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Showing entries tagged pharmacology.  Show all entries

October 23, 2011

Jalapenos...a treatment for arthritis?


We've all bitten into a jalapeno and experienced the slow burning pain that is associated with it. And whether you love it or hate it you've probably wondered why some people have a higher tolerance for spicy foods than others. The answer to that is two-fold.

To understand why we must first understand the mechanism through which capsaicin (the oily substance found in peppers which gives them their signature 'kick') works. Capsaicin targets a subgroup of sensory neurons called nociceptors. Prior research has shown that capsaicin excites these neurons by increasing the permeability of the plasma membrane to cations (K+, Na+ and Ca++ in particular) although it was unknown whether this was through direct disruption of the plasma membrane (capsaicin is hydrophobic and could thus perturb the phospholipids of the membrane)or though a ligand-system in which the molecule binds to specific receptors on the surface of the cell. The latter possibility was ruled more likely as capsaicin derivatives operate in dose-dependent manners highly characteristic of receptor activation via ligand binding. This was further supported through the use of resiniferatoxin, an extremely potent capsaicin analog derived from the plant genus Eurphorbia. This neurotoxin's extreme potency, eliciting responses at nanomolar concentrations, allowed scientists to assume that it bound with great affinity to the proposed capsaicin receptor. Using this, the molecule was radio labeled and researchers were able to visualize its binding to cell-surface receptors.

This provides the first the leg of the answer. The density of these receptors on an individual's nociceptors can influence the affect spicy food has. More receptors, more binding, greater response evoked.
An interesting side note...why do spicy foods produce a burning sensation? The specific receptors that capsaicin binds to are heat-gated receptors. These are analogous to our very well known voltage-gated channels but open is response to changes in ambient temperature and apparently capsaicin binding. This produces pain and the burning sensation that I for one love.

The second leg to our answer comes with a remarkably interesting point of immense pharmacological importance. Exposure to capsaicin initially excites a neuron leading to the pain response. However prolonged exposure (in this paper just a few hours) can cause cell death. Examination of dead cells revealed no evidence of DNA fragmentation meaning that no apoptotic events occurred. The actual cause of death was cytotoxicity caused by excessive ion influx, similar to the excitiotoxicity observed in TBI.
So as you can imagine eating spicy foods can actually kill these neurons, desensitizing your mouth to the pain a jalapeno can produce.

I did mention a pharmacological importance that is briefly covered by the authors, although they do not go into any sort of detail about it. In the opening paragraph they say that this nociceptor desensitization has lead to use of capsaicin as an analgesic agent in the treatment of n analgesic agent in the treatment of disorders ranging from viral and diabetic neuropathies to rheumatoid arthritis. While they do not elaborate on the mechanisms of this we can assume that these diseases cause pain through stimulation of these same nociceptors.

http://wwuneuroscience.com/Documents/Capsaicin.pdf
Posted by      Zach I. at 2:03 PM MDT
  Christina Uhlir  says:
Zach,

I am curious as to whether or not there was a discussion about the clinical uses of different peppers based on their Scoville scale heat, and the fact that they could induce excitotoxicity.
Posted on Sun, 23 Oct 2011 6:04 PM MDT by Christina U.

August 1, 2011

Making the Mind Spotless


In the movie Eternal Sunshine of the Spotless Mind, the average person in the not-too-distant future has the option to erase unwanted memories with ease. The film takes a bizarre trip through Impenetrable Symbolism Lane after the initial setup, but the idea was ultimately painted as residing in an ethical gray area. In that story, a man was forgotten by an ex-girlfriend, but it was implied that the same technology was being used to treat PTSD and help people forget highly secretive information as well. A recent pilot study by University of Montreal researchers at the Centre for Studies on Human Stress has suggested that, while such specific deletion of memories is a pipe dream at best, the dream of removing painful memories with an accessible treatment may not be so far from our grasp.

The drug metyrapone, a drug that inhibits the production of the so-called "stress hormone" cortisol and is used in the treatment of hypercortisolism, was given to 22 men, with half receiving double the dose given to the other and another 11 men receiving a placebo. The men were administered the drug four days after being shown "a slide show having neutral and emotional segments," according to the paper published in the Journal of Clinical Endocrinology & Metabolism, and asked to recall parts of the sequence. The study found a statistically significant decrease in the ability of those with the highest dose of the drug to recall those portions of the slide show which were most "emotional," while the more "neutral" parts were easily recalled by all three groups. This suggests a possible use for the drug in the treatment of PTSD.

