Edward Freis

Quotes

First there was the antimalarial drug pentaquine

So he [James Shannon] had one lead which was the red pigment in the lobster and he got the idea out of the Russian literature. It was supposed to reduce blood pressure. So he said he would extract that and let me test it. But he never did. In the meantime we were looking around for something we could use. So he had one other thing and that was pentaquine, an antimalarial. . . It was a quinine and it was found during the testing of it during war that it produced orthostatic hypotension. So he thought that since it did that, that it might be useful for treating hypertension. But it was only in big doses that it did it. . . So he sent me the pentaquine and I admitted about five guys with severe hypertension to a ward in the hospital. And boy, it was bad stuff. It produced methemglobinemia and it produced stomach cramps, and it produced severe orthostatic hypotension. . .

There was one physician patient who came to see Smithwick and Smithwick sent him to me because he was too far gone to be operated. And he had malignant hypertension, full- blown. I gave him some of the drug and his pressure came down and some of his signs of malignant hypertension disappeared. So I published a paper on that in 1947 and described the antihypertensive effects of enphroanequine and the reversal of malignant hypertension. And that was the first paper on drug treatment that really lowered blood pressure. (4)

Then Veratrim

So the quinine derivative we had given up because dosage required for effect was too high. In the meantime, a professor of pharmacology at Harvard was working with a drug and published on it called ratemverde (unsure of word), which was derived from a mistletoe-like plant that grew on branches of trees in North Carolina. So a lot of horse and buggy doctors had used it in treatment of eclampsia and pre-eclampsia. . .An elixir. A little company in Indiana made it also in tablet form. So I got a hold of it and we gave it and it had a critical dose where everything happened all at once. Nothing happened until this critical dose. When that critical dose was reached the blood pressure went zoom, way down. The pulse went way down. The patient had projectile vomiting. . .Intense parasympathetic, powerful parasympathic, I think part of it. But nobody ever had a fatal reaction. So then it was decided by Shannon [then with Squibb and Co.] that maybe we could purify it so that we could separate the hypotensive from the toxic effects. . . And he wanted us to test his extracts in human beings and we tested almost 100 extracts. And toxic reactions kept appearing at the same time as the antihypertensive effects. . . . these were derivatives of veratrim. We finally came down to a complex type of chemical that was the active principle and the side effects came along with it. So that was just a waste of time. But we did publish a couple of clinical papers on using it in very severe malignant hypertension. That was about 1949.(7)

Then the Kempner Rice (Low-Salt) Diet

HB: Did you pay any attention to his [the Kempner] diet?

Oh, yes. That’s where I formulated my ideas about sodium in hypertension because this was a very strict restriction of sodium. And people have been talking since about restricted diets. Well, they are nothing compared to what Kempner did. And they were talking about the primitive tribes and the Yanomama Indians who were restricted down to a few milliequivalents per day. And so they were comparing apples and oranges. Slight restriction —a couple hundred milliequivalents per day —was considered to be sodium restriction. They actually cut it in half from what was normally written. It was still far above what the primitive tribes had and what Kempner used.(7)

A Population Effect

HB: Can I get you to think a little bit about the population issue and not just tailored individual treatment: the role of sodium in evolution and the role of sodium in the differences between our populations, industrial societies and primitive societies.

EF: Sure. In primitive societies there is no question, I don’t think. There was a fellow by the name of Lowenstein who was trekking in primitive Africa and there were two tribes – the Caribous and somebody else. And one of them had been taken over by the missionaries who brought them the gift of salt. The other one was not given salt, but their customs were the same. They lived the same kind of life. The ones that got the salt got hypertension, just like we do.

HB: I hadn’t heard that story. I heard about the Berbers and the different salty waters in Morocco and that sort of thing. I heard about the Yanomamas. Missionaries tend to spread a lot of bad things. (24)

INTERSALT

And they [the Stamlers] drew a straight line from the top bunch [of salt intake] to the primitive tribes and there was nothing, nothing in between. And it was obvious that it was two different populations. So they didn’t prove a damn thing. The low sodium diet, I don’t believe, is really doing anything. I think it’s a lot of white-coat hypertension they are mistaking for effects . . . And also, we found that diet was a poor way to attack hypertension. Patients just weren’t compliant over any length of time. (8)

Finally it was Thiazides

So it was a complete blockade as far as we could see[from ganglionic blockers[. And, gee, that produced postural hypotension and impotence and, you know, all the side effects. So we didn’t give them a big play. Then we tried using mercurials. We just gave it for a few days, but it did result in a diuresis and that did result in a drop in blood pressure. So we said, “If we could just get an oral diuretic, we would have something.” Then we heard the people at Merck had developed chlorthiazide.

I said, “This is it.” And I really asked for it, to be on the initial group getting it. They used it first in people with cardiac failure and then a fellow at Georgetown was using it on a trial basis and I could see that edema was clearing and reducing plasma volume and I thought this was really the thing. So when we got it in 1956 we began to give it to our hypertensive patients and of course, they responded very well. It seemed to me that it was the same as the rice diet. It produced the same effects. We measured hemodynamics, cardiac output, and peripheral resistance, and blood volume and extracellular fluid volume, measured all those things. One [study] from New Zealand in which they did the same hemodynamics with the rice diet and there were exactly the same changes. (11)

A Fortuitous Journey

In the Fifties I was asked to speak a lot about diuretics and traveled a lot and I went with a friend of mine by the name of Pipberger. . . He was my fellow actually before. . . And we went to Germany to attend this conference and on the way back he started talking to me about controlled trials. And I said, “Gee, that would be a great thing to do in hypertension now that we’ve got diuretics that work and reserpine, too, and put them together we’ve got a pretty good blood pressure-reducing regimen that doesn’t produce much side effects if you use them in small doses.” So that’s how we started the [VA] cooperative study.(12)

Meanwhile reserpine had come along.

