Prazosin revisited

[Purple-Bike]

The sheer beauty of the retrospective study posted recently by Scout4answers is the vast superiority in Recurrence Free Survival for Prazosin users over a ten-year period not only against controls but against a similar drug, Tamsulosin. IMHO this means that selection bias is much less likely. Prazosin and Tamsuolosin are both used for lower urinary tract symptoms (LUTS) and high blood pressure. Both are α1- adrenoceptor antagonists but Prazosin is of a different subtype, quinazoline based, compared to Tamsulosin which is a sulphonamide derivative. These have some different characteristics which could account for their spectacularly different outcomes.

The adjacent graph posted by Scout4answers shows the most beautiful one I have seen in a long time.

What was left unanswered in the thread on Prazosin, reported on earlier by Patrick/Pjoshea 13, is the dosage and duration of Prazosin use to aim for if one wants to try this drug.

I had a telephone conversation with Professor David Christie, lead researcher in the ongoing prospective study on Prazosin, and a co-author of the retrospective study. My question was why the new study is using up to 10 mg prazosin daily, i.e. within the typical range used for high blood pressure, vs the 1-2 mg daily used of Prazosin in the first study, by patients with LUTS where lower doses are used.

His answer was that it is hard to translate the doses used in the preclinical trials to humans and that the hope is that the higher doses will prove to be even more effective than that indicated by the lower doses, even for the short time that the new study entails.

I asked him why the prospective study will only medicate with Prazosin for six weeks, vs 3- 5 months use in the retrospective study. His answer was that the new study, although progression free survival and PSA kinetics will be measured, is primarily a feasibility study to help guide development of a large-scale clinical trial for use of Prazosin by men undergoing radiotherapy for prostate cancer. Caution is used since there may be toxicity using Prazosin for prostate cancer patients without high blood pressure who are included in the study (men lower than 100/70 will be excluded).

My take is to start low with 0.5 mg avoiding hypotension, then slowly increase until 10 mg, or lower if there are noticeable side effects. If side effects don´t show up, I may aim for 3 – 5 months, as per the first study, before tentatively stopping for a considerable time to avoid risk of loss of efficacy. “Results (from Prazosin use) are rapid and can generally be evaluated by 4 weeks. When used for more than two years, prazosin becomes less effective and higher doses may be required. This may be due to tachyphylaxis (progressive decrease in response to a given dose after repetitive administration), or a progressive increase in prostatic size which is not influenced by prazosin's effects on muscle tone”.

“The most important adverse effect is postural hypotension, but stuffy nose, headache and retrograde ejaculation may also occur”. Hypotension = blood pressure under 90/60, often with no symptoms, but dizziness, fainting can occur.

The first, retrospective study linked by Scout4answers

nature.com/articles/s41598- ...

The newer prospective study anzctr.org.au/ACTRN12621000...

Any input from (potential) Prazosin users?

[Purple-Bike]

Oops, the first link doesn´t was bad here it is again nature.com/articles/s41598-...

[Tall_Allen]

Selection bias is not up to you, it is built into the study and you cannot get rid of it no matter how much you want to. Wanting it to be true does not make it true.

[Purple-Bike in reply to Tall_Allen]

Is it likely that Prazosin users are vastly different from Tamsulosin users?

[Tall_Allen in reply to Purple-Bike]

Yes - very likely. Prazosin is prescribed only for high blood pressure. Tamsulosin is prescribed only for BPH. Entirely different medical profiles. High BP affects and is affected by a number of steroids. BPH is affected by testosterone and DHT.

[Purple-Bike in reply to Tall_Allen]

Tamsulosin is indeed prescribed for BPH and not for blood pressure I was wrong on the latter.

But according to the study the prazosin users took this not for high blood pressure but for the second main use for prazosin, LUTS, lower urinary tract syndrom. with 1-2 mg which is the prazosin dose for LUTS (6-15 mg is the dose for BP).

LUTS and BPH have overlap: "Bladder outlet obstruction and/or changes in smooth muscle tone and resistance that can accompany BPH often result in lower urinary tract symptoms (LUTS)".

It seems to me that it´s not highly apparent that men using prazosin for LUTS would differ greatly from men using Tamsulosin for BPH. Am I likely to be wrong?

Table 1 in the retrospective study shows that

- Age, PSA and Gleason sum are very similar between prazosin and tamsulosin patients

- 62% of tamsulosin users are "high risk" vs 57 % for prazosin.

