Will PCSK9 Inhibitors Be the Next Blockbusters in Cardiovascular Disease?

DOC GUMSHOE EXAMINES A NEW CLASS OF NON-STATIN DRUGS

By Michael Jorrin, "Doc Gumshoe", April 24, 2014

[Ed note: Here is our latest piece from “Doc Gumshoe”, who is a medical writer (not a doctor) who shares his wisdom with us at Stock Gumshoe a couple times a month. As always, Michael’s words and opinions are his own.]

Lots of analysts and prognosticators give these cholesterol-lowering agents a big thumbs up. The dollar figures they throw around are in the $10 billion per year range in the aggregate, or upwards of $3 billion for any one of these drugs, which are:

• From Amgen (AMGN), evolocumab …
• From Pfizer (PFE), bococizumab …
• And from Regeneron (REGN) (with Sanofi [SNY]), alirocumab.

Before I go much farther with this, I need to reveal an underlying uneasiness whenever the term “blockbuster” turns up in connection with the prospects for a new drug, or, indeed, a new anything else. My initial association with that all-too-trendy word is that it might just as easily refer to a really big bomb – big enough to reduce to rubble an entire city block.

Eyes wide open, I do not think that potential potholes in the development path of any of these are deep enough to cause significant damage to any of those pharmas, nor do I think that their potential is large enough to be genuinely transformative to the developers, except Regeneron; another $3 billion or so would be nice for Amgen and Pfizer, but it wouldn’t rocket them to the moon.

But I do think that the path to becoming blockbusters, in that pleasing figurative sense, is complicated by more than the usual number of factors – which I will try to look at with a critical and skeptical eye and lay before you.

So, what are PCSK9 inhibitors & how do they work?

The full name of PCSK9 is proprotein convertase subtilisin/kexin type 9 (we won’t say that again). It plays a role in regulating cholesterol levels in the blood by affecting the number of receptors for low-density-lipoprotein cholesterol (LDL-C) receptors on cell surfaces. When this protein is overactive, it breaks down LDL-C receptors. These LDL-C receptors in the liver absorb LDL-C particles from the bloodstream for eventual excretion. As a result, overactive PCSK9 blocks one of the pathways through which our bodies get rid of excess cholesterol.

The discovery of PCSK9 came about accidentally, as do many discoveries in science. It started with the finding that some individuals have what might be considered freakishly low levels of LDL-cholesterol – somewhere in the range of a quarter or a fifth of the LDL-C levels in healthy individuals in the general population. In other words, if a normal healthy person has an LDL-C level around 100 milligrams per deciliter, there are a few – very, very few – persons whose LDL-C levels are down around 25 or 20 mg/dL.

After testing and analyzing every conceivable factor in these individuals, it was found that some had inherited genetic mutations in the production of PCSK9 from both parents, so that the protein that diminished the activity of the LDL-C receptors that took that form of cholesterol out of the circulation was not present in those persons. In short, no PCSK9 → undiminished LDL-C receptor activity → highly effective clearing of LDL-C from the circulation → extremely low LDL-C levels.

The number of people with inherited genetic mutations from both parents must be miniscule. However, there is a small but significant percentage – 2% to 3% – of persons with a single genetic mutation affecting the expression of PCSK9, and these persons also have quite low levels of LDL-C, although not as low as the “double-knock-out” individuals.

These findings were catnip to some pharma companies, which immediately launched programs to find drugs that would affect the cholesterol-raising activity of PCSK9. Initial findings from several drug companies were highly encouraging, and at least those three outfits mentioned above – Amgen, Regeneron/Sanofi, and Pfizer – have put the pedal to the metal with good results.

  • Amgen’s evolocumab is, at the moment, in the lead. Amgen has completed six Phase 3 clinical trials with that agent, which lowered LDL-C by 53% to 75% compared with placebo (the 75% decrease was seen in combination with atorvastatin). As many as 8 more Phase 3 trials are recruiting or in progress. Amgen plans to file for FDA approval for evolocumab late this year.
  • Regeneron/Sanofi’s alirocumab has completed one Phase 3 clinical trial, in which LDL-C levels were lowered by 48% compared with placebo. They expect to file for FDA approval for alirocumab early in 2015, as more trial results become known. Regeneron/Sanofi has 14 more clinical trials under way.
  • Pfizer’s bococizumab, in contrast, has completed one Phase 2b trial, in which their drug lowered LDL-C by 52% in patients taking statins. Six more trials are recruiting or in progress. The plans for filing for FDA approval are at this time uncertain.

All three of these agents are injectable rather than oral, and it’s expected that they will be quite expensive, in the range of a thousand dollars a month or more. Both of these features are likely to be obstacles to the kind of widespread adoption that would lead to blockbuster status.

What kinds of patients would likely benefit from these drugs?

The obvious patients for PCSK9s are those who are at very high risk for cardiovascular events who have not been able to lower their LDL-C levels to the 70 mg/dL target using conventional drugs – i.e., statins – or who are intolerant to statins. Another group would be individuals with very high cholesterol levels related to genetic anomalies – a disorder called heterozygous familial hypercholesterolemia, which manifests in high levels of LDL-C unrelated to lifestyle.

Persons with this genetic disorder are prone to develop heart disease at an earlier age than the general population, i.e., in their 40s or even in their 30s. This defect is relatively uncommon, occurring in about 1 in 500 persons. Most people with this form of elevated LDL-C respond well to treatment with statins, so it’s by no means obvious that the entire global population of people with abnormally high LDL-C levels due to familial hypercholesterolemia would need treatment with PCSK9s.

(Note: the heterozygous familial hypercholesterolemia population inherited the culprit gene from one parent only. Unfortunate individuals who got the bad gene – i.e., homozygous – from both parents are at even higher risk for cardiovascular disease (CVD), and may have serious CV events much earlier in life, even in childhood. I hesitate to use the word “fortunately,” but it is a fortunate fact that homozygous familial hypercholesterolemia is extremely rare, affecting a tiny fraction of the total population, perhaps 1 in 25,000. It is doubtful whether clinical trials will be mounted in these patients, although they would surely be eligible for treatment with PCSK9 agents in an effort to do whatever possible to lower their LDL-cholesterol.)

What will it take to demonstrate efficacy?

Most efficacy trials to date have focused entirely on bringing down LDL-C levels, working on the premise that doing so will lessen CV risk and reduce the number of acute CV events such as heart attacks, strokes, and episodes of severe heart pain (angina) at rest. In fact, there is plenty of evidence that lowering LDL-C results in very clear benefits for patients with established heart disease or at high risk for heart disease. For example, the famous 4S trial (Scandinavian Simvastatin Survival Study, which enrolled patients with existing coronary heart disease and baseline mean total cholesterol of 261 mg/dL, reduced coronary death by 55% at 5.4 years.

