Are PCSK9 inhibitors the new Statin?

Despite the widespread use of statins, patients continue to experience major side effects such us gastrointestinal disturbances, rhabdomyolysis, acute pancreatitis, headaches, dizziness, irregular sleep cycles, and possible heart failure. Statins work by inhibiting the rate-limiting step in hepatic cholesterol synthesis. They decrease intracellular cholesterol, resulting in increased expression of hepatic low-density lipoprotein (LDL) receptors and increased hepatic clearance of circulating LDL. Less recognized is that statins increase the expression of proprotein convertase subtilisin kexin 9 (PCSK9). PCSK9 acts by reducing the amount of LDL receptors in hepatocytes. Circulating PCSK9 binds to the LDL receptor on the cell surface and is subsequently co-internalized together with the LDL receptor. This promotes the degradation of the receptor in the lysosome, thereby reducing LDL receptor density and clearance of LDL particles.

The number of low-density lipoprotein receptors on the surface of hepatic cells determines how quickly cholesterol is removed from the bloodstream. Thus, inhibiting the role of PCSK9 leads to an increase in the number of low-density lipoprotein receptors on the surface of liver cells. The extra receptors can remove low-density lipoproteins from the blood more quickly than usual, which decreases the amount of cholesterol circulating in the bloodstream. Since excess cholesterol circulating through the bloodstream can be deposited abnormally in tissues such as the skin, tendons, and arteries that supply blood to the heart, a buildup of cholesterol in the walls of coronary arteries greatly increases a person's risk of having a heart attack.

In a Phase 2 trial PCSK9 inhibitor, AMG145, showed in can reduce LDL levels as much as 55% when combined with statin with patients genetically predisposed to high cholesterol. Patients treated with a placebo saw a 1% increase in LDL cholesterol. A second Phase 2 trial of AMG145 found that it reduced LDL by 51% in patients who are unable to tolerate statins. This drug was administered every 2-4 weeks through injections, and so far, the main side effects reported have been minor reactions at the injection site, diarrhea, and headaches. A Phase 3 trial is underway to see whether AMG145 can lower the risk of heart problems, though the researches stress that this phase could take as long as 5 years. Still all this is exciting because PCSK9 inhibitors appear to be very effective, well-tolerated, and have no allergic reactions or major safety issues associated with its use.

 

References:

http://journal.9med.net/qikan/article.php?id=410458

http://www.jlr.org/content/early/2012/07/17/jlr.R026658.full.pdf

Lab-grown kidney successfully transplanted into rats

For the first time, complete lab-grown kidneys have been successfully transplanted into rats, filtering and discharging urine as a normal kidney would. Researchers from the Massachusetts General Hospital and Harvard Medical School, took a rat kidney, stripped out its functional cells using a solution of detergent, and left behind a white extracellular matrix, the collagen scaffold that gives the organ its three-dimensional structure. This included scaffolds for blood vessels as well as the key filtering structures of the kidney, and the system for collecting the urine and transporting this to the bladder. The scaffolds were then ‘reseeded’ with new cells and grown in the laboratory, resulting in the generation of a functioning kidney. When they found that the engineered kidney worked, they then transplanted it into a rat and connected it to the rat’s blood system and found that the lab-grown kidney could filter blood, reabsorb important nutrients and salts, and generate urine. The results did show some differences between normal kidneys and lab-grown kidneys. These differences suggested that the kidney structure were immature and not functioning exactly as an adult kidney would. However the researchers concluded that they had achieved three important milestones. First, the generation of three dimensional natural kidney scaffolds which contained no cells. Second, the ‘reseeding’ of these scaffolds with viable kidney tissue using new cells is possible. Lastly, the generation of urine from these bioengineered kidneys both in the lab and in a living rat.

The team is now attempting the same procedure using human kidneys, and also pig kidneys, which could be used to make scaffolds if there was a scarcity of human donors. The team has already successfully repopulated pig kidneys with human cells, but further studies are vital to guarantee that the pig components of the organ do not cause rejection when transplanted into humans. This method would  reduce the need for immune system suppression with drugs, in contrast to when a donor kidney is used, because the kidney will be built with the patient’s own cells. There is no cure for kidney failure. The only available treatments are dialysis or receiving a transplant, which just buy a patient more time but come with considerable limitations on quality of life. And with nearly 1 million patients in the US living with end-stage renal disease (ESRD), with over 100,000 new diagnoses every year, this procedure could address the limited availability of donor kidneys.