- In tumor staging, T users are significantly worse than P users, with 39% being T3/T4 vs 19 % for P.

In total, T users are significantly worse in one of the parameters, with little difference in the rest. Even if the tumor staging was the only important thing, it won´t account for the huge difference in recurrence rates. There must be some other huge difference between P and T users, if prazosin is not a PCa warrior and if there are no other major things wrong with this study.

nature.com/articles/s41598-...

[Tall_Allen in reply to Purple-Bike]

You wrote: "But according to the study the prazosin users took this not for high blood pressure but for the second main use for prazosin, LUTS, lower urinary tract syndrome with 1-2 mg which is the prazosin dose for LUTS (6-15 mg is the dose for BP). "

Are we looking at the same study? Be careful about making up things to confirm your bias. It was just a retrospective study of men who took alpha-blockers while having RT for localized PCa. I see no info on dose or the reason they took it. It would be unusual for anyone to get prazosin for anything but high BP. I think you should assume they got the appropriate alpha-blocker for the approved indication.

[Purple-Bike in reply to Tall_Allen]

Prazosin's most common use is indeed for high BP, but it has other uses too. According to the retrospective study, P and T were both used for LUTS:

"Although doses were not available for each patient, typical dose ranges used at the clinic for the patients were 1–2 mg/day for prazosin and 0.4 mg tamsulosin/day. Treatments were started during radiotherapy and then continued for 2–3 months post treatment until problems with LUTS resolved".

This is not iron-clad, could have been better detailed, but still...

A study showing P and T both used for BPH

"Comparison of prazosin, terazosin and tamsulosin in the treatment of symptomatic benign prostatic hyperplasia: a short-term open, randomized multicenter study. BPH Medical Therapy Study Group. Benign prostatic hyperplasia"

So there seems to be overlap in the use of P and T for the same issues.

According to the study this was so in that case. If indeed both were used for LUTS, surely selection bias is less likely.

[Tall_Allen in reply to Purple-Bike]

The dose given for hypertension starts at 1 mg/day (up to 20 mg) the dose for BPH is the same 1 mg/day (up to 4 mg/day). It seems reasonable to assume that patients with hypertension were preferentially given prazosin, while the patients with normal BP were given one of the others. But that is just an assumption, equally invalid as your assumption that all patients were equal. Selection bias is built in, and since they did not even supply BP of patients (which was undoubtedly measured on their first visit) they are masking the confounding data that might have allowed us to see the bias. Was it intentional or just bad research on the part of the researcher? I couldn't say. Either way, wishful thinking doesn't clean up the data - only a randomized trial (with stratification by BP) can provide a useful answer.

[Purple-Bike in reply to Tall_Allen]

If we assume that the researchers are sloppy and wrong and that P was prescribed for high blood pressure, the two groups have different medical histories which introduces some selection basis. Still it seems this isn't likely to alone account for the huge difference in outcome. There must be other factors at play.

[Tall_Allen in reply to Purple-Bike]

It accounts for it to me, but I am not trying to confirm a preconceived notion.

[Tall_Allen in reply to Tall_Allen]

BTW- They should also stratify on beta-blocker use and other anti-hypertensives. There have been several retrospective studies on beta-blockers:

pro:

onlinelibrary.wiley.com/doi...

ncbi.nlm.nih.gov/pmc/articl...

eventscribe.com/2019/AUA201...

con:

sciencedirect.com/science/a...

wjso.biomedcentral.com/arti...

bjanaesthesia.org/article/S...

ejcancer.com/article/S0959-...

link.springer.com/article/1...

plausability:

science.org/doi/10.1126/sci...

ncbi.nlm.nih.gov/pmc/articl...

science.org/doi/10.1126/sci...

science.org/doi/10.1126/sci...

[Purple-Bike in reply to Tall_Allen]

TA, if the researchers are right and prazosin in fact was prescribed for LUTS, do you agree that selection bias in that case is less likely?

[Tall_Allen in reply to Purple-Bike]

Selection bias is never absolved in retrospective studies without at least multivariate analysis of potential confounders and eliminating sources of bias. Think of it this way - can you explain why some patients got prazosin and others did not? You seem to be asking a lot of "ifs" of the study, which is only useful as raising a hypothesis. Can you explain how it is plausible that it works better than other alpha blockers? I have seen too many retrospective studies in the trash heap to get excited about this one.