Subsequent studies, in patients who were at somewhat lower risk reported somewhat less dramatic results. An example was the Heart Protection Study Collaborative Group trial in the UK, which enrolled patients with lower baseline lipid levels. In this case, mean LDL-C levels were 131 mg/dL, which, at the time of the trial, was below the recommended cut point for initiating drug treatment except in patients at very high risk. Treatment with simvastatin lowered all-cause mortality in these patients by 13%, and lowered the risk for any major coronary event by 27%.

So, those studies would certainly seem to support the use of statins in patients at significant risk for cardiovascular events.

The question remains, do PCSK9s need to do more than demonstrate that they can lower LDL-C by margins equal to or greater than what the statins can achieve? And do they need to demonstrate that lowering LDL-C in patients at low risk for cardiovascular events results in significant clinical benefit? In other words, in order to achieve blockbuster status and justify their high price, do PCSK9s need to demonstrate a benefit in primary (as distinct from secondary) prevention.

The distinction between primary and secondary prevention is more pragmatic than absolute. Primary prevention mostly means taking fairly routine precautions against medical threats that might affect anybody; e.g., we should all get our flu shots, because the flu is out there, and, believe me, you don’t want to catch it. Secondary prevention means addressing specific factors that put an individual at elevated risk for some bad medical outcome. The evidence supporting the benefits of cholesterol-lowering treatment in persons with acute coronary syndromes such as history of stroke or heart attack or unstable angina is extremely strong. But in the larger population, with less severe risk factors, the evidence is less robust.

Some of the evidence for cholesterol-lowering as primary prevention might be called circumstantial. It is a fact that heart disease rates in the U. S. have declined quite substantially in the past 50 years. For example, the American Heart Association calculates that if the CVD mortality rate had remained at its 1963 peak, 621,000 additional CVD deaths would have taken place annually just from about 1996 onward – that’s almost 10 million people.

What could account for that huge decrease? In part, it might be because lots of people quit smoking. And many more people were controlling their blood pressure. But it’s also a fact that it was in the mid-1990s that lots of Americans began to take statins. So, based on that association, an argument can be made that cholesterol-lowering treatment constitutes a form of primary prevention for cardiovascular disease. And the new statin guidelines, promulgated in November 2013, are clearly an effort to increase primary prevention of heart disease.

But how will the PCSK9 agents fit in with the new statin guidelines?

When these guidelines were handed down from on high (i.e., the American College of Cardiology and the American Heart Association – ACC/AHA), the controversy erupted immediately. Doc Gumshoe had his say about them in a piece in December, and at the risk of repeating myself, here are the essentials of what these guidelines state:

  • They attempt to quantify total cardiovascular risk by arriving at a percentage figure for a ten-year risk of cardiovascular events (heart attack or stroke), based on an algorithm. Individuals aged 40 – 75 whose ten-year risk is 7.5% or higher are recommended to take statins.
  • They recommend that persons whose LDL-cholesterol levels are 190 mg/dL or higher should take statins.
  • They also recommend that all persons with existing heart disease or Type 2 diabetes should take statins.
  • However, specific LDL-cholesterol goals are not part of the new guidelines.
  • And regular monitoring of blood cholesterol levels is not necessary. The effects of treatment should not be based on how much cholesterol-lowering takes place.

It has been estimated that implementing these guidelines would result in 70 million people in the US being on statins.

It was pointed out immediately by some of the top cardiologists in the land that the guidelines overestimated risk by a significant percentage, so that a great many people who did not need statins would be taking them. In particular, the algorithm overweighted age, so that many older persons with no risk factors at all would be prescribed statins.

And, because LDL-C goals were not part of the guidelines and regular cholesterol monitoring is not part of the drill, there’s no way for doctors or patients to have any idea of whether the statin treatment is actually doing them any good. Patients would have to take it on faith, and this would likely lead to poor patient adherence to treatment.

A nod to the cholesterol skeptics …

There are among us those who are doubtful whether cholesterol is really the source of the cardiac problems. Instead, they point to a number of other related factors: inflammation, endothelial dysfunction, oxidative stress.

These are indeed real. But cholesterol is involved with all of them.
If you already know all about cholesterol, you can skip this – and I’ll try to keep it short. But here are some basics that a lot of people don’t know about.

Cholesterol is a simple molecule, solid at body temperature, and not soluble in water. In itself, cholesterol is neither “good” nor “bad”– the distinction is between the little bundles of lipids and proteins that carry cholesterol in our circulatory system. The larger, looser ones – low-density lipoproteins – are the ones called “bad” cholesterol (i.e., LDL-cholesterol), because they are more apt to shed cholesterol molecules, which can be deposited in the walls of our arteries. The smaller, denser ones – high-density lipoproteins (i.e., HDL-cholesterol) – convey the cholesterol molecules back to the liver, where they are taken up by the bile and carried in the bile duct to the colon, where they are eliminated in feces. Therefore, HDL-C is “good” cholesterol.

But remember that cholesterol is absolutely essential to life. It is present in all our tissues, providing structural integrity. And cholesterol is essential to the synthesis of every hormone in our bodies. We synthesize about 80% to 90% of our cholesterol; only a small fraction enters our bodies as cholesterol. You may read somewhere that cholesterol is only synthesized from animal sources. This is entirely untrue. Vegans make cholesterol just fine; if they didn’t, they would be dead.

LDL-C particles are not all the same size. It now appears that the smaller LDL-C particles are more susceptible to oxidative damage, and may also inhibit the synthesis of nitric oxide, which is thought to be one of the body’s natural mechanisms to combat atherosclerosis. The larger LDL-C particles are comparatively benign. And HDL-C has another decidedly beneficial effect. Its principal lipoprotein, apo A-1, plays a part in preventing particles involved in atherosclerosis from adhering to arterial walls.

So, indeed, those other factors play an important part in coronary artery disease and heart disease in general. But it’s hard to get away from the basic fact that what gets deposited in the arterial walls is cholesterol. That has been known for over a hundred years. What we’re beginning to understand better is how it gets there and how it causes damage.

What’s this about the “innocence” of saturated fats?

Recent evidence points to further complications in the cholesterol story. The accepted wisdom, up until recently, has been that the arch-villain in our diets is saturated fat. Now, at least some data seems to exonerate saturated fat as a principal cause in heart disease.

In a December piece (“Tidings: Mostly Glad”), Doc Gumshoe referred to a 2009 analysis of 21 studies in almost 350,000 subjects, observed for up to 21 years, which found that the persons who consumed the highest amounts of saturated fats did not have any increased risk of cardiovascular disease, compared with the persons who consumed the smallest amounts of saturated fats. (Siri-Taurino PW, Am J Clin Nutr 2009)

And in March of this year, another analysis was published, this one looking at 72 studies in more than 600,000 subjects. Again, these the results were that people who consumed the most saturated fats did not have more heart disease than people who consumed less saturated fats. And people who consumed more mono- or polyunsaturated fats, (e.g., olive oil or corn oil) did not have less heart disease. (Chowdhury R, Ann Int Med 2014)

Different types of fat were associated with varying levels of cardiovascular risk. Omega-3 fats, mostly found in fish, appeared to be protective, as did some fats found in dairy products. (Note: this doesn’t apply to omega-3 supplements, which have not been found to deliver cardiac benefit.) On the other hand, omega-6 fats, found in some vegetable oils and processed foods, were related to elevated risks.

