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But yet, and yet, I know many people who work in the industry, and they all seem nice, concerned about the world, caring. Trying to do good. The industry itself has also produced some great innovations and medications. Without which the world would be a much scarier and more unpleasant place.
In truth, I find the industry is a bit like capitalism. Both fantastic and dreadful. Which is a bit like humanity itself. Both fantastic and dreadful. Capable of the most amazing things, yet the darker side can be very dark indeed. Dr Jekyll and Mr Hyde.
To be frank, my personal problems with the pharmaceutical industry have mainly centred around cholesterol lowering. Various companies have made billions, nay tens of billions, nay hundreds of billions, pushing LDL-Cholesterol reduction with all their might.
However, I have oft sat with my head in my hands in despair at such nonsense. Pfizer with Lipitor (atorvastatin) pushed the hardest and made the most ... and horribly distorted the entire world of cardiovascular disease research in so doing.
However, thirty years ago, and purely by chance, the planets Pfizer and Kendrick were in a strange alignment. Briefly, I found myself on the same side as Pfizer when it came to cardiovascular disease.
How could this possibly be so? Well, gentle reader, let me take you back to a time when Pfizer had a very different drug to promote, called Doxazocin. It was a type of blood pressure lowering agent known as an Alpha-1 blocker. It was not selling terribly well, so they were looking for other angles in an attempt to boost sales.
I should mention that this was before Pfizer had a statin. A time that you could refer to as the 'BS' era. (Or maybe we are now in the true BS era - discuss). Then, in the year 2000, Pfizer took over Warner Lambert, which just happened to have a statin called atorvastatin (Lipitor). Yes, Pfizer didn't actually develop atorvastatin. They just bought out the company that did. Nifty move.
Anyway, in 1992, Pfizer was not much interested in lowering LDL-Cholesterol, as they didn't have a statin. Which meant they had other fish to fry with their cardiovascular drugs. They were more focused on blood pressure lowering. But their Alpha-1 blocker for this, doxazocin (Cardura) was a bit rubbish.
So, what to do? What to do indeed. What they did was to use the tried and trusted mechanisms of looking at different effects that this drug might have.
To explain, almost all drugs when they are launched are marketed for one indication, and that indication only - the thing that will make the most money. Achieving marketing approval, for any indication e.g., blood pressure lowering, costs vast sums of money. Which means that companies must keep their focus tight, to drive the drug through the clinical trials process.
However, almost all drugs will do many other things, and you cannot run separate clinical trials on them all. To long, too complex, too costly.
There may be some 'magic bullet' drug that hits one target, and one alone, and spares everything else. Sniper fire. However, with most of them, you select automatic, raise the gun over your head from behind a sheltering wall, close your eyes, and spray bullets vaguely towards the target. Hoping you manage to hit the thing you're aiming at.
Just to give a few well-known examples from history. Aspirin was initially found to reduce pain, inflammation and temperature. It was later discovered it helps to prevent platelets (small blood cells) sticking together. So, it was also an anti-coagulant - it reduced the risk of blood clots forming - and thus reduced the risk of dying of a heart attack. Now, it is being used to prevent cancer.
Sildenafil (Viagra) was initially developed as a drug for angina. The rest, as they say is history. It ended up being marketed for erectile dysfunction because it had an unknown, at the time, 'off-target effect' that had nothing, directly to do with angina at all. Or, at least, no-one could see the connection at the time.
Thalidomide was originally developed as a sedative. It was then sold for treating colds, flu, nausea and morning sickness. As everyone now knows, it caused horrible deformities in the unborn child.
Coincidentally, it was discovered the very same mechanism that led to the terrible deformities, also meant it was pretty good at treating a whole series of different diseases, such as multiple myeloma and leprosy. It is now prescribed as Thalomid - it has many different names. But certainly not thalidomide.
Last time I bothered counting, statins had thirty-four off-target effects. These are sometimes called 'pleiotropic' effects. I suppose this makes them sound more scientific. I am only surprised that statins have not yet been repurposed as anti COVID19 drugs. Probably because they are all off-patent, thus cannot make vast sums of money.
In an attempt to pull all these strands together, if your drug is not selling that well, have a closer look at all the other things it may do. The off-target effects, the 'pleiotropics'. It has already reached market, at great cost, and whilst you are not allowed advertise it for 'off-label' benefits i.e., benefits not studied in the clinical trials, you can hold educational meetings and produce educational booklets to promote these additional things.