[Purple-Bike in reply to Tall_Allen]

TA, I sincerely appreciate learning the limitations of retrospective studies and gladly take in the knowledge you share. I realize that the study was indeed sloppy in not discussing confounders for selection bias between prazosin and tamsulosin users, let alone make a multivariate analysis. I will try contacting the researcher again, to see if they have even thought about confounders.

That said, I do believe the study more interesting than most retrospective studies, for two reasons.

The researchers say that both prazosin and tamsulosin users were prescribed the medications for lower urinary tract syndrome, LUTS, at the dose of 1-2 mg per day for prazosin. They could be wrong, it could have been for high blood pressure for prazosin users since this is used for both issues but tamsulosin only for LUTS/BPH. But then they would probably have to have been wrong both in saying it was for LUTS in the case of prazosin, when it was for BP, and in saying it was 1-2 mg since this is the typical dose for LUTS but not for high BP. It can be so low, but typically it is higher.

“Prazosin – Adults Hypertension -Oral:

Initially, 1 mg 2 or 3 times daily. Do not initiate with higher dosages. May increase dosage gradually to 20 mg daily given in divided doses.

Usual maintenance dosage: Manufacturer states 6–15 mg daily given in divided doses. Some experts state 2–20 mg daily, administered in 2 or 3 divided doses.

Furthermore, it is apparently common with LUTS from radiotherapy, I had it myself. Why should we believe there is a significant likelihood of the researchers being wrong when they say both P and T were prescribed for LUTS for the prostate cancer patients undergoing radiotherapy? True, they were sloppy in giving details. But with LUTS often occurring from radiotherapy, and P and T both given for this, isn´t there a decent chance that the researchers are correct when they state this, to boot stating the dosages typically used for LUTS and not BP in the case of prazosin? Rather than making the blatant error of stating the wrong reason for medication? If so, it could boil down to a case of some doctors favoring P and others T for LUTS incurred by prostate cancer patients undergoing radiotherapy.

Added to this is the P and T patients being very similar in four out of five parameters, according to the study.

The second reason is the preclinical evidence. “There is substantial evidence that the quinazoline α1 antagonists (terazosin, prazosin and doxazosin) display cytotoxicity in prostate cancer cell lines, effects that are not observed with the sulphonamide derivative tamsulosin. ........ In vivo studies in mice have shown that these effects also occur at clinically relevant doses, with reduction in tumour growth, metastasis and decreased angiogenesis observed in models of prostate cancer”.

Preclinical evidence on its own may have limited value, but I think it can bolster what clinical evidence there is when the two point in the same direction.

For me it boils down to making a call on odds and likelihoods, vs certainty from waiting for the RCT some years ahead. If a substance can be judged to have some slightly decent chance of working, why not try it, if side effects are tolerable? Yes, it entails some degree of optimism but why not?

In my own case, I am starting to lean towards prazosin being a slam-dunk. A “side effect” of prazosin is lowered blood pressure and I wouldn´t mind getting my systolic 125/130 down to ideal 100. When was the last time one heard of a medication possibly beneficial for PCa that has a fantastic side effect?

[Tall_Allen in reply to Purple-Bike]

If you want to take it with radiation, why not? Just don't pretend there is good evidence.

[Purple-Bike in reply to Tall_Allen]

I will be taking prazosin without radiation, this is not the time for that.

True, the study relates to prazosin use during and after radiation, but if beneficial in that context I don’t find reason to assume prazosin can't be good in other contexts. The preclinical studies showing beneficial outcome were not radiation related and prozasin's possible effects against PCa are not believed to be radiation related, if I remember the literature correctly.

I'm speculating, but perhaps the retrospective study was in the context of radiation because researchers have a large set of men who start prazosin and tamsulosin due to radiation caused lower urinary tract syndrome. Will ask the researcher that if I get hold of him again.

I think there is some evidence for prazosin, whether good or not time will tell. We may know more when the first results are in from the prospective study.

I appreciate the exchanges with you, TA, it challenges and sharpens my thinking and I grow wiser, or at least a little less unwise, as a result

[Tall_Allen in reply to Purple-Bike]

The only clinical evidence was with radiation. And if you believe it was prescribed for LUTS, why would you take it without LUTS? You seem to really be stretching it with no evidence.

