Limits of the Placebo Effect

I was going through some of our older posts ... figured our blog is a more educational way to procrastinate than Facebook ... and reread the posts about placebos. Recently, I read this absolutely outrageous article that took the placebo effect a step further. A few scientist wanted to see if patients' conditions improved, i.e. had the placebo effect, even if they were told they were taking pills with no active ingredient. Basically, the scientist gave one group of patients placebos and told them they were taking fake pills. The other group received no treatment.

Surprisingly enough, some patients showed improvements even when told about the fake pills, and did much better than the no treatment patients. A caveat: The study is quite small. That said it still provides a great "proof-of-concept" and is definitely worth further investigation.

The article that gives new meaning to mind over matter:

http://www.guardian.co.uk/science/2010/dec/22/placebo-effect-patients-sham-drug

-Vinoo

Study Break

I figured we could all use a little study break from finals so I thought I would share this with everyone. I thought this was so awesome when I came across this the other day and immediately shared it with some of my other PSIO friends. After that I realized how much of a nerd I was. Anyways, enjoy this little break and check out the site below. Good luck with finals everyone and congratulations to all the graduates!

http://learn.genetics.utah.edu/content/begin/cells/scale/

More about resveratrol!

After reading the article about resveratrol and learning about its possible roles in the prevention of numerous pathologic processes from its cardio protective, anti-cancer, anti-oxidant, and anti-inflammatory properties, I was interested in looking more into the background of resveratrol and its content in foods.

In addition to the potential benefits mentioned above, recent studies on administration of resveratrol have also found it to extended lifespan in a number of species by altering gene expression in the heart, brain, and skeletal muscle, comparable to that induced by caloric restriction.

As for the resveratrol content in foods, below is a list of some foods with resveratrol:

Relating back to the article in class, for the daily resveratrol intake of the mice in the study to be equivalent to that to that of a human, which was 1,944mg/60kg person, one would have to consume approximately between 273-1,013L of red wine (global) or 7,477-19,4400cups of raw peanuts or 1,556-8,100cups of red grapes! This of course seems like a ridiculous amount because if anything, you’ll probably get alcohol poisoning from drinking too much wine before reaping any of the potential benefits of resveratrol. But as the paper mentioned there are commercial daily supplements that range from 50-2000mg of trans-resveratrol.

However, since resveratrol has only been mainly studied in animals, presently little is known about the effects of resveratrol in humans or the effective dose of resveratrol for chronic disease prevention in humans.

So I’m still not entirely convinced, and I definitely think the translatable effectiveness of resveratrol as potential therapeutic approach in humans is still questionable, how about you?

http://lpi.oregonstate.edu/infocenter/phytochemicals/resveratrol/#sources

http://www.createbalance.net/support/science/resveratrol_cancer_prevention.pdf

Potential personalized treatment to target inflammation?

This article talks about a new potential form of personalized therapy to target inflammation by mimicking the body’s natural mechanism of fighting inflammation. Microparticles are very small particles released by cells during inflammation. However, researchers at Barts and The London School of Medicine and Dentistry and Harvard Medical School have discovered certain microparticles that contain anti-inflammatory lipids that are beneficial to our health. These microparticles are precursors for compounds that stimulate the termination of inflammation and return the body to its normal balance.

Researchers are mimicking this natural communication process to produce new personalized delivery system for anti-inflammatory therapeutics based on natural human microparticles. Since these microparticles do not rely on synthetic biomaterials, they reduce potential toxicity. In this study, researchers used human neutrophil-derived MPs to construct novel nanoparticles containing anti-inflammatories asprin-triggered resolvin D1 and lipoxin A4 analog, and found dramatically reduced polymorphonuclear cell influx, enhanced wound healing, and protection against inflammation. These humanized nanoparticles termed nano-proresolving medicines may offer a new therapeutic approach that could have implications in a number of inflammatory diseases including cardiovascular diseases, arthritis and temporomandibular disorders.

L. V. Norling, M. Spite, R. Yang, R. J. Flower, M. Perretti, C. N. Serhan. Cutting Edge: Humanized Nano-Proresolving Medicines Mimic Inflammation-Resolution and Enhance Wound Healing. The Journal of Immunology, 2011

http://www.sciencedaily.com/releases/2011/04/110404111048.htm

Prevention... after the insult?