You can, effectively, launch it again as 'Cardura two point one'. Ladies and Gentlemen .... drum roll. 'A new era in cardiovascular disease prevention has begun.' Dun, dun, duuuuuuuuun!'
At which point you can purchase a few off the shelf cardiology opinion leaders to push Cardura two point one with great enthusiasm. Throw a few million - carefully labelled - free pens, sticky pads, and BP cuffs around as an appreciative gift to doctors. Take them to a free lunch, sorry, educational meeting. Bore them for ten minutes, then reward them with a prawn sandwich. Feed the sea-lions.
And lo it came to pass that Pfizer scrutinised Cardura in greater detail, and found that it, like aspirin, helped to stop platelets sticking together. Platelets are small cells that float around in the bloodstream and play the key role in blood clotting. They have been described as the conductors of the clotting orchestra.
If you stop platelets sticking together, you can reduce the risk of cardiovascular disease, as was discovered with aspirin. Aha! So, not only does Cardura lower blood pressure, but it also has 'anti-coagulant' properties. Even better, it reduced fibrinogen, and PAI-1 and increased TPa activity. These are all 'good' in reducing the formation and increasing the breakdown of blood clots. As Pfizer stated:
'These recent studies suggest that doxazosin may have a range of significant antithrombotic effects in many patients...'Unfortunately, in 1992 doctors had already been under heavy and continuous bombardment with the message that lowering cholesterol and blood pressure were, by far, the most important things you could possibly do to prevent cardiovascular disease.
Blood clotting? Well, aspirin was used, a bit. But this was mainly to help with the final event. The big blood clot that blocked a major artery. No-one was suggesting that blood clotting had anything to do with atherosclerosis itself.
After all, how can blood clotting possibly cause atherosclerotic plaques to develop? As everyone had already been told, and told, and told ... and told, and then told some more, atherosclerotic plaques (the entities that gradually grow and narrow down arteries) were full of cholesterol. Not the remnants of blood clots.
Love and marriage may go together like a horse and carriage, but platelet aggregation and atherosclerotic plaques .... You certainly cannot get a rhyme out of that - go on, I challenge you. Ergo, it must be wrong.
It was certainly a big mountain to climb. 'You know that stuff about cholesterol.... Sorry. Turns out we should have been looking at Platelets and blood clotting instead.' Here from a booklet on Cardura in 1992:
Platelets and atherosclerosis progressionGoodness me. Who said all this? Why, of course it was Pfizer ... Pfizer, Pfizer, Pfizer.
Several features of mature plaques, such as their multi-layered pattern, suggest that platelet aggregation and thrombus formation are key elements in the progression of atherosclerosis. Platelets are also known to provide a rich source of growth factors, with can stimulate plaque development.
Given the insidious nature of atherosclerosis, it is vital to consider the role of platelets and thrombosis in this process, and the serious events that may be triggered once plaques are already present.
However, they didn't get very far with this story. Merck were hammering away with simvastatin (Zocor) and Bristol Myers Squibb were also promoting pravastatin (Pravachol) with relentless fervour. The world of cardiovascular disease prevention was moving even more firmly in the direction of cholesterol lowering and statins.
As King Cnut (Canute to you and me) once demonstrated, once the tide starts to come in, not even a king can stop it. And the statin wave was very powerful. On the basis that, if you can't beat them, join them, Pfizer decided to ride that wave. So, they went out and bought a large part of it, then bought the surf-boards and the tinnies.
To their (money making) credit, they then rode the cholesterol wave exceptionally well. To be frank you would buy a used car from Pfizer. I don't know how they got so brilliant at spraying bull-shit with yellow paint, to make it look like one-hundred per-cent gold bullion, but there is no doubt they are the masters of pharmaceutical marketing.
At which point the Kendrick and Pfizer, planets were no longer in alignment. We span off on different orbits. I was still slowly plodding along the 'platelets and atherosclerosis progression' path, trying to make sense of it all.
Pfizer, to flip my analogies, firmly jumped on the 'all singing, all dancing' cholesterol lowering bandwagon.' Complete with dancing girls in fancy costumes, a brass band, champagne, hundreds of balloons - and all the key opinion leaders in cardiology singing 'We're in the money.'
We're in the money
We're in the money
We've got a lot of what it takes to get along
We're in the money
The sky is sunny
Old man depression, you are through you done us wrong, oh
We never see a headline
'Bout a breadline today
And when we see the landlord
We can look that guy right in the eye
Oh, We're in the money
Come, on my honey
Let's lend it, spend it, send it rolling around...