Yes, sample size was tiny, and I would argue that the experimental design is rife with subjectivity, but the idea is founded on good science. It's fairly well established that cortisol has a significant effect on how our brains process and store memories. Typically, higher levels of cortisol impair accurate memory recall while also causing powerful emotional associations with memories being stored. The idea that we can specifically target and inhibit the recall of these emotional aspects of bad memories, without destroying memories of an event outright, is an intriguing and enticing one. While many may raise concerns over tampering with our memories in this way, the availability of such an option to those struggling with truly agonizing emotional memories would be almost entirely positive, and the effects may well be more permanent than with drugs many use to cope with negative emotions (like alcohol). The truly interesting issue to me is that it is this easy to mess with memories at all.

It's already well established that the ability to process and store memories can be removed by removing certain parts of the brain. It's also well established that certain drugs can inhibit memory recall. This preliminary study hints at the possibility of removing certain associations in the brain with pharmaceuticals. That memories are as beholden to peculiarities of biochemistry as any other biological process is not surprising, but it suggests that the scenario portrayed in Eternal Sunshine isn't very far fetched, or far-off. It's difficult to argue that such a world would be better or worse than the one we have now, but it would be radically different. Imagine being able to purchase this drug over the counter (it has relatively minor side effects) when you lose a loved one, and dramatically cutting down on grieving time. Such a world may well be a more efficient, more callous world, but perhaps callousness is worth having a "cure" for PTSD.

Science Daily article summarizing the paper:
http://www.sciencedaily.com/releases/2011/05/110526064802.htm
Original paper:
http://jcem.endojournals.org/content/early/2011/05/18/jc.2011-0226
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July 31, 2011

Subjective Diagnosis


As the teacher speaks in front of the class, the majority of the students are attentive and taking notes. But there is one student in the classroom looking out the window daydreaming about being outside and able to run around, free, not trapped in his chair. He has attention deficit/hyperactive disorder (ADHD). More and more students are being diagnosed with this disorder. Why? Does it have to do with our genes, the environment? Is this just a reflection on our society always needing an answer and diagnosis for why we are different or is it the doctors wanting more money?

Currently the only way to diagnose this disorder is through a series of physiological tests and accounts from your teachers and parents. These methods are very subjective and may be leading to over diagnosis of children and overmedicating (2). These students may just need to learn discipline and learn how to motivate themselves to sit in a classroom and listen to a lecture or study for an exam. Just like many other psychological disorders the most logical answer to this is to study the differences between the brain structures of those with ADHD and those without.

In a recent study (1), the researchers were after the answer to see if there is a significant difference in the adolescent brain with ADHD with and without medication and without ADHD. The researchers wanted to determine if using an MRI of a child's brain would lead to better diagnosis of ADHD. The researchers studied the participants for ten years and took a total of four MRI's for each child. The researchers concluded that there is a significant difference in brain volume and specifically the white matter and the caudate nucleus. These two differences were seen to be developed at a young age due to genetics or environment and the growth of the brain paralleled the control participants. This means that as a child you have ADHD and do not generally develop it later in life.

According to the results even though there are differences in the anatomical brain structure, this still is not a clear answer to whether or not an MRI will be able to diagnose anyone with ADHD any time soon. The limitations to the study are the participants themselves. They are unable to keep still for the MRI and many of the images had to be thrown out because of movement. Also the lack of twin and sibling studies in the topic cause us to not be able to determine how much of the differences are die to environmental or genetic influences or if it is merely a correlation.

Similarly to other imaging discussions about the validity of the images and what they tell us we are unable to definitively say. At this point much more research needs to be done on the topic of ADHD and how brain imaging can enhance one's ability to be diagnosed with ADHD and allow the subjective tests to be replaced by a more concrete method of diagnosis.

1. http://jama.ama-assn.org/content/288/14/1740.full.pdf+html
2. http://www.hs-zigr.de/~wirsing/ASH%20Sozialmedizin09/ABPapersPDF/ADHD1%20Kopie.pdf
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Your Brain on Yoga: Better than an Antidepressant?


Depression [1] is a disease that afflicts millions of people and costs billions of dollars every year, and it is getting worse. One has to ask: besides the obesity epidemic, is our sedentary lifestyle contributing to a depression epidemic? Is exercise necessary for a healthy psyche? Can physical activity 'cure' depression?