In multiple previous studies evaluated by this class and blog, I have been critical of research methods that involve the administration of a drug or other treatment option before introducing the disease agent or disease state, such as in subjecting mice to stroke. I felt that while those studies may have cast new light on certain fields as proofs of concept, their clinical applications were minimal. The Candelario-Jalil et al. paper gives an incredibly thorough example of an inflammatory process that is affected differently by drugs given 30 minutes previous to an incident versus the same drugs given 6 hours after a transient global cerebral ischemia.

The adverse effects of global cerebral ischemia are biphasic, with a marked hike in hippocampal prostaglandin E2 (PGE2) 2 hours after the insult and another notable jump in PEG2 levels 24-48 hours after the transient ischemia. It was fortuitous that this study included so many animals and was planned with so many factors accounted, with administration of COX-1 and COX-2 inhibitors either before or after the ischemic event and in different doses, because their findings were significantly different for each drug at the different times of treatment. COX-1 inhibitors were more effective given before the ischemic event, as COX-1 was shown to play a stronger role in the hours directly following ischemia. In gerbils given COX-1 inhibitor six hours after ischemia, there was little improvement compared to sham gerbils. In contrast, COX-2 inhibitors exhibited better protection for hippocampal CA1 neurons at the 24-48 hour point following ischemia.

Had this study not looked at two different treatment timelines, would we have concluded that COX-1 inhibitors are entirely more effective at treating transient ischemia than COX-2 inhibitors? On the same note, two labs looking at the same drugs but with different timelines could publish diametrically opposed papers if they failed to evaluate the full course of disease progression. All this forces me to wonder if much of the conflicting material published in the scientific community is because of the narrow scope of certain studies which are then assumed to have wider application.

Candelario-Jalil, Eduardo, Armando Gonzalez-Falcon, Michel Garcia-Cabrera, Dalia Alvarez, Said Al-Dalain, Gregorio Martinez, Olga Sonia Leon, and Joe E. Springer. "Assessment of the relative contribution of COX-1 and COX-2 isoforms to ischemia-induced oxidative damage and neurodegeneration following transient global cerebral ischemia." Journal of Neurochemistry. 2003, 86, 545-555.

A general PPAR-gamma diagram...

PPAR-gamma pathway

I included this pathway to give a visual of the PPAR-gamma pathway presented...

it includes cytokines presented in the "Dietary Aloe Improves Insulin Sensitivity via the Suppression of Obesity-induced Inflammation in Obese Mice"

Roflumilast for treating COPD?

The paper titled “Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials” was studying the effects of Roflumilast on a particular subset of COPD patients. Though the authors state this is a double blind study are honest about their conflict of interest, I feel that the selection criteria for patients may have been chosen based on who they thought would have the best outcome from treatment with this drug. The paper seemed to be a follow-up to their original study to try and prove significant results from the use of Roflumilast, which did not lend to its credibility. Overall, the authors had a large sample size showing that lung function tests were generally improved with the use of Roflumilast.

As they state in the paper, chronic obstructive pulmonary disease (COPD) is a lung disease. It is characterized by a shortness of breath, fatigue, chronic cough, and increased respiratory infections. There are two main forms: chronic bronchitis or emphysema. One of the leading risk factors is smoking, but there are other causes such as air pollution. There is not a cure, but people can treat the symptoms using an inhaler with either bronchodilators or steroids.

Roflumilast itself is a Phosphodiesterase-4 (PDE4) inhibitor. When PDE4 is inhibited, cyclic adenosine monophosphate (cAMP) is not broken down as readily in cells. Increased levels of intracellular cAMP help to suppress TNF-alpha, IL-2, and INF-gamma production. PDE4 inhibitors also lower cytokine production along with degranulation by neutrophils and inflammatory cell adhesion.

In this paper, they were studying the use of oral Roflumilast to treat COPD. However, most drugs currently in use to treat COPD are from inhalers, so as to directly contact the most affected area. Therefore, I think that in the future it would be really interesting to look at PDE4 inhibitors such as Roflumilast in an inhaler to treat COPD. In fact, some researchers are looking into non-steroidal anti-inflammatories that can be inhaled. A paper I found called “Inhaled non-steroidal anti-inflammatories for children and adults with bronchiectasis” looked at NSAIDs that can be inhaled. The results of this recent paper show a great deal of promise for using these inhaled NSAIDs in the treatment of different lung diseases such as bronchiectasis or COPD.

