How can we weigh the efficacy and side-effects of a drug?

Computational molecular docking can be a useful technique

Nitish Jan 29, 2021

[1]https://www.hindawi.com/journals/bmri/2020/1357630/

[2]https://www.hindawi.com/journals/bmri/2020/4675395/

[3]https://www.hindawi.com/journals/cmmm/2020/1573543/

Shubhankar Kulkarnia month ago

Thank you for the contribution Nitish! All the papers you have cited explain ways that help predict the side-effects of a drug. What I am looking for is solutions to measure these side-effects. As a simplistic example, what I want to do is assign a number to each side-effect based on its impact on a person's life - if mild headache is assigned a value of 1, moderate 2, severe headache will be 3. Recurring episodes of headache will score more according to this measurement. Now, this was regarding a single side-effect - headache. If we were to expand this to other side-effects, how could we go about it? If headache was assigned a value of 1, what would nausea be?

However, I think this suggestion of yours can be modified slightly and posted on another session on the ways artificial intelligence can be used to improve aging research and medicine (https://brainstorming.com/sessions/in-what-ways-can-ai-be-used-to-improve-longevity-research-and-or-medicine/266). I will add it there.

Nitish25 days ago

Shubhankar Kulkarni25 days ago

Nitish Yes, the severity chart should be able to compare different intensities as well as different side-effects altogether.

I entirely agree with your point that side-effects may vary largely on the individual level. There may be inter-individual differences in the reactions to the same drug. Are the studies that you mentioned in your suggestion capable of detecting these inter-individual differences? Correct me if I am wrong but I thought these studies have built tools that try to identify the side-effects in humans in general. Since these tools take the docking, drug-effect, and drug-drug association data from sources that do not display data at the individual level, I think these tools would not be able to determine which individuals may show a particular side-effect and which may not.

Also, the side-effects vary between individuals in terms of intensity, too. That will be really difficult for the tools to predict with the information they use.

Also, although the side-effects affect different individuals differently, there are some effects of the drugs that affect most or all individuals. After all, the major beneficial effect of the drug is common to most. Similarly, there exist side-effects that are common to most.

The problems "behind the scenes"

J

Juran Jan 31, 2021

[1]https://www.aaai.org/Papers/Symposia/Spring/2006/SS-06-01/SS06-01-012.pdf

[2]https://www.aaai.org/Papers/Symposia/Spring/2006/SS-06-01/SS06-01-012.pdf

Shubhankar Kulkarni25 days ago

Hi Juran K. Thank you for your contribution. I agree with this completely.

Every drug has an FDA label attached to it, which contains reliable information regarding the composition, the use, the contra-indications, and the side-effects of the drug. However, as you pointed out, the media that present us the information regarding a drug do not need to include all that information in detail. Even if they mention them, it is in a tiny font. Also, even the drug labels do not contain the necessary information regarding the "intensity of pain, the frequency, length, specific location, pattern of occurrence" of the side-effect. Now that I think of it, even most clinical trial reports do not mention the intensity, frequency, and pattern of the side-effects. So basically, such information is not even noted. If it is noted, it is not made public.

One of the problems behind this may be the ignorance that comes with the word "side". The general norm is that side-effects are not mainstream effects and "should be" tolerable in light of the benefit that the drug brings. The second problem is we do not have a universal side-effect measuring system that attaches a cumulative score to a drug based on all its side-effects. Since we have not been able to measure different side-effects using the same scale, attaching such a score is currently not possible. This feels like a chicken and egg problem. Although this is not the only reason behind the problem, maybe if someone comes up with a reliable scoring system, such data could be noted.

How to know which side-effect is valid? Solution: "Reporter" in every drug

J

Juran Feb 01, 2021

Manel Lladó Santaeularia24 days ago

First of all, having the same reporter to every drug seems like a bad idea because in case a person takes more than one drug (even if they don't interact) you could not discriminate between them.

