotonin shifts to other receptors such as 5-HT5A, 5-HT4?

3.) REMAINDER RATIO. 
  • Based on the above. Is the remainder of a neurotransmitter going to have a better chance to bind to cognitive improving receptors after the 5-HT6 is blocked? To figure this out, calculate the effects of each serotonin receptor, and the ratio of pro-cognitive to generally anti-cognitive receptors...e.g 5-HT4, 5-HT5A and 5-HT1A agonists are shown to improve cognitive function, whereas 5-HT3,2A,7A,1B,1D are anti-cognitive. 


4.) Distribution of Receptors; mapped to brain regions. 
  • Specific brain regions have more of certain receptors than others in the human brain, thus we have to figure out whether the more substantial effects are due to the higher occurrence of binding by a particular compound, due to more receptors to bind to. E.G , is a 5-HT6 antagonist more effective than a 5-HT4 agonist because there are more 5-HT6 receptors in the hippocampi of the human brain.

5.) Receptor CO-LOCALIZATION :

  • Are the effects of agonizing a certain receptor or antagonizing it due that receptor being cross-wired or colocalized with another, e.g 5-HT6 receptors are also present on GABAergic terminals therefore is antagonizing it an actual result of dual GABA inhibition due to cross over effect. Nerve terminals are incredibly complex, and heterodimization is another key factor in receptor functionality and interactions.



6.)
Have an active knowledge of basic biochemistry principles. 
  • Does the substance in mention have a phenyl group, hydrazide addition, acetyl group or addition - and thus based on it's chemical principles, is it permeable to the blood brain barrier? Additionally, is it's molecular mass small enough for it to be considered bioavailable or usable by the body? Does the substance meet Lipinsky's Rule of Five?

7.) ADMINISTRATION METHOD

  • Is the substance orally active in the study? Do the chemical properties of the substance allow it to be orally available? 
  • Additionally, is transdermal or injection a better method , or 'preferred' in the study?


8.) HALF-LIFE  / ACTIVE-LIFE
  • Is the substance going to have translatable effects and a feasible half-life that doesn't infiltrate convenience? Thus display modern degrees of benefits.

9.) Whether the substance is metabolized by P-GLYCOPROTEIN, CYP34, and generally how the liver can process it.

  • If the substance has benefits, but is broken down too quickly or requires additional enzyme modification for it to reach consistent blood levels, then it may not be a valuable substance standalone.

10.) Whether the substances true effects are based off of co-administration in the study or it's interactions with other undocumented factors (such as hormone replacement or modification).

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