Anti-inflammatory Agents: Present and Future

This is an overview of the “Anti-inflammatory agents: Present and Future” paper similar to the handout that was given in class. Overall, the paper was somewhat repetitive and, as was mentioned in class, did not go into some of the serious issues associated with the use of some of these therapies.

-COX inhibitors:

• COX enzymes synthesize prostaglandins and thromboxanes, which participate in vasodilation, blood clotting, cell growth, and many other functions
• COX-1 is constitutive while COX-2 is inducible
• COX-2 inhibitors have decreased GI effects but increased cardiovascular effects

-Resolvins:

• Products of omega-3 fatty acid oxidation
• Lower infiltrating neutrophils and macrophages
• Decrease gene expression of TNF-alpha and IL-1beta

-Glucocorticoids:

• Suppress expression of cytokine-induced genes, T-cell growth factors, INF-gamma, NOX synthase, COX-2, and intracellular adhesion molecules
• Increase expression of anti-inflammatory molecules
• Chronic use is associated with organ toxicity

-Biologicals:

• Anti-cytokine therapies (block IL-1, TNF, IL-6, IL-12, IL-17, IL-18, or IL-23) are used to reduce inflammation by preventing responses such as T-cell activation
• Cytokines are more potent than hormones and can be produced by many cells
• Chemokines drive migration of immune cells while promoting angiogenesis, and can also be blocked to reduce inflammation
• Issue is innate immune response is important in defense against illness and cytokines can help with repair
• Synergistic action of cytokines means inhibiting only one is sufficient
• Effective at very low doses

-B cell depletion:

• Prevents antigen presenting and therefore T-cell activation

-Protease inhibitors:

• Proteases break down proteins and can activate cytokines
• Reduce inflammation by preventing proinflammatory cytokines from activating

-Small-molecule inhibitors of signal transduction:

• Kinases phosphorylate intracellular proteins to activate
• Example is to inhibit p38, which is important in cytokine, chemokine, COX-2 and NOX synthase production
• Tyrosine kinase inhibition reduces dendritic cell activation and proinflammatory cytokine production
• Possible renal or hepatic toxicity

-Statins:

• Reduce cholesterol levels
• Some work better than others in reducing inflammation
• Lower CRP and cardiovascular events were lowered
• Reduce cytokine production, adhesion molecules, and dendritic cell maturation
• Increase IL-10 production

-Histone Deacetylase inhibitors:

• Histone deacetylase maintains nuclear histones in deacetylated state to hold DNA
• Prevent transcription of certain genes and reduce production of cytokines
• Effective at very low doses

-Anti-coagulants and Thrombolytics:

• Activated protein C is the only approved therapy for sepsis
• Reduce cytokine production and endothelial activation by thrombin

-Activated Complement inhibitors:

• Reduce cytokine, chemokine, and adhesion molecule production

-PPARs (Peroxisome proliferator-activator receptors):

• Reduce expression of proinflammatory cytokines and adhesion molecules
• Used to treat type 2 diabetes
• Could increase cardiovascular events

-Prostaglandin (PGE) Agonists and Phosphodiesterase-4 (PDE-4) inhibitors:

• PGE2 is also immunosuppressive by inhibiting INF-gamma and IL-2
• Inhibitors of PDE-4 prevent breakdown of cAMP and are therefore anti-inflammatory
• Increased levels of cAMP lowers TNF-alpha

-Using small RNA molecules to downregulate gene expression holds promise

The paper “Anti-inflammatory Agents: Present and Future” stated the benefits of many treatments without listing the adverse effects. However, there can be serious side effects to using these various methods to treat inflammation. TGN1412 is a medication that binds to, and is a strong agonist for, the T-cells’ CD28 receptor. It was created with the intention of treating B cell chronic lymphocytic leukemia and rheumatoid arthritis. The disastrous Phase I clinical trial for this drug is an extreme example of the damage some of these therapies can cause. The clinical trials for this medication began in 2006, and were halted when many of the subjects had to be hospitalized with multiple organ dysfunction. These same effects were not seen in the pre-clinical trials on rabbits and monkeys, further proof that animal models do not accurately predict efficacy or safety in humans. Here is an article that I found about the clinical trials for this drug: http://www.i-sis.org.uk/LDTC.php