Secondly, as Shubhankar Kulkarni eloquently described, metabolism and excretion of drugs is a multifactorial trait that varies a lot between individuals. And most drugs and compounds are metabolized pretty fast. In some cases, actually, the metabolite of the drug we have delivered is actually the active component. So in this case we should decide whether this reporter is a reporter before or after being metabolized, and we should know very well what is its average half-life. 

Third, also because of metabolization and secretion of compounds, it would be very possible that once the patient comes in to describe their side effects, the drug and reporter are mostly gone, so I don't think it would be possible to correlate that directly.

Do you think we could find a way to assess those issues and make this original idea better?

J

Juran24 days ago

Shubhankar Kulkarni25 days ago

I like your idea, Juran K. . I am thinking about how this idea can be used to tackle our problem of measuring the side-effects. One way is to measure the concentration of the reporter that is attached to the drug molecule. Some individuals might be more efficient at excreting the drug from the body or degrading it than others. The intensity of the side-effects can be compared to the concentration of the reporter, and the intensity of each side-effect could be then attributed to the reporter/ drug concentration. This way we may be able to resolve the inter-individual differences of the effects of the drug. Any other way this idea can be used to measure and normalize side-effects?

Each drug comes with a bunch of contra-indications. I guess it is the job of the prescribing physician and the patient to check if they do not have any of the mentioned contra-indications. For example, ironically enough, the covid vaccine is contraindicated to the immuno-deficient individuals.

I feel that the side-effects due to improper use should not be included in the cumulative side-effect score for the drug. The drug should not be judged based on the people who use it.

PS: This idea of yours - "drug reporter" could be posted as a separate idea on the platform.:)

How can we be completely sure when we attribute a side effect to a drug?

Manel Lladó Santaeularia Feb 03, 2021

Shubhankar Kulkarni22 days ago

I don't think one can ever be 100% sure while attributing an effect to a drug. There are a number of physiological pathways and their interconnections we don't know about. Improvement in one pathway can mean destruction in the other. That is why we attach a level/ threshold of significance to both the benefits as well the side-effects.

If 1 out of 1000 participants has a heart attack, more in vitro and animal studies may be needed to confirm that the drug has some influence on the heart. Also, there exist only so many signaling molecules in the body to perform a large number of functions. Multiple functions are attributed to a single molecule and multiple molecules may perform the same function, and the location of the interaction in the body adds another level of complexity. So, one drug will have multiple effects - some might be beneficial and some, not so much.

For the immediate side-effects, Juran K. 's idea of a "reporter" in every drug can be used. For effects that build over time, multiple factors may have contributed to the effect.

Darko Savic23 days ago

Measuring side effects objectively - PAIN

J

Juran Feb 01, 2021

[1]https://associationofanaesthetists-publications.onlinelibrary.wiley.com/doi/full/10.1111/anae.13018

[2]Duerden EG, Albanese MC. Localization of pain-related brain activation: a meta-analysis of neuroimaging data. Hum Brain Mapp. 2013;34(1):109-149. doi:10.1002/hbm.21416

[3]https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6979466/pdf/f1000research-9-22472.pdf

[4]Ploner M, Gross J, Timmermann L, Pollok B, Schnitzler A. Pain suppresses spontaneous brain rhythms. Cereb Cortex. 2006 Apr;16(4):537-40. doi: 10.1093/cercor/bhj001. Epub 2005 Jul 20. PMID: 16033927.

[5]Nir RR, Sinai A, Raz E, Sprecher E, Yarnitsky D. Pain assessment by continuous EEG: association between subjective perception of tonic pain and peak frequency of alpha oscillations during stimulation and at rest. Brain Res. 2010 Jul 16;1344:77-86. doi: 10.1016/j.brainres.2010.05.004. Epub 2010 May 10. PMID: 20460116.

[6]Fernandez Rojas R, Huang X, Ou KL. Toward a functional near-infrared spectroscopy-based monitoring of pain assessment for nonverbal patients. J Biomed Opt. 2017 Oct;22(10):1-12. doi: 10.1117/1.JBO.22.10.106013. PMID: 29076307.