EF: That came from rauwolfia. . .It was Wilkins that introduced it. . .He had been to India and some Indian doctor told him about it and he brought some back. Then Ciba purified it to reserpine. It’s good to have in small doses. A very good drug. It was slandered by some guys. Said it caused cancer or something.

HB: I remember those studies. Mayo Clinic did the studies. I think my friend Darwin Labarthe did a study on that and abolished that idea.

EF: Oh, yeah. They caused all kinds of mischief. Those drugs never recovered from that.(14)

The VA Trials

So then I said, “Now we’ve got the drugs to do this study.” And I went to the central office at the VA and I said, “Can you get me a biostatistician?” They did and he was a young guy and he didn’t know much. We started out with the ganglia-blocking drugs and it wasn’t working at all. There was no discipline. It was a bad study. That was in the late Fifties. Then in the beginning of the Sixties, this fellow died. He was young, but he died. And I got another biostatistician who was really good and he designed a very good trial and he was a good policeman and kept us on the straight and narrow.

At a meeting of the chiefs of medicine at the VA – I went around to the chiefs of medicine asking if they wanted to join and they said they would, some of them. I got 15 altogether. We had our first meeting at the May meetings in Atlantic City. Do you remember those? And we planned out the study on the mezzanine floor of the hotel that was on the Steel Pier there. We used nurses paid by the VA; we used the VA laboratories and everything. I think the whole study cost us less than $100,000. . .We studied a combination of hydrochlorthiazide, reserpine, and apresoline. Boy, that really knocked the pressure down, too. It was a very good combination. So you know the rest of it.

We wrote the protocol in ’63, started the study in ’64 and it went on for three and a half years and then we finally decided that we had an answer. Or the biostatistician decided. The first publication was in ’68 or ’69 and it was on the most severe cases. Remember that one?. . . It was a terrible thing. So many died who were in the placebo group. I had no idea they were going to be that bad. So they stopped it prematurely and the others kept on until ’71. So we had three and a half years on them. We only had less than a year on those severe ones. That was the one that made the newspapers – the ’71 – because it covered blood pressures elevated from mild to moderate. This turned around the thinking of how hypertension should be treated. (16)

Elevated blood pressure or hypertensive disease.

But I always had this notion that hypertension was a disease of the arteries and you had to find out what was causing the arteries to constrict. It wasn’t necessarily true. It was a disease of the arteries all right, but instead of saying that, in spite of that, the complications were not due to any ‘disease,’ it was due to the hypertension itself. And that was the hypothesis that we worked under and it was proved to be right. (17)

Machinations

EF: Today we are in a position to really control hypertension. We have a great bunch of drugs. We have the diuretics, which is the best of all. And that was another one that the drug companies tried to trash.

HB: Why? Why did they do that?

EF: They did that so they could sell their new brand name drugs.

HB: They really tried to turn the whole thing around, didn’t they?

EF: Yeah, they did.

HB: And MRFIT was partly responsible.

EF: It was, it was.

HB: We got bad results in the small subgroup with ischemic ECG findings taking diuretics…

EF: Absolutely! That’s right. And they kept quoting that and they had other studies that were not controlled clinical trials, but they were anecdotal and they blamed sudden death on it, diabetes and high cholesterol. We did a study on the effect of cholesterol and we found that it does go up temporarily, but then it goes back to where it was.

HB: Doesn’t it affect glucose tolerance?

EF: Yeah. It goes up. It don’t know if it goes up temporarily or not. The important thing is that the studies have been done on the long-term effects and the clinical trials did not indicate that diabetes was any more frequent than it was in the placebo group. So that’s good enough evidence. (17)

Modern Combined Therapy

But the one thing that we find about diuretics is that about 1990 we did all the drugs in a cooperative study – all the drugs that were well known – individual entities. I mean a comparative controlled clinical trial and the results of that showed that the calcium channel blocker was the most effective in reducing blood pressure. That’s all we did was to see if it reduced blood pressure. But, the other drugs mostly were about 50% reduction to normal and the calcium channel blocker was about 65 % or something like that.

Then when we finished the trial, at my insistence, they re-randomized them so that you had combinations. And we found that the combinations that contained a thiazide were significantly more effective in reducing blood pressure than other combinations. That’s because the volume reducing action makes the whole system more reactive in a downward way. But that never caught on and nobody paid any attention to it and still don’t. And it’s so obvious. So that led me to combination drug therapy.

We did that study and we did another study with an ACE inhibitor with and without a diuretic and there’s a marked difference when you added a small amount of each together. On the strength of that we decided that diuretics are unique in that they enhance the antihypertensive effectiveness of other drugs. So diuretics should always be used as a baseline.(21)

Not the Drugs but the Pressure Lowering Achieved

What the big clinical trials in Europe showed – Swedish and English – was that it didn’t matter much what drugs you used. What mattered was how far you reduced the blood pressure. And there was even a difference if you reduced it to below 130 instead of below 140; there was a significant difference in the morbid endpoints. The same for diastolic blood pressure. The ideal diastolic blood pressure was about 82 mm. So reducing it below 90 you could still reduce it further and get further benefit. (22)