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QofQuimica

QofQuimica

Seriously, dude, I think you're overreacting....
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This thread is a journal club discussion thread. Any interested pre-med or med students can join. For those who have never attended grad school, the way a journal club works is that each week, one member is the discussion leader and picks an article, and all of the participants read it. Normally the article is from a high-impact journal and is not a review article, but in this case, it's ok to pick review articles on topics of interest since some of our members are college students. The discussion leader will post the link to the article here, and then all of the members have a week to read the article. At the end of the week, the leader will post a brief summary, and then other members can ask questions and discuss the article. A new leader will pick an article for the following week, and we will keep going until everyone who wants to participate has taken a turn.

Leaders: To find articles, go to PubMed and enter in a search topic. You will see a bunch of articles, most of which we do not get free access to. The ones that do have free access have a little green-tipped sheet of paper next to them. Pick one of those articles that sounds interesting and isn't too technical for a college student to read, and post the link for the rest of us. You should post your article for the rest of us by the date next to your name, and we'll discuss it the following week.

Readers: Click on the linked article, and read it. Then come here to discuss it. It's ok if you don't understand every word of an article; it's still good practice for you to read journal articles, and you will always learn something from them. You'll also learn more from the discussion here; the leader is supposed to help you understand the topic better.

Thanks to everyone for participating.

Updated Schedule:
  • Week of May 22: QofQuimica: Pharmacogenetics of Drug Abuse
  • Week of May 29: megboo: Brain Imaging
  • Week of June 5: none, due to SDN server issues
  • Week of June 12: continue with megboo's article due to SDN server issues
  • Week of June 19: beary: TBA
  • Week of June 26: mshheaddoc: TBA
  • Week of July 3: EvoDevo: TBA
  • Week of July 10: dante201: TBA
  • Week of July 17: Xanthines: TBA
  • Week of July 24: Open
  • Week of August 1: Open
  • Week of August 8: GradTX: Genetics of Neurological Diseases
 
My summary:

Background

-The terms pharmacogenetics and pharmacogenomics are often used interchangeably to refer to the study of how drug activities are affected by a particular patient's genes. That definition really describes pharmacogenetics; pharmacogenomics is a broader term that refers to applying genomic techniques to drug discovery and studying the entire genome instead of just a few genes of interest involved with a particular drug.

-Although there was initially a lot of buzz and optimism about tailoring drugs to a particular patient's genome, this has not yet translated into much success in the clinic for various reasons. One notable and happy exception is Herceptin, which is an antibody used in women with metastatic breast tumors that overexpress the Her2 protein. Approximately 25% of breast cancers fall into this category, so most women with breast cancer actually would not be helped by Herceptin.

-Substance abuse is a prevalent problem in our society, and certain people are genetically more likely to become addicts if they are exposed to drugs. Analyzing the genetics of drug use can help us to learn more about the overall relationship between drugs and genetics.

Key Concepts

-When different individuals take a given drug, it may affect them in different ways due to such things as the enzymes they have present in their body. The dose that would cure me of an illness might be toxic to you, or vice versa, if one of us has a particular drug-metabolizing enzyme variant and the other lacks it.

-The cytochrome P450 system in the liver metabolizes many drugs, and there are multiple variants of some of these enzymes. We have some data about the effects of this variation on drug metabolism, but this knowledge has not yet been effectively used in clinical treatment.

-The brain, which also produces cytochromes, can also be adversely affected by drugs depending on cytochrome variants. This is an important consideration for drugs that target the brain.

Smoking:
-Some people who smoke 1-5 cigarettes per day do not become addicted, while others who cut back to that many remain addicted.

-A table with several genes related to addiction is presented. CYP2A6 is the cytochrome that is most responsible for metabolizing nicotine. There is an allele that is responsible for high metabolic activity of CYP2A6, and people with two copies of that allele metabolize nicotine very quickly, while those with normal alleles metabolize nicotine slowly. Heterozygotes metabolize nicotine in an intermediate amount of time.

-Some small studies suggest that smokers with certain cytochrome subtypes are more likely to benefit from nicotine replacement therapy (NRT) than others. Work with the new drugs rimonabant and varenicline is focusing on identifying which subgroups of patients are most likely to be helped by them based on their genetic profiles.​
Opiods (heroin and morphine):
-Heroin addiction is known to have a large genetic component. There is evidence supporting the idea that a point mutation in the OPRM1 gene causes greater susceptibility to heroin addiction. (This is an A to G change at position 118, leading to an Asp residue replacing Asn in the resulting protein.)

