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