Reference:                                                                                                                                     

http://www.nature.com/nm/journal/vaop/ncurrent/full/nm.3154.html

The Sound of Diabetes

An interesting article come out recently about how long-term exposure to road traffic noise can increase your risk of  diabetes.  The study used data collected in the population-based Danish Diet, Cancer and Health cohort using 57,053 participants between the ages of 50-64 and followed these people for 9.6 to calculate the amount of traffic noise they were exposed to. It was impressive how much data this study had collected, due to all subject living in Denmark the researchers had access to their medical records plus questionnaires the subjects filled out about diet, lifestyle habits, present or previous smoking, physical activity level, health status, and social factors. Subjects were determined to have diabetes if they had five blood glucose measurements within 1 year, or two blood glucose measurements per year for 5 consecutive years; or > 1 purchase of insulin or oral glucose-lowering drugs within 6 months registered in the Register of Medicinal Product Statistics (n=3869).  The researchers decided to further refine their sample by including people who had confirmed diabetes based on just their blood glucose levels (n=2752) and run there test on both groups. 

To determine the amount of traffic noise the subjects were exposed to a complicated model calculated by SoundPlan. This software used multiple variables such as point for noise estimation, road links with information on annual average daily traffic, vehicle distribution, travel speed, and road type, polygons for all buildings etc to determine the amount and level of noise the subject was exposed to. Three models were then ran with this data, model 1 was adjusted to the sample's age, model 2 adjusted for age, sex, lifestyle confounders, socioeconomic confounders, calendar year, railway and airport noise, model 3 was the same as model 2 plus the addition of residential exposure to NOx gases.  The study found that a 10-dB higher level of exposure to road traffic noise at during a 5 year period was associated with statistically significant 8% (95% CI: 1.02, 1.14 all diabetes) and 11% (95% CI: 1.05, 1.18 confirmed diabetes) higher risk of incident diabetes, respectively, based on model 3 adjustment. However they found that railway noise (noise ≥ 60 dB) did not seem to be associated with either the confirmed or all diabetes groups.

While this article was interesting I believe it should be taken with a grain of salt and perhaps wait for more research to be conducted. The article had many variables to work with and any one of them could have been miscalculated considering we are dealing with noise level which can fluctuate greatly. The data presented here is only as good as the model used and considering this experiment was not done under a controlled laboratory setting there is a lot of room for error. The experimenters also did not select which type of diabetes the subjects had. The assumption was that due to the older age of the subject and that type II diabetes is more prevalent, the subjects most likely had type II diabetes which is not necessarily the cause. To say that traffic noise effects all types of diabetes is probably not the case and further research should be done on how it affects each type.

Thomas Becker, Anne Tjonneland, and Kim Overvad. "Long-Term Exposure to Road Traffic Noise and Incident Diabetes: A Cohort Study." Environ Health Perspect 2nd ser. 121 (2013): 217-22. PMC. 10 Dec. 2012. Web. 1 May 2013. <http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3569689/>

"Double Diabetes" a New Phenomenon

I was reading through some of my old emails today and I came across an article talking about a new phenomenon that is appearing in today's youth, where children have both symptoms of type I and II diabetes. Type 1 diabetes (T1D) is characterized as an autoimmune disease were the body's immune system begins destroying beta cells in the pancreas needed produce the insulin. Type 2 diabetes (T2D) involves the cells of the body become resistant to the insulin the pancreas is making, thus the pancreas increases the output of insulin to compensate for the resistant. Over time the pancreas can not keep up the rapid production and burns itself out. Factors such as lack of exercise, too much body fat, and poor diet increase the risk of developing T2D.

In this new form of diabetes called hybrid diabetes (11) or double diabetes (DD), overweight children with T1D are developing resistance to the insulin they are taking or T2D patients are developing an autoimmunity to beta cells. Petraikina et al. provides a good review over the world-wide progressing of overweight/obesity epidemic and the increasing cases of T1D/T2D. The article shows an increase in the number of obesity cases in Moscow raising from 6.24 per 1000 in 1996 to 10.3 per 1000 in 2005. Similar trends are seen in other European countries as the number of cases have increased dramatically in only the span of ten years. T1D and T2D cases are also raising at an alarming speed. The highest incidence rate of T1D occurring in Finland (40.9 per 100,000) with a majority of European countries experiencing a constant increase in the number of cases. Thailand, reported that 5% of children who were referred to a diabetes clinic were affected by T2D in 1996. By 1999, this percentage had risen to 17%. The article claims that these sudden increase can not be accounted for by genetic variance but is in fact more likely due to the environment interactions. 