In the last decade, a new kind of brain chemical has been discovered that plays a pivotal role in the healthy balance of the other chemicals in our brain. This chemical is called brain-derived neurotrophic factor (BDNF) [2] and is discussed by Rassmusen, et al. in the article 'Evidence for a release of brain-derived neurotrophic factor from the brain during exercise.' BDNF has been found to regulate the maintenance, growth and survival of neurons; to influence learning and memory; is low in patients with Alzheimer's Disease and clinical depression; and affects body weight, energy homeostasis, and blood glucose levels. In addition, genetic mutations of the BDNF gene are associated, in both mice and humans, with the entire laundry list of metabolic syndrome problems. Where does BDNF come from in our brain? Why does it affect so many aspects of a healthy self? What can we do to 'balance' our brain chemicals without resorting to Prozac« or Abilify«, which we are beginning to find out are more like temporary bandaids for a much deeper problem of brain chemical imbalance and are only slightly better than a placebo [3]?

Recent studies have shown that exercise raises circulating BDNF levels. Exercise has been found to enhance BDNF transcription [4] in the brain and to effectuate brain uptake [5] of insulin-like growth factor 1, which is a necessary ingredient for increasing mRNA expression of BDNF. BDNF has also been shown to promote [6] the health of serotonin-responsive neurons and to interact with serotonin-producing genes. Instead of a prescription for an antidepressant, should doctors be prescribing 30 minutes a day at the gym? And what if the exercise had the added benefit of reducing stress? What if doctors prescribed yoga classes instead of Prozac«? Could we expect to see even more benefits than exercise alone: reduced stress, improved mood, thinner waistlines, less Type II diabetes, and better sex lives? If I was depressed and yoga could do any of those things, it would be enough to undepress me, BDNF levels aside.

Recent studies show that there is a positive correlation between yoga and circulating BDNF levels. In his master's thesis [7], NL Pan discovered that a form of yoga called Sudarshan Kriya yoga (SKY) increased serum BDNF level in patients that had high initial depression indices, and as an added bonus, reduced cortisol. This effect was determined to be independent of circadian rhythm levels. Other researchers have investigated the effect of yoga on depression with positive results (Pilkington, et al. [8], Javnbakht, et al. [9], Janakiramaiah, et al. [10]) but linking yoga to BDNF levels is a more recent finding.

As controversial as the idea sounds, maybe it is time for doctors to stop doing the easy thing by prescribing a pill and just tell patients to get off the couch and go to yoga class. And if patients don't believe their own doctor, while they are sitting on the couch they can just tune into Dr. Oz, our new national guru of all things health, who promotes exercise as a cure for many ills. I don't mean to trivialize the problem of depression, but the idea that it is we ourselves who are responsible for our health, even our mental health, should not be revolutionary or controversial. But depression is like a lot of things these days: someone else or something else is supposed to provide an easy fix.

[1] http://www.huffingtonpost.com/robert-leahy-phd/the-cost-of-depression_b_770805.html
[2] http://onlinelibrary.wiley.com/doi/10.1113/expphysiol.2009.048512/full
[3] http://www.thedailybeast.com/newsweek/2010/01/28/the-depressing-news-about-antidepressants.html
[4] http://www.ncbi.nlm.nih.gov/pubmed/9795193
[5] http://www.ncbi.nlm.nih.gov/pubmed/10751445
[6] http://www.nature.com/npp/journal/v33/n1/full/1301571a.html
[7] http://ethesys.lib.ncku.edu.tw/ETD-db/ETD-search/view_etd?URN=etd-0808107-104238
[8] http://www.sciencedirect.com/science/article/pii/S0165032705002570
[9] http://www.sciencedirect.com/science/article/pii/S1744388109000048
[10] http://www.sciencedirect.com/science/article/pii/S0165032799000798
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Neurotherapeutics: Helpful or Harmful?


Who wouldn't want to take a pill that would enhance their mental capabilities? Instead of studying for hours and hours, how much more enjoyable would it be if you took a pill, enhanced your memory making capabilities and thus only had to spend an hour or two studying for that big cumulative exam? These days research and scientific developments have allowed the range of pharmaceuticals to alter mood, cognition and other cognitive skills such as memory to go beyond what we previously would have believed to be to be impossible. Drugs that have been developed to treat some of the most heinous diseases now bring the promise of, not only treating illness, but enhancing performance. Today, the debate between treatment and enhancement has already begun to be a hot button topic in neuroscience.

According to an article by Paul Root Wolpe, there are two fundamental questions that we must address pertaining to this issue. First, "what do terms such as average or normal functioning or even disease and enhancement mean when we can improve functioning across the entire range of human capability?" Second, "should we encourage or discourage people to ingest pharmaceuticals to enhance behaviors, skills and traits? What are the social implications of using drugs or other neurotechnologies to micromanage mood, improve memory, to maintain attentiveness or improve sexuality?"