And lo it came to pass that Pfizer and I were no longer friends. But there was a time when I like to think we could have danced all night, and still have begged for more. I could have spread my wings, and done a thousand things, I've never done before. Yes, my bandwagon would have been much better. Better music too. John Martyn, Fleetwood Mac, Randy Newman, The Pretenders, Jools Holland ....
Yes, it's a little bit funny that Pfizer knew, thirty years ago, that blood clotting and atherosclerosis were intimately connected. They had seen the research. They knew:
Important evidence is now emerging that the selective alpha-1 inhibitor, doxazosin, in addition to its beneficial effects on elevated blood pressure and the serum lipid profile, may help to intervene in the evolution of thrombosis, a key component of atherosclerosis.In my recent book The Clot Thickens, I said I would put up the Pfizer booklet for all to see. It proved a bit more of a technical challenge than I thought, but here it is. And when people tell me that atherosclerotic cardiovascular disease (ASCVD) is all due to raised cholesterol I can say, not even Pfizer believes that. Not really. Not deep in their hearts .... They have a ghost in the machine that still stalks the corridors of Pfizer HQ. And if it doesn't, it should.
They knew, oh yes once upon a time, they knew. It's just not very profitable for them to admit it. To quote John Martyn:
Half the lies I tell you are not true.Introduction
To date, most of our attempts to prevent atherosclerosis have centered on the control of hypertension and hyperlipidaemia, as well as lifestyle factors . However, recent insights into the pathology of coronary heart disease have sharpened our focus on the natural history of atheroma and its relentless progression to acute cardiac events.
Platelets and atherosclerosis progression
Several features of mature plaques, such as their multi-layered pattern, suggest that platelet aggregation and thrombus formation are key elements in the progression of atherosclerosis. Platelets are also known to provide a rich source of growth factors which can stimulate plaque development.
Given the insidious nature of atherosclerosis, it is vital to consider the role of platelets and thrombosis in this process, and the serious events that may be triggered once plaques are already present.
Fibrinolysis
If fibrinolysis is incomplete, thrombus may become incorporated into the plaque, and may cause severe stenosis. Alternatively, any residual thrombus can act as a powerful stimulant to further platelet aggregation. The growing mass of fibrin, platelets and enmeshed red cells may become solid enough to cause complete vessel obstruction.
It is significant to note that complete obstruction and myocardial infarction often develops from mild lesion initially causing less than 50% stenosis. Rupture of these plaques and the cascade of events that leads to thrombosis can occur rapidly and it now recognized as a common and major precipitant of unstable angina, myocardial infarction and sudden cardiac death. Studies suggest that thrombotic events may account for up to 90% of acute myocardial infarction.
Triggering factors in thrombosis
Hypertensive patients are known to have greater platelet adhesiveness and aggregability, which could increase clot formation at the site of plaque injury. In addition, thrombolysis is often defective in hypertension and hyperlipidaemia, which may result in an impaired ability to dissolved clots in the presence of atherosclerosis.
Clot propagation
Any residual thrombus can act as a powerful stimulant to further platelet aggregation. The growing mass of fibbing, platelets and enmeshed red-cells may become solid enough to cause complete vessel obstruction.
It is significant to not that complete obstruction and myocardial infarction often develops form mild lesions initially causing less than 50% stenosis. Rupture of these plaques and the cascade of events that leads to thrombosis can occur rapidly and it now recognized as a common and major precipitant of unstable angina, myocardial infarction and sudden cardiac deaths. Studies suggest that thrombotic events may account for up to 90% of acute myocardial infarctions.
The atherosclerotic process begins with infiltration of low-density lipoproteins or LDL into the arterial intima to create lipid-rich foam cells which form the basis of the 'fatty streak.' This early lesion contains large amounts of cholesterol, but its development to atherosclerosis is not inevitable. Progression appears to depend critically upon endothelial injury, caused by oxidation of LDL by the shearing forces of hypertension and by smoking.
Conclusion
With each decade, new insight is gained into how drug therapy can reduce the risk of coronary heart disease and stroke, the primary goal in the management of the hypertensive patient.
Important evidence is now emerging that the selective alpha-1 inhibitor, doxazosin, in addition to its beneficial effects on elevated blood pressure and the serum lipid profile, may help to intervene in the evolution of thrombosis, a key component of atherosclerosis.
The Document is called Pathological Triggers 'New Insights into Cardiovascular Risk.'
Produced by Medi Cine Inc
488 Madison Avenue
New York
NY 10022
For Pfizer Inc
New York
NY 10017 Copyright 1992 Pfizer Inc. All rights reserved.
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