The more interesting piece of the article is when they discuss DD and possible pathology. One of the theories is that an increased BMI in patients who might also be at risk for T1D can cause an imbalance of Th1/Th2 lymphocyte and a reduction of T-cell regulatory functions. The major contributor of down regulation is attributed to leptin, which is directly correlated to total body fat. Leptin is negatively correlated with the frequency of regulatory T cells in peripheral blood, and has been shown to promote early inflammation of the pancreatic islets with an increased production of interferon gamma in NOD (non-obese diabetic) mice. Leptin levels can also be increased as macrophages infiltrate the adipose tissue they can secrete cytokines such as tumor necrosis factor alpha (TNF-a) and interleukin 1 (IL-1) beta which cause the adipocytes to produce leptin. Due to youths with DD having both the symptoms of T1D and T2D it is theorized that they could be at a high risk of complications associated with both types of diabetes. Treatment options for DD might better be focused on the intervention capable of interfering with some of the mechanisms involved in the disease process due to the DD be-cell functions seems to decline slower than in classical T1D. Unfortunately, there is limited information about the effectiveness of any treatment approach on pediatric patients and most standard treatments are based off of adult treatments.

 Elena Petraikina, et al. "Double Or Hybrid Diabetes Associated With An Increase In Type 1 And Type 2 Diabetes In Children And Youths." Pediatric Diabetes 8.(2007): 88-95. Academic Search Complete. Web. 2 May 2013.

MELOXICAM IN OSTEOARTHRITIS COMPARISON WITH DICLOFENAC

This article caught my eye while I was searching more data for NSAIDs. This study is about the two drugs I talked about in class today, meloxicam (MXC) and diclofenac (DCF). They used random patients with osteoarthritis (OA) of hip or knee. There were 300 patients for this study, 169 treated with MXC and 167 with DCF. Their results showed that both drugs were well tolerated, although severe adverse events, treatment withdrawals and clinically significant laboratory abnormalities were more common with diclofenac than with meloxicam. Thus, meloxicam 7.5 mg is a safe and effective treatment for OA of the hip and knee, which demonstrates a trend towards an improved safety profile compared with diclofenac.

The paper expressed there is limitation with NSAIDs in the treatment of OA due to relatively high incidence of GI adverse events. They also suggested that selective inhibition of COX2 over COX1 could prevent this issues which we talked about it today in class that new research actually saying the opposite thing. 

http://rheumatology.oxfordjournals.org/content/35/suppl_1/39.full.pdf

Meloxicam and Diclofenac on the recruitment of leucocyte dung acute arthritis

Non-Steroidal anti-inflammatory drugs ease the acute inflammatory reaction and impair pro inflammatory events dependent on neutrophils but their main action is to inhibit cyclo-oxyganase, which are accountable for prostaglandin biosynthesis. There are two kind of COX, COX1 is theoretically dependable for homeostatic function of PGs and COX2 are important in PGE, production during inflammation.

This study focused on two NSAIDs drug named meloxicam (MXC) and diclofenac (DCF). The experiment was done on rabbit with antigen-induced arthritis that they were treated with MXC, DCF and control group. The results showed that, these two drug reduced arthritis due to down regulated interleukin 8(IL8) production but they did not prevent the monocyte chemotactic peptide-1 (MCP-1). Both IL8 and MCP-1 over expression in the rheumatoid synovial tissue cause the arthritis progression. These chemokines correlated with the severity of leucocyte infiltration.

Both drugs reduced PGE levels and the polymorphonuclear cells (PMN)

Concentration in synovial fluid, in other hand mononuclear cells (MN) concentration was not change at all in treated group but their data showed there was increased in MNN density due to active expression of MCP-1 in synovial membrane.

This study showed that, depletion a total PGE might not be pleasing because NASIDs reduced IL8 in arthritis but it also help MN recruitment, so there should be more research on this field.