Saturated fats do increase the levels of some LDL-cholesterol, but not of the smaller, denser LDL-C particles that deposit plaque in the arteries. These more dangerous LDL-C particles are linked to high carbohydrate diets and foods with a high glycemic index – i.e., “sugary” or high-fructose . This finding reinforced the conclusions of a Danish study that found that persons who substituted low-fat, sweet foods for higher fat foods experienced more cardiovascular events. (Astrup A, Am J Clin Nutr 2011)

So, what does all this have to do with PCSK9 agents?

As of now, Doc Gumshoe’s prognostication is that at least Amgen’s and Regeneron’s drugs will get fairly prompt FDA approval. What happens after that remains to be seen. There was a flurry of worry about possible cognitive side effects in connection with evolocumab, but careful analysis of the data did not reveal any increased risk. They do lower LDL-C by big margins, and, at least in the short term, the side effects profiles seem to be benign.

To get comparable LDL-C reductions with statins, high doses have to be employed, with an elevated risk of side effects. Statin side effects, particularly the muscle aches – and in the most severe cases, destruction of muscle tissue – are by now very well known, statins having been on the market for more than 20 years. There certainly may be side effects with the PCSK9 agents. It may just be too early for them to emerge.

There is likely to be considerable resistance from the payers. Statins now are inexpensive, and in most cases it would be difficult to justify substituting an expensive drug, given by injection, for a cheap oral drug. The response from the insurance companies will be, “You need to justify to us, on a case-by-case basis, why you need this expensive new drug.”

Compliance may also be a big deal. For the PCSK9 inhibitors to attain blockbuster status, it’s going to be necessary to get a lot of new patients on those drugs – not just the ones who aren’t getting satisfactory results on statins. Many of those new patients will have to be people who don’t currently know they’re supposed to be on cholesterol-lowering medications – the ones who get swept in under the new ACC/AHA guidelines. Most of those patients have no current symptoms – they’re merely “at risk” based on the numbers in the new algorithm. How many physicians are going to prescribe an expensive new drug to those patients? And how many patients, with no symptoms to remind them that they have a condition that needs treatment, are going to stick with the treatment plan?

And there’s yet another body of inconvenient data that does not bode well for the PCSK9s. The studies showing that the evils of saturated fats are greatly overestimated are only part of a trend that goes back to the Exoneration of the Egg. (Remember when the Evil Egg was the embodiment of what we had to avoid in order to keep out cholesterol?) Saturated fats were to be avoided not only because they cause us to gain weight, and there’s no doubt that obesity contributes to ill health in lots of ways. But when we’re considering heart health, the link was always between saturated fats and elevated levels of LDL-cholesterol.

Now, there’s evidence that what saturated fats do is increase the levels of the larger LDL-C particles, which don’t appear to be particularly harmful. It’s the smaller, denser LDL-C that most contributes to atherosclerosis, and those are more related to sugars and carbohydrates – not to saturated fats.

But cholesterol-lowering drugs, whether statins or PCSK9s, don’t discriminate between the “innocent” LDL-C and the “guilty” LDL-C. It seems possible, and even likely, that people who are not specifically at high risk for heart disease can manage their risk quite adequately by following a diet, and a not-particularly-stringent diet at that.

The benefits of cholesterol-lowering drugs for the high-risk population are very well established, and Doc Gumshoe doesn’t anticipate any change in that perception.

But for the rest of the population, not at high risk based on clinical evidence, but only on statistical modeling, this new class of drugs, the PCSK9 inhibitors, may be swimming against the tide.

* * * * * * *

Please keep the comments coming! Doc Gumshoe got a couple of demerits for the HRT blog, including one for just referring to hormone replacement therapy in the title as HRT, which looked like a stock symbol to some folks. But I want to know what people are interested/curious about, as well as when I hit or miss the mark with these pieces. Miss Truesdell didn’t shrink from telling me, “Michael, you made a mistake on line 3 of that proof – fix it!” I (eventually!) was grateful to her, and I’ll be grateful to you for correcting any goofs. Thanks again, Michael Jorrin (aka Doc Gumshoe)

Leave a Reply

102 Comments on " Will PCSK9 Inhibitors Be the Next Blockbusters in Cardiovascular Disease?"

avatar

Joseph E Fasciani
Guest
0
April 24, 2014 5:00 pm

There’s a simple solution to all this medical folderol over cholesterol.
You see, it is easily dissolved by a common organic solvent, so much so that people who consume this solv ent on a regular and generous basis have sq

JoelJ. Carlson
Guest
0
JoelJ. Carlson
April 24, 2014 8:07 pm

So, what is it????????????

archives2001
Irregular
29
archives2001
April 24, 2014 10:49 pm

Organic solvent?? Doesn’t make any sense. Where’s the rest…???

bncn
Guest
0
bncn
April 28, 2014 5:39 am

Alcohol I presume???

Dr. KSS MD PhD
Author
19010
April 24, 2014 5:02 pm

Nice commentary Michael.

Alnylam is merely waiting to see if, in an evidence-based-medicine way, the PCSK9 inhibitors change outcomes. if they do, they will deploy RNAi to silence PCSK9.

And if Alnylam does so, Benitec will then follow with liver-directed AAV8 loaded with shRNA to shut down PCSK9 expression.

Michael Jorrin,
Guest
0
Michael Jorrin (aka Doc Gumshoe)
April 25, 2014 12:51 pm

I’ve been watching Alnylam for quite a while, with increasing dissapointment, As for Benitec, will they have the resources to get this to market, or will they get scooped up?

Dr. KSS MD PhD
Guest
0
KSS
April 25, 2014 3:02 pm
Michael…oh, I am not suggesting taking a position in Alnylam. It has been heinously overvalued. Its anti-TTR siRNA for amyloidosis will never earn back what it has cost to develop it, and in fact the company is concealing that stem cell transplantation works for the condition. But they are clever….they will sit back and let the EBM’ers have at the PCSK9 mAb’s: these antibodies do cause LDL to fall by 75 per cent but that they improve outcomes isn’t yet proven. If it is proven, then they will move ahead with their PCSK9 siRNA (which they have patented). Whether Benitec… Read more »
analog68
Irregular
153
analog68
April 25, 2014 4:18 pm

They need to induce labor or change the protocol for cohort 1…..No?

Dr. KSS MD PhD
Guest
0
Dr. KSS, MD, PhD
April 25, 2014 3:40 pm
Michael: Oh, don;t get me wrong. I am not espousing Alnylam as in investment thesis. Its anti-TTR si RNA will get to market for amyloidosis though no one mentions that stem cell transplantation works for this and no one mentions the disease is rare enough that the company is not likely to recoup development costs. Also, no one is factoring in the issue that long term exogenous RNA has not been proven safe (may agonize TLRs). Alnylam is watching this, Sun Tzu-like, to see if there is EBM-worthy data that PCSK9 mAB’s alter outcomes. If they do, it will then… Read more »
Dr. KSS MD PhD
Guest
0
Dr. KSS, MD, PhD
April 25, 2014 4:08 pm

Two replies because the first seemed to disappear into an interweb void and I then tried to replicate it. The void regurgitated it.