[7]Zhang J. How far is arterial spin labeling MRI from a clinical reality? Insights from arterial spin labeling comparative studies in Alzheimer's disease and other neurological disorders. J Magn Reson Imaging. 2016 May;43(5):1020-45. doi: 10.1002/jmri.25022. Epub 2015 Aug 6. PMID: 26250802.

[8]van der Miesen MM, Lindquist MA, Wager TD. Neuroimaging-based biomarkers for pain: state of the field and current directions. Pain Rep. 2019;4(4):e751. Published 2019 Aug 7. doi:10.1097/PR9.0000000000000751

[9]Koyama, S., LeBlanc, B.W., Smith, K.A. et al. An Electroencephalography Bioassay for Preclinical Testing of Analgesic Efficacy. Sci Rep 8, 16402 (2018). https://doi.org/10.1038/s41598-018-34594-2

Shubhankar Kulkarni24 days ago

This is helpful Juran K. This is one way to normalize all the side-effects - check the amount of pain they cause. I have some questions:
1. Is the amount of pain observed/ measured during brain imaging the same for people who can tolerate more pain and those who cannot? Does the level of tolerance of pain affect the measurement? It would be true normalization if the level of tolerance of pain did not affect the pain measurement.
2. A follow-up of the above question - If it is true that the level of tolerance of pain did not affect the pain measurement, is that pain measurement a just (or unjust) measurement? Here, both those who can tolerate pain and those who cannot show the same pain measurement due to a side-effect. I think it is a just measurement. The amount of pain due to a drug should not be dependent on any other parameter (like fitness) of the individual. What do you think?

This imaging method can account for all the side-effects that cause pain. What about those that do not? I don't think nausea causes any pain or does it? And do psychological side-effects cause pain that can be measured using this technique?

Anyhow, this technique will be highly useful and will take us multiple steps closer to our goal, if realized. This should be used in drug clinical trials and personalized medicine.

J

Juran24 days ago

Shubhankar Kulkarni I was not using the pain to normalize all the side effects, but the pain itself as a side effect (e.g. headache, arm/leg pain, belly ache, ...). Nausea probably has different approaches that can be used to measure the intensity, type, and other characteristics. If the described system was developed for every side effect, the network could be built and the general side effect index could be calculated.

I understand your concerns. It is true that a poor correlation was reported between the regional tissue damage and the subjective feeling of pain [1], meaning people feel pain differently.

Summary: 
1 _ I think the level of tolerance (and other factors) affects the measurement. 
2_ In my opinion, non-integrative neuroimaging itself is an unjust measurement. 
________________________________________________________________________________________

1 _ I think the level of tolerance (and other factors) affects the measurement. 

It was shown that repeated painful stimulation over several days resulted in substantially decreased pain ratings to identical painful stimuli [2] (measured by neuroimaging techniques). Not only that. Studies confirmed that doing a task while experiencing pain stimuli can reduce the pain experience [3]. Therefore, many things, not only tolerance, can change the experience of pain and parallelly, the neuroimaging measurements. 

To explain this in detail, as mentioned in the paper [3], pain disrupts the behavior in various ways - by interfering with sensory, motor, and cognitive processes. Therefore, it's could easily be true that the same pain stimuli provoke the same patterns of nociceptor activity in all individuals (except the isolated cases of mutated receptors mentioned below), but results in different subjective feelings (neuroimaging measurements, as well as reports/questionnaires). 

The supporting evidence for your proposed solution could be the paper stating that the identical brain activities evoked by pain were observed in healthy individuals and the ones insensitive to pain [4] (questionnaires + neuroimaging). But I think it is an isolated case of loss-of-function SCN9A mutations, which affect the nociceptor signal reception (neurochemical or other physiological defects). Also, the experiment was performed on 6 individuals, which is an insignificant sample size.

In addition to the neuroimaging techniques themselves, to normalize the pain intensity as a side effect, we should measure the nociceptor reception and activation directly, while taking into account possible mutations that affect them.