Side note:  PMN and MN are both white blood cells. MN cells contain lymphocytes, monocytes and macrophages and PMN cell contain neutrophils, basophils and esoinophils. 

Alternate Study Demonstrating Curcuminoids Positive Effects on Rheumatoid Arthritis

An estimated 1.3 million people in the United States have RA, a form of arthritis where the immune system attacks the body’s own tissues, specifically the synovium, a thin membrane that lines the joints. As a result, fluid builds up in the joints, causing pain in the joints and inflammation. This article is titled: “Rheumatoid Arthritis and Curcumin, What Studies Show” is provided by Emaxhealth: Daily health news, a reliable source for timely health and medical news information. This very succinct article explores the various effects and benefits curcumin could have on those suffering from rheumatoid arthritis. It then goes on to mention how a study that was published in Phytotherapy Research covered a clinical study where researchers were randomly assigned to the following three group: a group taking a daily dose of curcumin, a group taking diclofenac sodium- a non-steroidal anti-inflammatory, a group that was taking both the anti-inflammatory drug and curcumin. Results of this study were that patients who had the daily dose of curcumin had the highest percentage of improvement in both DAS and ACR scores, which have not been defined in the article but stand for Disease Activity Score and the ACR score. ACR socre is a scale to measure change in rheumatoid arthritis symptoms such as reduction in tenderness and swelling of the joints. While not much more is revealed about this particular study in this article, the results of the clinical study where that patients who had the daily dose of curcumin experienced the largest improvement in both DAS and ACR scores. In addition, they found that curcumin had better DAS and ACR scores than the participants who took the anti-inflammatory drug. This study wanted to emphasize the need for future trials to validate the data and results in patients with RA and other arthritic conditions.

This article focuses on comparing the effects of curcumin vs the effects of anti-inflammatories on rheumatoid arthritis. The study that I read for this week was about Dr. Funk’s work on how turmeric extracts containing curcuminoids prevent experimental rheumatoid arthritis. Dr. Funk and her colleagues wanted to see efficacy of this chemically complex turmeric extract and compare to that of a commercially available curcumin product.  The aforementioned study varies quite a bit from the study that I saw on Emax health.

For future studies, where do you think greater research efforts should be made towards: to see how curcumin compares to other anti-inflammatory medication or to see how the bioavailability of curcumin can be increased so that it can have a clinical application in the future by solely focusing on the major curcuminoids? In addition, even if curcuminoids turn out to improve the ACR and DAS score significantly, do you think it is reasonable to think that physicians will prefer to prescribe oral doses of curcumin habitually instead of anti-inflammatory medications? Let me know what you think! Also, the links to both articles are at the bottom of this post.

References:

1. http://zp9vv3zm2k.ssscom.ezproxy2.library.arizona.edu/?eissn=1520-6025&sid=Entrez%3Apubget&pages=351-5&issn=0163-3864&date=2006&epage=355&volume=69&aulast=Funk&title=Journal%20of%20Natural%20Products&issue=3&atitle=Turmeric%20extracts%20containing%20curcuminoids%20prevent%20experimental%20rheumatoid%20arthritis.&id=doi%3A10.1021%2Fnp050327j&genre=article&spage=351

2. http://www.emaxhealth.com/1275/rheumatoid-arthritis-and-curcumin-what-studies-show

3. http://www.arthritis.org/conditions-treatments/disease-center/rheumatoid-arthritis

NSAIDs and GI Damage

For this last week, I looked at the article titled, “Comparison of the Intestinal Toxicity of Celecoxib, a Selective COX-2 Inhibitor, and Indomethacin in the Experimental Rat”. In this article, celecoxib a highly selective COX-2 inhibitor, and indomethacin, a nonselective COX-1/COX-2 inhibitor, were given to rats to study and compare the effects on the gastrointestinal system.
COX or cyclo-oxygenase is a key enzyme in prostaglandin synthesis.

The toxicity of NSAIDs has been suggested to be due to the “topical” effect in addition to the inhibition of the COX-2 enzyme.  COX-2 selective inhibitors have great GI tolerability, but this article set out to determine whether that was because of their selectivity or the lack of a “topical” effect.
From what I found, a “topical” effect in terms of pharmaceuticals is speaking about it working locally, rather than systemically.
That being said, indomethacin is thought to be causing two types of damage: topical damage and COX-1 inhibitory damage.
The topical damage of NSAIDs is due to the uncoupling of mitochondrial oxidative phosphorylation and an increase of intestinal permeability and inflammation.
The damage caused by COX-1 inhibition is the drive of intestinal inflammation to ulcerative damage by vascular effect.