-Opiods are commonly used to treat pain, but they don't work for some people, and they cause a lot of bad side effects (like constipation and nausea) in others. It appears that there is even some heritability to the amount of pain that a person feels.​
Stimulants (cocaine, amphetamines):
-Some evidence suggests that meth abusers are more likely to possess a specific polymorphism in the DRD4 gene. Another gene (COMT) may also be involved.

-The DAT1 gene alleles appear to affect the response that users have to cocaine and amphetamines in terms of whether they become paranoid or not. It is not clear how having the gene variant associated with paranoia causes the person to become paranoid.

-BChE is a protein that metabolizes cocaine. Some people have a variant of this protein that metabolizes the drug slowly, potentially leading to an overdose at a cocaine level that would not kill a person who has a normal variant.​
-The author suggests that in the future, pharmacogenetics can be used to determine drug dosing schedules to try to minimize toxicity and side effects.

-S/he also points out that there is a major environmental component to addiction as well as a genetic one, and that both factors must be considered when developing treatment programs for addicts or programs to try to prevent addiction.

-The NIH is attempting to collect pharmacogenetic data from clinical trials to form a database and otherwise promote the use of this data to improve treatment efficacy.

Topics to Discuss

-I thought it was interesting that addicted smokers take in the same amount of nicotine regardless of how many cigarettes they actually smoke. The authors suggest that this is due to genetic differences between them and nonaddicts (so-called chippers). Most addicts have a great deal of difficulty quitting. But there are a small minority of smokers (my dad was one) who are able to just put down the cigarettes one day and never smoke again. Do you think there could be different genetic variants even among addicts that would explain why some heavy smokers can quit on their first try, while others can't? Or do you think it's more a matter of willpower?

-I also thought it was interesting that there is a nicotine vaccine that actually induces antibodies against nicotine and prevents nicotine from getting into the brain. What are your thoughts about using a nicotine vaccine to try to prevent genetically vulnerable people from becoming addicts?

-If a doctor is treating a patient and can't find a cause for the patient's pain, how likely do you think it is that the patient really feels the pain versus is faking it? Do you think you'd be more likely to suspect that the patient is faking it if you knew that they were genetically susceptible to opioid addiction? What about if you knew that they were also genetically susceptible to feeling a larger amount of pain than most people are?
 
QofQuimica said:
-I also thought it was interesting that there is a nicotine vaccine that actually induces antibodies against nicotine and prevents nicotine from getting into the brain. What are your thoughts about using a nicotine vaccine to try to prevent genetically vulnerable people from becoming addicts?
Click to expand...

This makes me raise my eyebrows a bit. If you vaccinate someone who is genetically vulnerable to nicotine addiction, would that then make them more likely to try cigarettes? They could think, "What is the harm in doing it once or twice to see what it is like? I'm not going to get addicted."

It seems to me that if we get to a point where we identify people in the general population who are likely to become addicted to nicotine, wouldn't it make more sense for them to simply never smoke? It would certainly be cheaper.

I do suppose this raises the issue that certain people who know they are likely to become addicted to nicotine will try smoking anyway - evidenced by all the teenagers who smoke even though most of them probably knew beforehand that it is bad for their health and easy to become addicted.

I'm sure I'll have more thoughts on the article later on. I did find the section on nicotine addiction very interesting. I have a grandfather who smoked for decades. When he decided to quit, he just stopped one day and never smoked again. My in-laws both smoke and have tried to quit unsuccessfully about ten times in the 8 years I have known them. I never thought before that there could be a genetic factor for why some people can quit and some just cannot.
 
QofQuimica said:
-I also thought it was interesting that there is a nicotine vaccine that actually induces antibodies against nicotine and prevents nicotine from getting into the brain. What are your thoughts about using a nicotine vaccine to try to prevent genetically vulnerable people from becoming addicts?
Click to expand...

This sounds like a good idea on paper, but there has been research that suggest that nictonic agonists may be beneficial to diseases such as Alzheimer's, Parkinsons, and chronic pain. If someone opted for a vaccine early in life, then they may run the risk of ineffective treatment options if they developed these diseases.

Plus, nicotinic receptors aid in muscular contraction.