More experiments are necessary to distinguish the relation of the nociceptor activity and subjective experience of pain, but I personally think that neuroimaging techniques are affected by the level of tolerance (and other above-mentioned factors).


2_ In my opinion, non-integrative neuroimaging itself is an unjust measurement. 

The second question refers to the fact that it would be interesting if we find a technique that can objectively measure the intensity of pain, without taking the subjective feeling and/or tolerance of the patient into consideration. If you read this again, it means that it doesn't make a lot of sense to believe that people can differently experience anything, but we should trust just the physiological/neurochemical proofs. Then it also wouldn´t be true that women are generally more resistant to epilation than men (which is really not true 22 ).

The pain is not a simple nociceptor expression, but a "psychobiology, attentional processes, and expectations of pain resulting from past and learned pain experiences" [1], and should therefore be evaluated individually based on the physiological and psychological parameters measured by the AI-driven neuroimaging techniques, normalized with a generally accepted cross-individually consistent features and correlated with subjective scale results.

[1] https://associationofanaesthetists-publications.onlinelibrary.wiley.com/doi/full/10.1111/anae.13018
[2] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5019436/
[3] https://pubmed.ncbi.nlm.nih.gov/20460116/
[4] https://pubmed.ncbi.nlm.nih.gov/27111250/

Shubhankar Kulkarni23 days ago

Side Effects are Extremely Complex and Patient-Dependent

Manel Lladó Santaeularia Feb 02, 2021

[1]Kaufman G. Adverse drug reactions: classification, susceptibility and reporting. Nurs Stand. 2016 Aug 10;30(50):53-63. doi: 10.7748/ns.2016.e10214. PMID: 27507394.

Shubhankar Kulkarni24 days ago

Manel Lladó Santaeularia24 days ago

Pay for both, positive and negative feedback

J

Juran Feb 19, 2021

[1]https://www.fda.gov/drugs/surveillance/questions-and-answers-fdas-adverse-event-reporting-system-faers

Shubhankar Kulkarni4 days ago

Juran Thank you! Yes, it seems like most of the rules favor money-making rather than pharmacovigilance. Maybe the FDA report was not made public before 2014, keeping in mind that after the patent expires, other companies can manufacture the drug, too. The sales, will then, obviously go down. Therefore, it would have been better for the drug if the negative report came after the expiry of the patent. This will keep the sales up during the period the drug has no competition.

I agree that FDA should enforce the rules regarding pharmacovigilance more strictly. I like the idea of paying for positive reviews, too. Most people, today, rely on reviews when buying anything. The only problem I see is that when it comes to drugs, as compared to other things, the patient may rely more on the doctor's prescription. And, the doctors are approached by the salesman employed by the companies. The salesman provides free drug samples and other perks to the doctors. This is a strong and influential relationship and does affect the sale of the drug. We might need to emplot alternative measures to tackle this part.

On a side note, who should pay for the reviews of the drugs - the companies of the FDA? I think it should be the FDA, which we consider to be unbiased.

J

Juran4 days ago

How can we weigh the efficacy and side-effects of a drug?

Creative contributions

Computational molecular docking can be a useful technique

The problems "behind the scenes"

How to know which side-effect is valid? Solution: "Reporter" in every drug

How can we be completely sure when we attribute a side effect to a drug?

Measuring side effects objectively - PAIN

Side Effects are Extremely Complex and Patient-Dependent

Pay for both, positive and negative feedback

Add your creative contribution

Sign up or

Guest sign up

General comments

How can we weigh the efficacy and side-effects of a drug?

Creative contributions

Computational molecular docking can be a useful technique

The problems "behind the scenes"

How to know which side-effect is valid? Solution: "Reporter" in every drug

How can we be completely sure when we attribute a side effect to a drug?

Measuring side effects objectively - PAIN

Side Effects are Extremely Complex and Patient-Dependent

Pay for both, positive and negative feedback

Add your creative contribution

Sign up or Login

Guest sign up

General comments

Sign up or