The hope of this experiment is that celecoxib can suppress prostaglandin synthtesis at sites of inflammation, without inhibiting constructive prostaglandin synthesis in the GI tract.

They tested the four different drugs through rats using various tests. The different drugs and doses they used were: 10mg/kg of indomethacin, 30mg/kg of celecoxib, 300mg/kg celecoxib, and 10mL of 10% dimethyl sulfoxide (DMSO). To make this easier to read, I will keep the information for each test separated.

Mitochondrial Experiment
The livers of the rats were removed from the rats and the oxygen consumption, Phosphate:Oxygen ratio, and respiratory control ratios were measured for each liver. They also took a baseline reading beforehand to compare these values to.
The results showed that indomethacin caused an initial increase in respiration percentage (up to 230%) and proceeded to inhibit respiration as the dosage increased, all the way until respiration was completely inhibited. DMSO and celecoxib had no effect on mitochondrial respiration.
Mitochondrial morphology was also assessed through electron microscopy. It was found that the indomethacin caused significant damage to the mitochondrial cells, while DMSO and celecoxib caused very little damage. The damage was measured in percentages.

Intestinal Permeability
Intestinal permeability was assessed through use of two 5-hour urinary 51-CrEDTA assessments. The first assessment starting one hour after the drugs were administered and the second starting 19 hours after the drugs were administered. The results of these assessments were compared to a previously recorded baseline testing done before the drugs were administered, following an overnight fast.
The results showed that indomethacin increased intestinal permeability significantly, while both doses of celecoxib had only a little effect on the 1-6 hour permeability and almost no effect on the 19-24 hour permeability.

Granulocyte Marker Protein (GMP)
Three days prior to drug administration, fecal samples were taken after an overnight fast to form a baseline. After dosing, fecal samples were taken for 7 days and the GMP levels were calculated by use of daily fecal weights. GMP was used as a measure of intestinal inflammation.
The results showed that indomethacin significantly raised GMP levels on days 2, 3, and, 4 after drug administration. After day 4, the GMP levels rapidly went back down to baseline.

Intestinal Prostaglandin E (PGE)
Rats were fasted and were administered the drugs three hours before samples were collected. Proximal small bowels were snap frozen with liquid nitrogen and ground up with mortar and pestle. The ground samples were mixed with buffer, purified, and then the PGE was extracted. The PGE levels were determined in duplicate by radioimmunoassy.
The results showed that the 30mg/kg dose of celecoxib slightly raised PGE levels, the 300mg/kg dose of celecoxib slightly lowered PGE levels, and indomethacin caused a significant decrease in PGE levels.

Macroscopic Damage
For this test, there were eight groups of rats. Four of the groups (one for each drug/dose) were sampled after 24 hours. The other four groups were sampled after 7 days. The small intestines of these rats were removed and examined for the presence of ulcers.
The results showed that there were no ulcers present in either dose of the celecoxib groups or the control group. There were ulcers present in both groups administered with indomethacin. There were significantly more ulcers in the group sampled 24 hours after the administration of indomethacin than the group sampled after 7 days.

The take-home message here seems to be that celecoxib is a better choice of NSAID, when compared to indomethacin, when it comes to GI damage. The reasoning for this seems to be the fact that celecoxib is a COX-2 selective inhibitor and lacks a “topical” effect. The combination of these two are present in indomethacin and that seems to be what is causing damage in the GI tract.

What are your thoughts on this? Does this make you worry about the number of nonselective COX inhibitor NSAIDs out there? Should we exclusively use COX-2 selective inhibitor NSAIDs? Do you see any drawbacks of using COX-2 selective inhibitors?