Enhancement has been defined by medicine and its implications. Medicine treats disease but what it does not treat is enhancement. So if we begin allowing or encouraging people to take pharmaceuticals in order to enhance their well-being, where do we draw the line? A good example used in this article is the use of Prozac and other anti-depressant drugs. If drugs like Prozac can increase a user's mood, what emotional state then becomes normal? If it becomes normal for everyone to take mood enhancing drugs, than does being in a sad state become taboo? Furthermore, if more people start taking drugs like Prozac, will insurance companies still cover these sorts of drugs? Insurance companies pay for treatments and injurious events, but if everyone is using a drug does this drug then become a commonality such as the use of Advil, which is not covered by insurance companies?

As humans, we have always been able to find techniques to enhance our performance and general functioning. We go to school, take vitamins, and go through training programs. But is it acceptable to bypass all of these "external" strategies and directly alter our brains? Sure, the drugs we have currently developed may help us increase cognitive function but what about the long term side effects? Take the use of drugs that are supposed to treat disabilities like ADD and ADHD. Drugs like Adderall and Ritalin prescribed for attention deficit disorder are becoming more and more popular among students. These drugs boost cognitive function and enable the user to study for hours with full concentration without getting tired or distracted. But at what cost? Long term use of cognitive enhancers like Ritalin cause serious side effects such as severe sleep deprivation and heart problems. More troubling, however, is that these drugs can be highly addictive. Users can get to the point where what we now define as "normal" cognitive function is unachievable without the use of cognitive enhancers. So if drugs like Adderall can have these results, can our pharmaceutical strategies backfire on us and destroy the delicate balance in our brains?

On the other hand, think about a world where we have not only found a cure for degenerative diseases like Alzheimer's, but where people in general have a higher standard of living because our brains are functioning at the fullest extent! It's a fine line between helpful and hurtful when it comes to our emerging neurotechnologies and pharmaceuticals.

For more information on this debate check out the article by Paul Root Wolpe at: http://www.chem.arizona.edu/courseweb/081/CHEM4361/reading_pdfs/guest_lecturers/treatment_enhancement.pdf
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Cosmetic Neuro-tinkering


Altering your body for aesthetic reasons has become social norm in society. What if you could alter your brain functions to improve motor skills, attention, learning, and mood, would you do it? Advances in neuropharmacology are beginning to progress to the point that they are able to use drugs to enhance these abilities. This emerging technology is becoming known as cosmetic neurology.

In an article entitled, "Cosmetic Neuorlogy: The Controversy Over Enhancing Movement, Mentation and Mood," Anjan Chatterjee MD outlines three general categories, motor systems, attention/learning/memory, and mood, that could have a prospect for better bodies and mind.

Chatterjee says that all three of these areas of improvement already have neuophamagological drugs that can improve them. For example, Insulin-like growth factors (IGF) can be given to men over 60 to increase muscle mass, decrease body fat, and improve skin. This in turn improves the quality of life of these people? In addition to IGFs, there are drugs that can improve plasticity, block receptors that cause depression, and decrease unpleasant memories.

Unfortunately, any time you wish to alter the brain there are several ethical dilemmas. In this case safety, individuality, distribution and coercion become the prominent issues.

Safety is a main concern with any form of drug treatment. In disease, a person weights the risks against the potential benefits. Which is why people with terminal cancer are willing to endure toxic chemotherapies to prolong life. Where as in a healthy state any risk is harder to accept because the alternative is "normal" health (Chatterjee 2004). This is where ethics plays in. Is it ethical to treat someone with something that does not save them for something else? Some people think it is, as long as that person is equipped with enough information about the potential side effect. But then again where did the information come from and did the person use it?

Another issue in this cause is individuality; Chatterjee says that a major concern is that chemically changing the brain threatens to eliminate personhood. This then leads into a more ethical issue of if tinkering with brain chemistry is going to threaten what it means to be human?

As in most discussions, who gets them becomes an important question to ask. Because these mind-altering drugs are expensive it is unlikely that the government or insurance companies are going to pay. Does that mean that the rich prevail again? Then we have to ask ourselves? what happens when the rich get stronger, smarter, and sweeter than "normal" people? A critical ethical issue when talking about new drugs is distribution.

Finally, we must look at how choices can evolve into forces of coercion (Chatterjee 2004). One form of this is the common feeling that you want to be better or at least maintain your position in society. As people become smarter, fast, and stronger, pressures increase and smaller groups of people will be competing for larger prizes. Imagine what you could do if you could work 100 hours a week without becoming tired! Another issue is demand for superior performance. Pilots taking donepezil preformed better in emergencies than those on a placebo. Should that then mean that all pilots should take it, or that people will pay more for flights where their pilot takes it?

It does not take much imagination to see how the media will advertise for "better brains." We must look follow these topics and developments. Up until now, I did not realize the extent of these mind-altering substances. Did you?
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