George
Guest
0
George
April 24, 2014 5:12 pm
NIce, quick overview. As someone who has work in this field for a while: 1. I wouldnt worry too much about the new guidelines. Part of the reason they are what they are is the lack of morbidity and mortality (M&M) data: only statins have that and if the only drugs recommended were ones with M&M data, well.. there was nothing but statins to consider. 2. Statins have a lot of unpleasant side effect and people stop taking them. The fact that it is a silent disease also depressed compliance. 3. Dosing will be important for acceptance: these will be… Read more »
rubber
Irregular
13
rubber
April 24, 2014 5:15 pm

For 40 years when first checked my cholesterol has remained above 270. Had I been on statins this long, might not have been living due to other statin related complications. I am 72 now.

astrid
Irregular
3
astrid
April 28, 2014 10:54 pm

Mine has never got down to 270, i also passed on statins, and i am fine at 78

Ira H Monosson
Guest
0
Ira H Monosson
April 24, 2014 5:51 pm

As a physician who specializes in internal medicine and a cardiology fellowship in my resume’, I wish to compliment the author for the accuracy and clarity of this first class article. Well done! As for the new LDL-C guidelines, there are leading cardiologists who disagree. I side with them, but that is a discussion for another time and place.

blackwolf
Irregular
93
blackwolf
April 24, 2014 6:10 pm

Thanks Travis for a great article.

nortie
Member
0
April 24, 2014 6:13 pm
“Now, there’s evidence that what saturated fats do is increase the levels of the larger LDL-C particles, which don’t appear to be particularly harmful. It’s the smaller, denser LDL-C that most contributes to atherosclerosis, and those are more related to sugars and carbohydrates – not to saturated fats.” I have been following an Italian doctor who proposes the theory that blood type determines compatibility with food types. He has also been saying for years that it is carbohydrates (as in cereals) and refined sugars are the cause of elevated cholesterol, not fats which upon ingestion are broken down anyway. I… Read more »
megfk
Member
7
April 24, 2014 6:59 pm
This subject intrigues me. And I really enjoyed your approach to it, as well as your lively writing style. I became interested in cholesterol in 1954, when my father (a PhD research chemist who specialized in fatty acids and oils) joined a group of chemists to give a presentation at the AMA. Their message was similar to yours regarding the crucial role of cholesterol in the body. They also presented findings from numerous studies about health problems that are associated with cooking with vegetable oils. For several years, the recommendation had been for people to get rid of lard, bacon… Read more »
Joel J. Carlson
Guest
0
Joel J. Carlson
April 24, 2014 8:16 pm

K3 and K7. What are these?

megfk
Member
7
April 25, 2014 7:06 am
Joel – I neglected to add VITAMIN K. We are familiar with the variety we get in leafy vegetables…that promote blood clotting. We get a different variety of Vitamin K in meat. This variety assists in the utilization of calcium, and prevents calcium from being deposited into organs or being laid down in arteries as plaque. Vitamin K3 and Vitamin K7 are particularly high in a food eaten in Japan, called Natto or Nattokinese (a fermented soybean dish that I’m told smells awful). The Vitamin K that I take is derived from Natto. A study was done at Bethesda Hospital… Read more »
Kris Prasad
Guest
0
Kris Prasad
April 25, 2014 10:12 am

Margaret, Did you mean Vit K2, which is in fermented foods like Natto, which chaperones Calcium to bone rather than to heart? I take that along with Vit D3 and they are the only Vitamins I take. As for K3 (menadione), it is not a naturally occurring vitamin and is a synthetic. One company selling menadione (Sciencelab.com /see its MSDS section) warns that menadione is “toxic to kidneys, lungs, liver, mucous membranes. Repeated or prolonged exposure to the substance can produce target organ damage.”

megfk
Member
7
April 25, 2014 4:12 pm

Kris, I’m glad that you caught my mistake. I checked my bottle – – and you are correct. It is Vitamin K2 that I take. And now I know that K3 is one to avoid.

Michael Jorrin,
Guest
0
Michael Jorrin (aka Doc Gumshoe)
April 25, 2014 12:56 pm

Thanks, Margaret. I would love to see the study that you mention – if you can provide the citation I will get it. There’s be more on cardiac-related developments as things come up.,

megfk
Member
7
April 25, 2014 4:59 pm
Doc GumShoe – I did not keep my copy of the study on Vitamin K. And I do not know whether it was published. In 1999, my doctor (who held to the party-line of anti-supplements) went with other doctors from his clinic to a presentation at Bethesda Hospital, and was stunned by the results of their Vitamin K study. My uncle (the cardiologist) was instrumental in starting the study. His own health history drove a lot of his work. He was one of seven boys. Their father died at age 41 from a heart attack. And my uncle’s 6 brothers… Read more »
Rusty Brown in Canada
Guest
0
Rusty Brown in Canada
April 25, 2014 7:13 am

According to my research, K3 and K7 are either:
models of Kia automobiles;
a type of motorcycle;
alternate forms of vitamin K.
Take your pick.

tanglewood
Irregular
170
April 25, 2014 9:29 pm

Hi Margaret, I use a coffee grinder to grind up about 25 grams (not ounces) of Flaxseed and add it to my cereal every day. Do you know if that is an adequate replacement for Flaxseed oil?

megfk
Member
7
April 26, 2014 9:35 am
tanglewood – Dr. Johanna Budwig (in Germany) treated cancer patients with Flaxseed oil, based on the work of oil chemists that revealed deficiencies of linoleic acid in people with cancer). Even though all the patients were viewed as beyond help, the Flaxseed-oil cure rate was impressive. Maybe you saw things about her work, that sparked a bit of a craze about 12 years ago. The Flaxseed oil was mixed in a sulfur-producing protein (milk or cottage cheese) and aerated by mixing vigorously. The patients also added Flaxseeds to food. My guess is that it takes a LOT of Flaxseeds to… Read more »
Solyom
Guest
0
Solyom
April 24, 2014 7:13 pm

Are the individuals with this type of PCSK9 genetics located in a particular locale in Italy? If so ischemic Cerebral-vascular Disease and Cardio-vascular Disease are not found in that population no matter the age.

Michael Jorrin,
Guest
0
Michael Jorrin (aka Doc Gumshoe)
April 25, 2014 6:12 pm

There are probaably people everywhere who have the gene from one parent & thus less CVD; those who have it from both sides are much rarer. I think the case that piqued the curiosity of reseaarchers was a young woman in Texas, if I remember correctly.