My mistake. I forgot to add a link to the article when I first posted this.
Here is a lnk: http://ehis.ebscohost.com/ehost/pdfviewer/pdfviewer?sid=13076d80-a005-4fb3-9aed-255b1a91471e%40sessionmgr12&vid=2&hid=17

Spice-derivatives Capable of Inhibiting Inflammatory Responses of Adipose Tissue in Obesity

Obesity is a growing health concern in the United States and all around the world. According to the Center for Disease Control (CDC), obesity rates in the U.S. are about 35.7% in adults and 17% in children. Obesity is such a health concern, because it is characterized by chronic inflammation and can lead to type II diabetes, cardiovascular disease, and even cancer. The biggest link between obesity and inflammation is the release of adipocytokines from adipocytes. Adipose tissue is seen in greater concentrations in the obese and therefore there is a greater release of adipocytokines causing inflammation. In addition, macrophages from adipose tissue release pro-inflammatory mediators such as TNF-a, IL-6, MCP-1, and ROS. These pro-inflammatory mediators are present in much higher concentrations in the obese and can lead to further complications. 

http://www.sciencedirect.com/science/article/pii/S002432050600912X 

            Researchers suggest that an agent that suppresses the ability of macrophages to release pro-inflammatory cytokines should decrease inflammation and prevent the development of obesity-related disease. Woo and fellow researchers decided to look into spice-derived compounds such as diallyl disulfide (DADS), allyl isothiocyanate (AITC), piperine, zingerone, and curcumin to look for suppression of macrophages and pro-inflammatory cytokines. The results of their experiments showed that all of the spice-derived components significantly reduced the migration of macrophages. In addition, AITC, curcumin, and zingerone were the only ones that significantly reduced the concentration of nitric oxide and TNF-a. Meanwhile Curcumin, DADS, and Piperine had the greatest inhibitory effect on MCP-1. With a reduction in these inflammatory cytokines, there is likely to be less damage to the body from inflammation.

            The research in this article shows that spices and their derivatives can play an important role in reducing inflammation from obesity. These spice-derivatives could potentially help cause weight loss, reduce atherosclerosis and insulin resistance. With these potential effects of spices, do you think there is any possible danger to incorporating high concentrations of spices into our diet? Do you think spices alone could prevent the onset of other obesity-related disease or potentially reverse obesity all together?

A natural approach to inflammation

This week we started talking about anti-inflammatories. My article focused on a more natural approach to reducing inflammation. Marcelle Pick discusses ways we can reduce inflammation without the use of prescription drugs and its nasty side effects. There are several things you can do to help with inflammation but you would have to be willing to do some lifestyle changes. Such as changing your diet by adding more whole foods, exercising, taking a multi-vitamin, getting more rest, and avoiding foods that can trigger an allergic response. I decided to look more into natural remedies that can help with inflammation and I came across another article written by Dr. Mark Hyman. He talks about "hidden inflammation" and how taking anti-inflammatory drugs is dangerous because it interferes with our body's own immune system, which is true. We have our immune system for a reason and these drugs are messing with our body's natural response. At the end of his article he discusses 7 steps to living an Anti-inflammatory life to help reduce your inflammation. All of his same steps are pretty much the same as discussed in the article written by Marcelle Pick. 

7 Steps to Living an Anti-inflammatory Life

1. Whole Foods 

2. Healthy Fats

3. Regular Exercise 

4. Relax 

5. Avoid Allergens 

6. Heal Your Gut 

7. Supplement 

So if several other people agree that with these lifestyle changes you can reduce the problem of inflammation without drugs and avoid the side effects of those drugs why aren't more people leaning towards this. Another good question was in the article and it asked if you think inflammation is at the core of your health? what do you guys think?

http://www.huffingtonpost.com/dr-mark-hyman/is-your-body-burning-up-w_b_269717.html

NSAIDs for Athletes

I found this really interesting article titled, "Non-steroidal anti-inflammatory drugs for athletes: an update". (http://www.sciencedirect.com/science/article/pii/S1877065710000576) This paper gave a great overview of the effects of chronic NSAID use in athletes, especially their possible negative consequences in regard to the long-term healing process of injuries. The article discusses the fact that many athletes constantly take NSAIDs in order to continue participating in their sport after severe injury. It's all about speeding up their recovery time and getting back in the game as quickly as possible. In American football players, 1 in 7 high school athletes took NSAIDs daily and 29% of college athletes took them on the day of a game or event to prevent pain.