[Purple-Bike in reply to Tall_Allen]

Prescribed for LUTS but I will take it for hoped PCa effect, with the dose at BP level. With all respect, I differ I believe there is some evidence.

[Tall_Allen in reply to Purple-Bike]

Show me clinical evidence without radiation

[Tall_Allen in reply to Tall_Allen]

You also may be interested in the following. Pseudoscience is usually practiced by smart guys like yourself, and is a danger you may want to be alert to:

prostatecancer.news/2021/07...

Why haven't you gone for beta blockers? - there is even more "evidence"

[Purple-Bike in reply to Tall_Allen]

I have much gratitude to the enablers of this forum and all its fine contributors, with a large variety between them making the forum all the greater. The single contributor I hold in the highest esteem of all is TA, whose great knowledge and understanding, and generous willingness to contribute, is a major feature of the forum.

I think his and my different opinions on the retrospective study on prazosin may, I grant, in part be due to his superior knowledge base. But I think it is also a reflection of different attitudes to levels of evidence, certainty and risks. I thrive on taking calculated risks in all aspects of my life and find no reason not to do so for PCa. I will gladly believe in the merits of a substance if the risk/benefit ratio appears promising, with levels of evidence that others may find abhorrent.

I have looked at TA:s newsletter on pseudoscience that he posted, I think I understand the points and agree with the soundness of criticizing the kinds of statements and judgments highlighted. I may be blind to my own shortcomings, but I don´t see myself obviously fitting the bill of pseudoscience. For one thing, I make no claim of certainty on prazosin and I have tried to grasp the criticisms of the study.

Quite possibly, this retrospective study, like so many others, will wind up in the trash heap of history, as TA put it. Retrospective studies are rife with limitations with selection bias being a huge bane and I have learned this from TA. Perhaps prazosin users will turn out to be vastly different from tamsulosin users. Of course it can be like that. This study can turn out to be absolutely useless!

But maybe not. This study and prazosin just may have a higher chance of success than the average. Since the info has been scattered over three threads, I sum up the pros of the study and of prazosin in bullets, to the best of my understanding.

• The retrospective study was unusual in comparing a substance, prazosin, to not only controls but also a similar drug, tamsulosin.

• Both are α1- adrenoceptor antagonists, with the issue addressed by tamsulosin, LUTS, being the same as one of two addressed by prazosin.

• It is more likely than not that the researchers are correct in that prazosin was prescribed for LUTS and not for high blood pressure.

• Contrary to stated earlier, the researchers did try to identify confounders. Although more parameters would have been desired, prazosin and tamsulosin users were highly similar in four out of five parameters.

• Intriguingly, preclinical evidence points the same way. Prazosin, a quinazoline subtype, induces apoptosis in prostate cancer cell lines, which is not seen with tamsulosin, a sulphonamide subtype.

• Likewise, mice studies show quinazoline α1 antagonists including prazosin causing reduction in tumor growth, metastasis and decreased angiogenesis in models of prostate cancer at clinically relevant doses.

• The study was connected to radiation, but preclinical evidence makes no mention of radiation and no indications can be found that possible effects of prazosin on PCa are inherently limited to being radiation connected.

• If taken for PCa, the major side effect of prazosin is lowered blood pressure which may be an advantage or not (for someone like myself this is pure icing on the cake).

• The study showed an 83 % recurrence free survival rate after 10 years for prazosin users, vs 27 % for controls and zero % for tamsulosin users. P<0.0001

• The study showed prazosin users had a lower PSA velocity (0.31 ng/mL/year) when compared to the control (2.98 ng/mL/year) and tamsulosin (3.36 ng/mL/year) groups.

[RCOG2000 in reply to Tall_Allen]

Prazosin has also been found to be helpful in PTSD with combat vets Interesting drug

[Scout4answers]

My MO readily switched me to Prazosin from Silodosin, after I showed him the trial results even though it is retrospective. I am taking 2Mg twice a day, ( I started with 1/4 and then 1/2 doses for the first week thanks to Mateo Beach's comments)I am now almost one month into the drug's use and have had no noticeable side effects.