[Quote = QofQuimica]

-If a doctor is treating a patient and can't find a cause for the patient's pain, how likely do you think it is that the patient really feels the pain versus is faking it? Do you think you'd be more likely to suspect that the patient is faking it if you knew that they were genetically susceptible to opioid addiction? What about if you knew that they were also genetically susceptible to feeling a larger amount of pain than most people are?[/QUOTE]

It would definitely be interesting to see how this would play out. I've always been an advocate for brain imaging research, and the rACC areas have shown up in fMRI during pain. (http://www.pnas.org/cgi/reprint/102/51/18626).

This would be a great research topic for someone interested in Pain Management!
 
QofQuimica said:
Topics to Discuss
-I also thought it was interesting that there is a nicotine vaccine that actually induces antibodies against nicotine and prevents nicotine from getting into the brain. What are your thoughts about using a nicotine vaccine to try to prevent genetically vulnerable people from becoming addicts?

-If a doctor is treating a patient and can't find a cause for the patient's pain, how likely do you think it is that the patient really feels the pain versus is faking it? Do you think you'd be more likely to suspect that the patient is faking it if you knew that they were genetically susceptible to opioid addiction? What about if you knew that they were also genetically susceptible to feeling a larger amount of pain than most people are?
Click to expand...

Awesome summary and questions. :clap:

I haven't thought about it a ton, but initially I'm not a fan of using a nicotine vaccine to prevent genetically vulnerable folks from becoming addicts. I am sure that like any vaccine there is some risk of side effects or an allergic reaction, which would not be worth it given that someone may just choose to avoid cigarette smoking (unlike contagious diseases, which I am totally pro-vaccination). I would be more interested in using a vaccine for smoking treatment, in which someone already has the risks of smoking.

Opioid addiction is one of my favorite topics. I have "hunches" that some folks are seekers. But I would tend to be pretty liberal with narcotics because I think if someone is addicted and is trying to fool you, feeding their addiction a bit more is not as bad as denying treatment to someone who is in pain.

I saw their statistic in their paper that 10-30% of chronic pain pts do not respond to opioids. This is not what I learned or what I have seen. If someone is truly not responding to opioids, either they are tolerant from previous use or have some weird genetic thing, in either case higher doses will treat their pain. Pain control always comes before respiratory depression or death. Unfortunately, people may experience significant sedation/nausea/constipation/itching with adequate pain control, but this can be managed.
 
Yeah, SDN has definitely been screwy this week. I think that we should have megboo's article continue on for this week. GradTX would like to postpone presenting anyway, so that way we'll hopefully have some time to discuss megboo's article without SDN crashing on us constantly.

beary, any thoughts yet about your article for next week?
 
Ok...
I didn't do my part, but let's not let this die off before it has a chance to catch on. Anyone up for trying again???
 
TypeA said:
Ok...
I didn't do my part, but let's not let this die off before it has a chance to catch on. Anyone up for trying again???
Click to expand...
Yes. I've been busy moving, but I'd like to get us started again. Would you be interested in doing the next article?
 
QofQuimica said:
Yes. I've been busy moving, but I'd like to get us started again. Would you be interested in doing the next article?
Click to expand...

I have never done one before, but I would be willing. Cut me some slack people. When should I post?
 
TypeA said:
I have never done one before, but I would be willing. Cut me some slack people. When should I post?
Click to expand...
How about by the end of the week? Take a look at the one I did. Basically you want to post the link to the article, then write up some brief notes for the rest of us to read and discuss. 🙂
 
A little late, but I thought I would chime in some thoughts...

Smoking, like most complex behaviors, involves both genetic predisposition and environmental factors. I wouldn't doubt that there are genetic variants that explain why some people have no trouble quitting, while others have much difficulty. Addiction is a complex phenomenon involving plastic changes within the central nervous system (i.e. the nucleus accumbens). While much of the current pharmacogenomics focus has been on drug metabolizing genes, I suspect that this is a very narrow part of the whole picture. One could imagine variants of genes involved in plasticity (i.e. NMDA, AMPA receptors, immediate-early genes, etc) that could modify a person's drug-craving behavior. Instead of a simple drug-receptor perspective, we need to develop a more expansive view that involves how drugs interact with neural systems to mediate complex behaviors.

The vaccine probably would not work for those people already addicted. Preventing people from getting addicted via vaccination may work, but it is riddled with ethical issues, not the least of which are privacy and medical insurance concerns.

About the pain issue, I don't think knowing a patient's genetic susceptibility to opioid addiction would have any bearing on whether the patient is "faking it" or not. Pain is a subjective experience and as a physician, it is your duty to treat the patient's pain. There is an extensive literature on the undertreatment of pain, and I would be much more concerned about undertreating than overtreating.
 
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