It has been widely established that NSAIDs cause GI disorders and disrupt renal function. The article goes into several recent studies that show NSAIDs can also negatively affect cell metabolism and growth of the major tissues in the muscular and skeletal systems. The article discusses many different types of athletic injuries and how NSAIDs either benefit or harm the healing process in particular situations. It was found that with ligament injuries (sprains), NSAIDs are helpful in reducing pain and swelling if used for less than 5 days (short term). However, after long term use, patients showed reduced joint amplitude, increased anterior laxity, and higher recidivism rate. There is no evidence that NSAIDs are effective at treating tendon injuries, since tendinopathy does not involve inflammation.

In regard to bone injuries, prostaglandin E stimulates bone resorption by recruiting osteoclasts and driving osteoblast differentiation. If a particular drug interferes with prostaglandin synthesis, it can negatively impact bone growth and strength. Since NSAIDs work in part by blocking prostaglandin synthesis, they can be detrimental to bone formation and healing immediately following a fracture or stress fracture. In regard to muscular injuries, when NSAIDs are administered for about a week surrounding the traumatic event, there was observed to be a reduction of satellite cells induced by effort. Satellite cells are important for muscle regeneration, and they depend on the presence of prostaglandin, which we know is blocked by NSAIDs. Taking NSAIDs on a regular basis may decrease the ability of the muscle to heal.

I think it is extremely worrysome that NSAIDs effectively allow athletes to mask the severe symptoms associated with their injuries, simply because they want to continue participating in a sport. I believe that athletes should try to put aside their immediate desire to play a sport, and take a good, hard look at the long term consequences of chronic NSAID use, and the quality of life they will have long after they step off the field.

Acupuncture and its effects as an Anti-inflammatory

On Monday, I went over the article, “The Neuroimmune Basis of Anti-inflammatory Acupuncture”. I’m just going to go over the basics of what I took from the article and what I thought of it.

Acupuncture is an ancient Far East healing process that dates back somewhere between 8000-5000BC. Its main objective was originally to help open up the 12 main channels of Qi (“chee”) through insertion of needles into 360 principle points. These needles could then be stimulated through heating and, more recently, by sending a small electric shock through them. The ancient way of heating the needles involved the use of mugwort (plant) incense. I pointed out in class that this might not be the best way to heat up the needles if one was trying to use acupuncture as an anti-inflammatory because plants contain allergens.

It doesn’t seem to have been until recently that some of the anti-inflammatory effects of acupuncture have really been published in the United States. In 1997, the National Institute of Health published about its usefulness in a variety of conditions, some of which are nausea/vomiting induced by operation and chemotherapy, post-operative dental pain, and as an anti-inflammatory.

One of the mechanisms proposed as the pain-relieving effect of acupuncture was “counter-inflammation” (or “counter-irritation”, seems more common). A harmful/noxious stimulus is known to cause a sort of rebound or reactive analgesic effect immediately following the stimulus. This is known as “diffuse noxious inhibitory control” or DNIC.
A simple view of this mechanism: DNIC -> opioid neuropeptide release -> pain relief

DNIC is proposed to be the cause of this counter-inflammatory response that acupuncture seems to cause. Say, for instance, one has pain and inflammation in the hand. This individual goes to get acupuncture treatment. This individual gets a few needles stuck in his/her back. The pain and inflammation in the hand dissipate or disappear completely and now the pain and inflammation is localized to the area of the acupuncture needles.
As Dr. Cohen said, it works as stomping on your toe might relieve one of his/her headache because (s)he is now focused on his/her toe pain.
So, my two ways of seeing this is (1) your brain absolutely does focus on the most recent stimulus and/or (2) the macrophages that were at the sight of the original pain are now traveling to the site of the most recent stimulus, due to recruitment.

More recent research has shown that, when an injury occurs, sensory C-fibers (in most major tissue and organs) send signals to the brain, informing it about the injury, then the brain leads an inflammatory response to that site. These sensory C-fibers release substance P and other tachykinins that induce vasodilation, increased vascular permeability, and leukocyte margination. According to Figure 1 in the article, it’s substance P that binds to macrophages that triggers the release of proinflammatory cytokines that travels through the afferent vagal pathway, notifying the brain of the injury and causing the overall inflammatory response.
This process is mediated efferent vagal stimulation causing acetylcholine to bind to β2-adrenergic receptors on immune cells. This inhibits the production of proinflammatory cytokines. The signal is also relayed to the hypothalamus and dorsal vagal complex, which causes a release of adrenocorticotropic hormone, which activates the humoral anti-inflammatory pathway.