Joseph E Fasciani
Guest
0
April 24, 2014 7:55 pm

OK, Something Happened and there isn’t an Edit feature, so here we go again.
MDs have long known that heavy drinkers of any form of alcoholic beverages have little cholesterol to clog their arteries, etc., so it’s clean tubes vs liver damage & brain cell death! Ya picks yer poison and takes yer choice: that’s what makes fer freedom in North America!

Rusty Brown in Canada
Guest
0
Rusty Brown in Canada
April 24, 2014 11:30 pm

Can you substantiate that claim re alcohol consumption?
I wish it were true, but my cholesterol is “too high” according to my G.P. and the local cardiologist told me years ago that he was surprised that a guy with arteries as badly clogged as mine would still be alive at this point. All this despite years of enthusiastic application of the panacea you seem to prescribe.
Conversely, on the other hand, there are lots of credible articles on the net about “Alcoholic Cardiomyopathy”.

Dr. KSS MD PhD
Author
19010
April 24, 2014 8:35 pm
I don’t regard it as accurate or evidence based to assert that alcohol consumption is associated with blanket protection from vascular disease. it isn’t. Moderate consumption may be associated with diminutions in all-cause mortality, but absolutely no cause-effect relationships have ever been demonstrated. Meanwhile, any cardiologist or intensivist will tell you that among the most notorious patients in hospitals are the men who have MI’s and conceal their drinking history and go into withdrawal while recovering. Drinkers have strokes and MI’s all the time. It is my job to deal with alcoholics, and to assert that they are less likely… Read more »
Joseph E Fasciani
Guest
0
April 24, 2014 9:11 pm

Sorry, but I was combining humour w/some factual stuff.
Alcohol is an organic solvent, but I wasn’t advocating drinking vats of it as a cure-all.
By the bye, what is an MI? I’ve never had withdrawals of any kind.

arch1
Irregular
4341
April 24, 2014 9:30 pm

Joseph; I think MI is myocardial infarction,,,heart attack. If you like humor don’t try this at
home, for professionals only!! Theorem of brain cleaning: as it is well known that predators lead to the overall fitness of the herd by eating the ill & the weak,The very old & young….
Since ethanol is said to kill brain cells perhaps the same sort of thing goes on with daily use. You wind up with fewer brain cells but faster??? Think I can sell that? fa

Ira H Monosson
Guest
0
Ira H Monosson
April 24, 2014 10:01 pm

Yes, MI is myocardial infarction (heart attack). Heavy drinkers who develop liver disease do have low cholesterol because the liver can’t synthesize it anymore. However, heavy drinkers usually develop hypertension, and that causes arteriosclerosis that leads to heart attacks and strokes. That’s if they don’t die from cirrhosis first.

Rusty Brown in Canada
Guest
0
Rusty Brown in Canada
April 24, 2014 11:34 pm

No argument there, but, by the bye, the silly notion that alcohol “destroys brain cells” was discredited years ago. Simply not true, as far as my experience is concerned.

archives2001
Irregular
29
archives2001
April 25, 2014 7:30 am

Rusty, Here’s an opposing presentation from an MD:
http://www.wctu.org/alcohol_and_the_body.html

megfk
Member
7
April 25, 2014 7:35 am
Rusty – A liver increasingly damaged by alcohol cannot function effectively…resulting in a build-up of ammonia. Ammonia then mixes with blood and does a number on the brain. Ammonia is one of few substances that readily passes the brain/blood barrier. The high ammonia levels are evidenced in an uneven gait when walking and difficulty writing. A further increase of ammonia is evidenced in slow, slushy speech, and inability to communicate intelligibly. When the ammonia level gets higher, the person becomes more and more groggy. Then the ammonia snuffs consciousness. In all stages of hepatic encephalopathy, brain cells are harmed by… Read more »
Rusty Brown in Canada
Guest
0
Rusty Brown in Canada
April 25, 2014 8:58 am

Thank you both for your concern. In reply, I would mention Winston Churchill as an example of someone who consumed alcohol regularly, lived a very long life, was knighted and won the Nobel Prize for literature (1953). There are other examples, such as
“…that oldest woman in France, who was supposed to have said in her last
interview, at age 112, that she owed her long life to a certain local wine…”
The evidence just doesn’t seem to support the idea that intemperate (but not extreme) drinking causes brain deterioration.

Joseph E Fasciani
Guest
0
April 24, 2014 11:01 pm
Thank you both for these illuminations. At 71, w/a pretty vigorous life [so far!] behind me, I’m always amazed by what the human body can do when it REALLY has to perform or lose its owner’s life! I should have died several times over, but like that damned rabbit, I take a licking and keep on ticking! I’m familiar w/genetics from my career in horticulture, and developing new cultivars of improved species. There are plenty of other factors that enter into one’s life that are far from free choices, and we must accept & live w/them. I recall reading about… Read more »
Dr. KSS MD PhD
Author
19010
April 25, 2014 9:35 am

Ammonia has absolutely nothing to do with altered mental status owing to liver disease. Not sure why or how that notion persists.

Alcohol does not so much directly harm the brain as it does lead to long-term excitotoxicity from chronically augmented brain glutamate synthesis and release.

Diminished synthesis is not necessarily the basis for cirrhotic hypocholesterolemia.

jonken
Irregular
53
jonken
April 25, 2014 10:05 am

Doctor KSS. Now that this subject of alcohol has arisen I have the temerity to ask a question on a subject on which I really would like YOUR opinion. My oncologist (remission of NHL) says that alcohol kills WBCs – a poison for me). My primary care MD says a glass won’t hurt me. I love big Zins and Syrahs and used to drink about 12 ounces 4-5 days/week.
Many many thanks for YOUR take on this.
Ken M.

megfk
Member
7
April 25, 2014 5:13 pm
Dr. KSS – Nonetheless, ammonia levels are measured when a patient is in liver failure (decompensation). And patients are given a product such as Lactulose to help expel ammonia and bring down the levels. As ammonia levels rise, speech and movements of the patient do become become uncertain. And after ammonia levels pass a “tipping point,” the patient lapses into a coma (a state of non-responsiveness). In a situation of a patient with liver disease, who has not consumed alcohol for years, to what do you attribute the altered mental state during decompensation, if not to elevated ammonia levels?
Rusty Brown in Canada
Guest
0
Rusty Brown in Canada
April 25, 2014 8:03 pm

NHL = non-Hodgkins lymphoma
WBC = white blood cells
apparently, if my Googling is accurate.
Maybe save a few readers from having to look this up.

Al
Guest
0
Al
April 24, 2014 8:50 pm

Speaking of cholesterol: A year ago last February my doctor said I had high cholesterol and if I didn’t do something about it, I would have to start taking medication. The doctor also said I had some indication of gout. So I gave up red meat and ate mainly chicken and in general tried to eat more vegetables and fruit. At my appointment last February, the doctor said my cholesterol was way down!

Bud Wood
Guest
0
April 25, 2014 2:03 am

Many years ago. a physician told me that I had better take his suggested statins to lower my cholesterol. I said “no statins”. He responded saying that I knew a little, but what I didn’t know would kill me.
Well, here I am at 87 and I suspect that he was done-in by ingesting statins to lower his cholesterol.