Anti-Inflammatory Agents

After class last week I was curious to the extent to which common anti-inflammatory drugs like Tylenol and Advil are taken by the general public. In one report produced by the FDA it was noted that over 100 million people consume products containing acetominophen annually, and that there are over 600 products that contain this substance on the market today. When I looked up Advil, I found that the sale of Advil generates 498 million dollars in revenue in a nine month period---that's a lot of anti-inflammatory power. While we were informed of the risks of taking these medications, I wonder to what extent are the majority of Tylenol and Advil users familiar with the product they pop everytime they have a headache. It seems to me like this would be a great area to introduce a placebo study.

NSAIDs and Antidepressants...

The study presented investigates how concurrent intake of antidepressants and anti-inflammatories modulate p11 levels in the body. p11 is a small regulatory protein of selective serotonin reuptake inhibitors (SSRIs). Past studies have linked low p11 levels to depressive like symptoms and higher levels of p11 to antidepressant activities. This was shown using p11 knockout mice and mice that were induced to express more p11.

In the context of the paper, they claim that p11 regulates some sertonin receptors by modulating their respective cell trafficking and localization in cell membranes. Doing such actions lead to different behaviour
The anti-depressants citralopram and fluoextin were shown to increase levels of p11 in mouse models. Coadministration of an NSAID with citralopram and fluoextine did not increase p11 levels.

Furthermore, the Tail suspension test (TST) and the forced swim test (FST) were administered to determine any change in depressive behavior in mice. Mice that were taking NSAIDs in addition to antidepressants scored more poorly than those that did not take NSAIDs.

The authors also investigated what cytokines are linked to increased levels of p11. TNF-a and IFN-g were injected into the frontal lobe of mice brain and western blot analysis revealed that mice injected with these cytokine yielded higher p11 levels compared to controls. This supports the idea that inflammation is involved with depression.

Based on the data, the authors feel that concurrent treatment of pain with NSAIDs and SSRI antidepressants minimizes the improvement of depressive symptoms.

Paper title: Antidepressant effects of selective serotonin reuptake inhibitors (SSRIs) are attenuated by antiinflammatory drugs in mice and humans

paper published online 4-25-11
link to paper: http://www.pnas.org.ezproxy2.library.arizona.edu/content/early/2011/04/20/1104836108.long

Revisiting the "Spicing Up" article...

The study investigated whether curcumin could be allosterically used to modulate HIV-1 (HIV-1P) and HIV-2 protease (HIV-2P) activity and (in vitro). They say that curcumin is a “modest inhibitor” of HIV protease but that complexing boron with curcumin increases inhibition by almost 10 fold.

Curcumin was complexed with boron in a variety of ways (see diagram) and each complex’s inhibitory activity was monitored. The researchers also investigated whether boron effects HIV-1P independently from curcumin and the results show that HIV-1P activity was not modulated.

So the article that we read in class last week advocated curcumin because it is all- natural. In the study that I just described the researchers acknowledge that curcumin’s activity is “modest” yet the “Spicing” study makes it seem as if curcumin in its natural form is a significant inhibitor. Clearly, in the study above curcumin is modified so the “spicing” authors (I think) poorly explicated the cited results and should have mentioned synthetic modifications of curcumin that may yield potential therapeutic benefits.

So, I would agree that Spicing up authors may have overhyped curcumin in some cases but I do think that curcumin consumption is a great herb that has a variety of useful purposes.

Sui, Z., Salto, R., Li, J., Craik, C., & Ortiz, . M. P. R. (January 01, 1993). Inhibition of the HIV-1 and HIV-2 proteases by curcumin and curcumin boron complexes. Bioorganic & Medicinal Chemistry, 1, 6, 415-22

The Strange Powers of the Placebo Effect

Placebos are powerful in that they can have real physical effects on the body without the risk of introducing foreign toxins that could have detrimental side-effects down the road. These physical effects can be attributed to the usually underestimated ability of the mind. The ability to influence physiological changes through the power of thought shouldn't be overlooked as a treatment for a variety of disease states including inflammation.

This is an interesting video I found that explains the placebo effect and really gets you thinking about how easily our brains can be manipulated to get the desired physiological response.