Another pathway that has immunoregulatory pathways is the cholinergic anti-inflammatory pathway. This is show in Figure 2 in the article.
In a nutshell, efferent vagal activity causes acetylcholine to α7nicotinic receptors on macrophages, which inhibits the production of proinflammatory cytokines. It actually only takes nanomolar amounts of acetylcholine to inhibit the production of proinflammatory cytokines in human macrophage cultures challenged with lipopolysaccharide.

What ties all of this to acupuncture are the similarities in the stomach and spleen acupuncture pathways and the vagus nerve pathway. This can explain why the stimulation of ST-36, a key point on the stomach acupuncture channel, has been shown to induce peristalsis in the post-operative ileus of men and rabbits. What is most likely happening is the acupuncture is stimulating the vagus nerve, which can induce peristalsis. More evidence that this is what is happening showed up in a 1996 article that showed gastric acid secretion enhancement in rats after stimulation of ST-36, but not in rats that had their vagus nerve removed. If there’s not vagus nerve to be stimulated, the ST-36 point has no nerve to directly stimulate.

The final findings of this articles talked about how frequencies in electrical stimulation (electro-acupuncture) is much more effective than the actual placement of the needle; most likely due to the electrical current traveling to and along the vagus nerve. This was confirmed in another study that told how many irrelevantly placed needles can cause a broad array of physiological effects, “although perhaps to a lesser degree.” The “lesser degree” is likely due to the proximity of the needles the nerve pathways.

The article ends on a couple of things that require more research:
(1) Are the effects amplified by the number of needles inserted?
(2) Does more intense electrical stimulation amplify the effects?

I have to say- I would have never expected ANTI-inflammatory actions coming from acupuncture, but this article sure made a believer out of me.

I actually feel that this article really goes to show that we need to further explore our methods of treatment in the medical field.

I hope you all enjoyed the article as much as I did.

What do you think about acupuncture as an anti-inflammatory? What about acupuncture as a different kind of treatment?
Would you try it? Why or why not?

Original article can be found online at: http://ict.sagepub.com/content/6/3/251.full.pdf+html

The Anti-Inflammatory Diet

Anti-Inflammatory drugs act to reduce inflammation and the pain that is caused by it. Non-steroidal anti-inflammatory drugs (NSAIDs) relieve pain by inhibiting cyclooxygenase (COX) enzymes. COX enzymes produce prostaglandins that cause inflammation. By inhibiting prostaglandin (PG) production there is a reduced level of inflammation and pain. NSAIDs are commonly used to treat diseases like Rheumatoid Arthritis (RA) and Pleuropericarditis (inflammation of the pericardium). However, adverse reactions to NSAIDs include (but are not limited to) damage to the esophagus and stomach lining. These drugs can also be dangerous in hemophiliacs that have trouble with blood coagulation/clotting.

While researching anti-inflammatories, I came across some information regarding anti-inflammatory diets. One specific article caught my attention.

http://www.webmd.com/food-recipes/features/anti-inflammatory-diet-road-to-good-health?print=true

According to the article, chronic inflammation will lead to poor health. By avoiding foods that lead to inflammation we might be able to prevent the development of many diseases. Advocates for the diet suggest that it can reduce the risk of heart disease, reduce blood pressure/triglycerides, and soothe arthritic pains. According to Dr. Russell Greenfield, the American diet consists of too many omega-6 fatty acids from processed food and too few omega-3 fatty acids from fish. So what does an anti-inflammatory diet consist of? Many suggest that a Mediterranean or Asian-style diet might also be good anti-inflammatory regimen. Some of the recommended food for these diets include fruits, vegetables, omega-3 fatty acids, reduced carbohydrates, increased whole grains, chicken, and spices.

Experts say that the possibilities for an anti-inflammatory diet may be preventative for some diseases more than others. We also cannot actually prove that an anti-inflammatory diet will work and will reduce the risk of diseases like Coronary Heart Disease. Another downside is that if anti-inflammatory diets were used they would also take longer to work than anti-inflammatory drugs. Specialists say that food should not be the only focus for reducing inflammation, but maintaining a healthy body weight is also important.

Given the information above, what is your opinion on the trend towards anti-inflammatory diets? Do you believe these diets will work? If these diets do work, should everyone be on one?