Judy
Guest
0
Judy
April 24, 2014 9:23 pm

Ii has been discovered that high LDL cholesterol level is a symptom and not a cause of a heart disease. The inflammation is the cause of heart disease, hence statins will supress the symptoms and hurt your liver. A typical side-effect of being on statins is muscle weakness; isn’t a heart a muscle?

Dr. KSS MD PhD
Author
19010
April 25, 2014 9:36 am

Statins affect skeletal muscle. Which the heart isn’t.

Judy
Guest
0
Judy
April 25, 2014 8:35 pm
#1 harm statins cause is CoQ10 depletion. If statin drugs are taken without supplementing with CoQ10 = ubiquinol, one’s health is at serious risk. CoQ10 is used by every cell in our body and especially heart cells. Cardiac muscle cells have up to 200 times more mitochondria, and hence 200 times higher CoQ10 requirements than skeletal muscle. Deficiency in this nutrient that is caused by statins accelerates DNA damage and depletion leads to fatigue, muscle weakness, soreness and heart failure. My mom’s cardiologist laughed at me that it was not proven by any research and so we never returned to… Read more »
archives2001
Irregular
29
archives2001
April 25, 2014 9:09 pm

Good pt, Judy…
thnx so much!

T.L.
Guest
0
T.L.
April 24, 2014 9:45 pm

I suggest that doc gumshoe do a article on medical marijuana. I have herd that it can treat certain illnesses but it does have bad side affects. Overall is it good or bad for humans?

archives2001
Irregular
29
archives2001
April 25, 2014 9:13 pm

LOTS of new research coming out on it, pro and con.
The con seems to be considerably more devastating
now and it is supposedly coming from unbiased* (?),
sources.
* “He who pays the piper calls the tune”

midorosan
Irregular
46
midorosan
April 24, 2014 9:52 pm

Totally off subject but I am so excited about the AAPL share split would like to hear thoughts of others especially Travis.

Ty
Guest
0
Ty
April 25, 2014 7:08 pm

The 7:1 split is a good time for investers, who normally couldn’t afford $500+ share prices, to get on board the stock and that should increase share value !! A release of new products won’t hurt either !

graham
Member
31
graham
April 26, 2014 1:11 pm
Ty, generally agree with you. However if a person can get in before the split even if only for 10 to 25 shares I believe they will be better off for these reasons, 1. The split will put the stock at around $80-per share, if you have 10 shares before the split you now have 70-shares and the stock is going to go to $100-per share very rapidly and those 70 shares will put up $1400 right away (nice cushion while we wait for new product) 2. I think it will be very difficult for those who are going to… Read more »
graham
Member
31
graham
April 26, 2014 6:20 am

Mike me to. Was thinking we should start a thread just to discuss Apple. I have to go
back to one of the other discussions to remember who it was . . . but there are others interested in Apple and it’s intriguing way of thinking. Who ever it was (Leo?) i think had started buying AAPL at $16. I think Travis has a bunch of Apple. Apple is so intriguing.

steven
Irregular
4
April 24, 2014 10:17 pm

Hi Doc, do you follow Paul Jaminet’s research and diet approach.
I am sure you will find this interesting
http://perfecthealthdiet.com/2011/07/serum-cholesterol-among-the-eskimos-and-inuit/

megfk
Member
7
April 25, 2014 7:59 am

Steven, Thank-you for posting that link. Really interesting.

steven
Irregular
4
April 25, 2014 9:33 am

This might also be interesting for you.
I find most of his reasearch is pretty spot on and objective. Paul Jaminet is a scientists and his wife a molecular biologist and cancer researcher at Harvard Medical School.
http://perfecthealthdiet.com/2011/06/blood-lipids-and-infectious-disease-part-i/

megfk
Member
7
April 25, 2014 5:15 pm

It would be fun to listen in on this husband and wife as they chat, wouldn’t it?!

George
Guest
0
George
April 25, 2014 10:08 am
One issue I see when discussing topics like this is that people cite 1 or a couple cases (for example, themselves) as proof or indication of something. Perhaps you lived to 112 but if you didn’t drink wine, you would have lived to 124. You just don’t know. Individual cases are meaningless. You need to look at a very large amount of cases in a well controlled study… thousands and thousands,,, to be able to derive any meaning. Of course, for cardiovascular event risk, very few of these are done. Statins happen to be the subject of many of these.… Read more »
bobbill
Member
22
bobbill
April 27, 2014 8:09 pm
Along those lines I have seen a heavy smoker live to the age of 89. How long would they have lived if they had not smoked heavy for 70 years? My belief in how long someone lives is determined by their “body chemistry” and what they do with their body over their lifetime. So many good and bad variables exist that certain people may do to the same degree but their outcomes may be completely different. I am not near as knowledgeable on these medical subjects as most on this site. This is just the way my simple mind sees… Read more »
John Harris
Guest
0
John Harris
April 25, 2014 10:30 am
First I note that Louis Navallier in his Blue Chip Growth service just sold Amgen after holding that for a couple of years for about a 35% gain. Don’t know what he knows but evidently he does not think this new drug will be a blockbuster. Second there is lots of evidence and some admission of that by Doc Gumshoe and others here that inflammation may be a far bigger causal element in heart disease than cholesterol and inflammation is of course highly associated with cancer and Alzheimer’s and virtually every chronic disease of aging that we know of. For… Read more »
Rusty Brown in Canada
Guest
0
Rusty Brown in Canada
April 25, 2014 7:53 pm

Or maybe “sat fats” aren’t a problem at all. I seem to be encountering more and more information these days that this may be the case.

archives2001
Irregular
29
archives2001
April 25, 2014 9:03 pm

The jury is still out on the long term effects of statins:
Whether they raise or lower inflammatory issues.
Would like to see current research from both sides.

sfimar
Irregular
98
sfimar
April 25, 2014 11:39 am

I would suggest Grain Brain for anyone interested
http://www.amazon.com/Grain-Brain-Surprising-Sugar-Your-Killers/dp/031623480X
to know more about the colestherol myth and many other things…

Renowned neurologist David Perlmutter, MD, blows the lid off a topic that’s been buried in medical literature for far too long: carbs are destroying your brain

Michael Jorrin,
Guest
0
Michael Jorrin (aka Doc Gumshoe)
April 25, 2014 1:00 pm

Yes, enough alcohol and your liver stops synthesizing cholesterol.. But you can achieve the same resultby stepping in front of a bus.

Tim
Irregular
2
Tim
April 25, 2014 1:39 pm

From my experience unless there is a life or death situtation people do not like injectable drugs. Many patients have problems adjusting to injectable insulins, which explains the research into inhalable insulin. As i read the article, i can see a place for these drugs but not as first line agents.

Ray R..
Guest
0
Ray R..
April 25, 2014 2:35 pm
In the subject of arterial plaque, I have seen no posts regarding University of Israel 3 year research that had 35% plaque reduction in a group of people with significant carotid artery blockage. They used a standardized extract from pomegranate. I had very high levels also, one being over 95% plugged and surgery clean-out and have been on the extract for five years, experiencing big time, significant drops in blood pressure and reduction of plaque; additional subsequent memory recovery and several other health related wonderful improvements. To see results, google University of Haifa pomegranate plaque research. My sister died of… Read more »
archives2001
Irregular
29
archives2001
April 25, 2014 8:57 pm

Amen, and thnx frm me too!
Gonna begin drinking lots of it!

Ray R..
Guest
0
Ray R..
April 26, 2014 4:49 pm
The original Haifa research used the juice extract standardized to 30% punicalagins, and an article I read at the time suggested 8 oz per day juice off the shelf, but because I had cancer at the same time, I was avoiding most sugar/glucose sources; as a result, I searched for the capsule extract and found both 400 and 800 mg standardized 30%, so it is best to go for the capsules. I purchased a year supply of the 800mg for under 200$ (5 bottles of 60). I still use some of the juice but mix 6 oz juice to 4… Read more »
tanglewood
Irregular
170
April 25, 2014 10:11 pm

Hi Ray, How do you take your pomegranate? Juice, extract or the actual fruit? How much?

archives2001
Irregular
29
archives2001
April 25, 2014 10:18 pm

I’ll bet the ‘real fresh stuff’ wud be best if u can afford a crate of ’em!

Rusty Brown in Canada
Guest
0
Rusty Brown in Canada
April 28, 2014 1:00 am

Don’t be too sure about that. My understanding is that pomegranate juice is extracted from the entire fruit, peel and all, and that the peel – which is inedible – contains much higher concentrations of the “good stuff” which then ends up in the juice instead of being discarded. A damn sight more convenient, too.

david 'archivesDave' clumpner
Guest
0
david 'archivesDave' clumpner
April 29, 2014 4:17 am

Rusty,
When I eat a pomegranate, I EAT a pomegranate, skin and all.
I simply use a wire brush scrapping just a little off the skin to make
certain I don’t ingest any wax or pesticides. I then place the rest
in a blender with some other juice and herbs and guzzle it down.

megfk
Member
7
April 25, 2014 5:21 pm

Thank-you, Ray, for telling about this study.

Dr. KSS MD PhD
Author
19010
April 25, 2014 5:31 pm
Margaret: I am a hepatologist. If you are not going to listen to my explanations about portosystemic encephalopathy, advanced in many of the threads, I am genuinely not sure who you will listen to. This is my field, my specialty, what I have published and spoken on nationally. No one measures ammonia levels. In fact, I do not even know of hospitals that will run them. They have no validity, no utility. A clinician who would actually order an ammonia level is so out of touch with clinical medicine and so lacking in clinical acumen as to need retraining. Even… Read more »
megfk
Member
7
April 26, 2014 10:03 am
Dr. KSS — Please know that it was not my intention to “dispute” everything you say about a topic. I simply asked you a question. I will ask it again, providing more detail about the patient’s situation. I posed a situation in which the patient has liver disease, and has not consumed any alcohol for 10 years. This patient is hospitalized due to symptoms of liver decompensation (raised liver enzymes, low blood platelets, raised bilirubin, loss of physical co-ordination, and slurred speech). In this hospital (year 2013), ammonia levels WERE examined, and WERE found to be high. In this hospital,… Read more »
Michael Jorrin,
Guest
0
Michael Jorrin (aka Doc Gumshoe)
April 26, 2014 11:07 am

On this subject, I am inclined to agree with Margaret. My Textbook of Medical Physiology (Guyton & Hall) notes that ammonia is released during the process of protein metabolism. In a healthy liver, this ammonia is converted to urea and excreted in the urine. To quote Guyton & Hall, “In the absence of the liver or in serious liver disease, ammonia accumulates in the blood, often leading to a state called hepatic coma.”

Dr. KSS MD PhD
Author
19010
April 26, 2014 1:51 pm
Uh, OK. A textbook that got the relationship between clothing and evaporative heat loss in humid hot climates wrong. And that has said that stress causes gastric ulcers. By a man whose polio was treated by the rigid splinting technique subsequently shown to be the worst possible way to manage the disease. Miasma and phlogiston were once surefire absolute certainties too. And if the tidy little model propounded by the urea hypothesis is correct, then why do encephalopathic patients whose kidneys work not merely urinate away their toxin so readily and rapidly incorporated into urea??? And why does urea never… Read more »
omcdac1
Irregular
448
omcdac1
April 25, 2014 5:34 pm

Thanks dr good one

cmessinger
Irregular
2
cmessinger
April 25, 2014 9:41 pm

Following…thank you!

rvpatel50
Member
36
rvpatel50
April 25, 2014 10:35 pm

Dr KSS
Any reason for delay in first patient dosing by Benitec? Can you please find out from your company contacts? Thanks a lot for your insightful and knowledge enhancing articles and comments.

Dr. KSS MD PhD
Author
19010
April 26, 2014 4:10 pm

Thanks Rex. I’ll be happy to discuss it. Not sure if you are an irregular or not, but the bulk of the Beni investors are over on those threads and it might be easiest to put it there in one place so all can have at it. Yes, I do know what’s going on.

Joseph E Fasciani
Guest
0
April 26, 2014 6:02 am
Gadzooks, but we have a solemn bunch of folks here! Yo, Rusty Brown, many thanks for your typically Canuckian sage observations re life, liquor, and livers, such as they are. It looks as if our lives up here are moderated by our climate, so that we have different outcomes from the similar inputs in those South of the border. At any rate , I note this is going to be one of the blog’s longest-ever running commentaries, so apparently alcohol brings out the spiritual juice in most readers. And boy! Are we ever SOLEMN instead of serious on this! Look:… Read more »
Dr. KSS MD PhD
Author
19010
April 26, 2014 6:51 pm

You’re only an alcoholic if you drink more than a hepatologist Joseph.

Joseph E Fasciani
Guest
0
April 26, 2014 11:32 pm
Very good, and glad to see you do have a sense of humour, as well as a deep knowledge of your healing arts! I had an inguinal hernia repair Wednesday night, and while I arrived at 9:00 a.m., I wasn’t in the Operatory until 3:10. I elected for my first lumbar spinal block, so I could remain conscious throughout the procedure, as I did w/my cardiac catherisation @ age 36. Both experiences were very instructive on multiple levels. While I’ve always been a fast-healing sort, since I started taking laminine regularly on August 03, 2012, the amount of recovery and… Read more »
Dr. KSS MD PhD
Author
19010
April 27, 2014 10:03 am
Thanks Joseph. I hope you are recovering well from what can be a quite painful procedure. I know that you mean it well and are well-intended, but I would be quite cautious as regards laminine. I have known about it for a while, and I have to be honest: it has all the makings of a scam. A person cannot do a randomized controlled trial on self, and so while it seems to have helped you in some way, in fact there is no data that your experience is generalizable. Companies marketing this are being sued for scamming, the putative… Read more »
bobbill
Member
22
bobbill
April 27, 2014 10:44 pm

That 95%-5% theory is what I’ve believed for decades!

Dr. KSS MD PhD
Author
19010
April 26, 2014 11:52 am
Margaret: Go to Outback, or go to a Ruth’s Chris, and eat a huge piece of whatever cut of red meat strikes your fancy. Lap it up. Enjoy it. Revel in it. Then draw your blood. I will wager my entire position in Benitec, which is quite large that, mirabile dictu, your blood ammonia level will be sky-high! And yet, I will also raise you another 10,000 shares that you will not be confused, dysarthric, stumbling or unable to add 2 and 2. You said almost nothing about what the friend has, about what the liver tests are, about what… Read more »
Rusty Brown in Canada
Guest
0
Rusty Brown in Canada
April 27, 2014 9:31 am

Thanks Doc. I learned a very useful new word today:
mump·si·mus
noun
1. a traditional custom or notion adhered to although shown to be unreasonable.

Mary Ann White, CNS, NP-c
Guest
0
Mary Ann White, CNS, NP-c
April 26, 2014 1:18 pm

Dear Mr Jorrin
I recently attended the annual ACC meeting in DC (american college of cardiology). The excitement over these new agents was very evident and the word “blockbuster” was frequently heard. As an advanced practice nurse who has been treating cardiac patients with hyperlipidemia since the mid 1980s (PRE-statin era!), I want to compliment you on your excellent and coherent explanations of lipid metabolism and pathways. And your ability to explain the drug mechanisms and interpret research data is beautifully done.
Mary Ann White, NP
Kaiser Permanente CO, dept of cardiology

David B.
Irregular
477
David B.
April 26, 2014 1:36 pm

Dr. KSS you are our true medical Gumshoe as you help all of us cut through the hype and crud to get at the truth. You do so in a way that is understandable as well. It is a pleasure being able to dialogue with you and to learn from you.

megfk
Member
7
April 26, 2014 2:07 pm
Dr. KSS — Thank-you for conveying so thoroughly your approach to treating hepatic encephalopathy. But I do still expect to see a mermaid, and the Loch Ness monster, too. As I understand your view of ammonia in regard to mental confusion…although protein-metabolism’s bi-product of ammonia much increases when the liver is not functioning properly, your position is that the elevated ammonia is inconsequential – and that Lactulose is administered to lower pH, not ammonia. Many liver specialists continue to view the ammonia itself as relevant to the mental confusion exhibited during liver decompensation. So clearly, understandings of those specializing in… Read more »
Dr. KSS MD PhD
Author
19010
April 26, 2014 3:50 pm
Margaret: to borrow from a president, “there you go again.” I know what confusion is. But “mental confusion”? What is that? I do not understand. If by mental confusion you mean confusion then, hey, why not let’s call it confusion? It confuses me, mentally you know, to call it mental confusion. I think you need to re-read what I wrote, perhaps a few times. Your fixation on old hypotheses is framing the way you approach this. As I said, lactulose, in acidifying stool, protonates certain nitrogen-containing moieties. The goal is therapeutic acidification to achieve defecation of those protonated moieties. Lower… Read more »
Michael Jorrin,
Guest
0
Michael Jorrin (aka Doc Gumshoe)
April 26, 2014 4:32 pm

Checking further, Sherlock and Dooley (Diseases of the Liver and Biliary System) cite an association between ammonia and hepatic coma, but do not assert a clear causal link. Goetz and Pappert (Textbook of Clinical Neurology) mention azotemia, among others, as a likely cause. Despite Dr KSS’s assertions, I think the case is not proven either way. And what does it have to do with anything that Guyton was put in splints when he had polio?

Dr. KSS MD PhD
Author
19010
April 26, 2014 7:17 pm
By this analogy, one should be able to spend an hour at a library and completely get, from flipping through a physics book, everything there is to know about the Higgs boson and totally grasp what supercolliders do. When people are not part of a profession and have no formal training in it but then try to harangue those that are on the basis of flipping through a textbook (totally out of date by the time they are published and not something anyone in medicine actually reads), it conveys something quite discomfiting to me about the state of intellection that… Read more »
Dr. KSS MD PhD
Author
19010
April 27, 2014 12:18 pm

And what, by the way, does hepatic coma have to do with this discussion of portosystemic encephalopathy? Hepatic coma is a completely and utterly different issue. But, never having treated a liver patient, you might not know that, and might conflate these two different entities. Which is my point. Caddies may know an awful lot about golf, but in all other pursuits, it is safe to bet that spectators will never have the ability, facility, and utility of doers.

megfk
Member
7
April 26, 2014 6:41 pm
Dr. KSS… If I failed to appropriately respond to things you said to me, you maybe can chalk that up to my lack of comprehension, and certainly to my perspective regarding “truth.” I do not think that anyone has fully grasped “truth” about anything. Understandings in both medicine and science significantly changed during my lifetime and will, I hope, continue to change. Given my perspective about “truth,” I recoiled from what you said about me “enchaining” myself, keeping myself “intellectually earthbound with what [I] am dead certain [I] know.” I certainly have no basis for being “dead certain” that I… Read more »
Dr. KSS MD PhD
Author
19010
April 27, 2014 9:55 am
I “chose” to be in dialogue because you asked Margaret. I am a bona fide expert on this subject and have spoken on it all over the country in academic medical centers, Because I am a nice guy, I took time out a Saturday afternoon to explain it to you, only to get what seems to be your replies that you don’t buy it and that you know better. Very very odd, I think. Most people would be merely grateful that someone took aside the time to explain it. Instead, you are citing data from 1993. !993! Medical knowledge, the… Read more »
Dr. KSS MD PhD
Author
19010
April 27, 2014 9:20 am

“The distinction between primary and secondary prevention is more pragmatic than absolute.”

Uh, no. Primary prevention is preventing the first vascular event. Secondary is preventing an event after a patient has had a first one. This is absolute. And right now, no one is considering deploying PCSK9 inhibitors for primary prevention except possibly in the familially dyslipidemic.

As I have discussed before in my threads, primary prevention is always a matter of negotiation and wiggle-room where the role of cholesterol modulation is incompletely understood. Quite different from secondary prevention, where statins or what may follow them are ignored at one’s peril.

omcdac1
Irregular
448
omcdac1
May 1, 2014 2:19 pm

Alnylam Pharmaceuticals, Inc. ALNY +8.08% announced today the presentation of new pre-clinical data from ALN-PCSsc, targeting PCSK9 for the treatment of hypercholesterolemia.
Here is more detail –
http://seekingalpha.com/pr/9767223-alnylam-presents-new-pre-clinical-data-on-subcutaneously-delivered-rnai-therapeutics-for-cardiovascular-metabolic-disease-at-arteriosclerosis-thrombosis-and-vascular-biology-2014-scientific-sessions

omcdac1
Irregular
448
omcdac1
May 1, 2014 2:23 pm

ALNY is working on Single dose of ALN-PCSsc for ALN-PCS program.

wpDiscuz