I had a discussion with my RO yesterday about the study. He is a world class guy ( Open and Curious) and immediately Googled the study and read and discussed it with me right there in his office. He was unimpressed with the journal in which it was published and was very skeptical of the fantastic hazard ratio. His quote "Its too good to be true." He questioned the methodology and how the Prazosin group was selected. My comment was that I was already on an Alpha Blocker so I felt there was little downside and the potential for a very positive outcome was a possibility which seemed of very low risk, unless I were to get undesirable side effect from Prazosin. He conceded that the risk/reward made sense for me.

He told me that they had done a study on Asprin for PCa at the U of Chicago and that it showed mild efficacy.

Thank you for taking the initiative to contact David Christie author of the study . Would you please IM me his contact info as I would like to have a conversation with him.

Thanks

Scout

[MateoBeach in reply to Scout4answers]

This is a great new possible adjunct for my treatment as well, Scout. I am already on BP meds, so will pursue switching one of them to Silodosin soon.

[MateoBeach in reply to MateoBeach]

Actually, I will go with the Prazocin since Silodosin is said to be highly prostate-specific, And I don't have one of those. 🤣

[MateoBeach in reply to MateoBeach]

Deeper in the weeds comparing A1-antagonists now for High BP. Doxazosin seems to be the closest related in chemical structure and is a quinazoline. Nice once-daily dosing (Cardura). But still not exactly Prazosin, a quinazoline polythiazide, but may be the closest and has good mechanisms in vitro for PC cell apoptosis.Otherwise could titrate dose on prazosin and then switch to once daily Minipress XL.

pubmed.ncbi.nlm.nih.gov/127...

pubmed.ncbi.nlm.nih.gov/118...

Add this to the retrospective analysis you reported and it becomes pretty compelling IMO. Thank you!

[Scout4answers]

Purple BikeWould you comment on your use of N-acetylcystein+glycine any relevant studies?

[Purple-Bike]

100/55 is not that different from where I would like to be. How did you get there, how are you finding the dose? I was fine at 90/60 some 25 years ago after starting my diet, but aging has inexorably pushed it up to 125/70. I understand prazosin cuts diastolic more than systolic which is the opposite to what I want, on the other I believe it does not affect low blood pressure so it may only target systolic in my case. I will start prazosin at 0.5 mg, going up slowly to avoid hypotension, with the goal of 10 mg if tolerable side effects.

[Scout4answers]

No Reply yet to my e-mail that I sent to Christie, have you had anymore contact?

[Purple-Bike in reply to Scout4answers]

I'm not surprised. Christie was reserved when we talked, he doesn't seem that keen on contacts with patients. I haven't contacted him again, preferring to see if he answered you first. There is a Mr King who is given as the person for contacts.

I think the odds are good that Prazosin is indeed a game changer, as you called it in that trailblazing post. It's no 1 on my list of substances to take. But I have a problem accessing it. My MO readily prescribed it, after I sent him the full info I posted, thanking me. But it turns out that here in Sweden Prazosin is deregistered and needs a complicated application to be approved, which needs a Swedish MO and my doc is based in Finland. Do you by any chance know of a supplier who will accept a "European Medical Prescription"? (and ideally post it in a neutral envelope to reduce the risk of our vigilant customs rejecting it).

My MO did not recommend more than two or possibly 4 mg per day for someone in my situation, citing the risk of harm at higher doses. Perhaps he is being very cautious.

I haven't forgotten your question about my nr 2, glycine + Nacetylcysteine, I feel the need to do some more research about possible negatives first.

Scout4answers, great to hear about your progress in your post the other day. Let's keep moving and the future has a good chance of being bright!

[Scout4answers in reply to Purple-Bike]

As an aside BellaS60 commentated on another thread that her husband has been taking Prazosin for two years. I think we should follow her posts. His PSA has risen from 0.02 up to 0.10 since he stopped Lupron in 2019.He saw another study back then that was similar to the one I posted.

BruceSF is also taking it.

[Scout4answers]

I used to buy Cialis that was made in India in Hong Kong.I get Prozasin from my local Osco drug.

Do you by any chance know of a supplier who will accept a "European Medical Prescription"? (and ideally post it in a neutral envelope to reduce the risk of our vigilant customs rejecting it).

I do not, but it is a question I would put to the whole board in a new thread.

If you can find a source here I would be happy to facilitate the mailing.

[Purple-Bike in reply to Scout4answers]

Scout, I greatly appreciate your offer to facilitate mailing, in case I need it. Am trying a source in Canada now.

[Purple-Bike]

You certainly did what you could with Prazosin, you can´t be blamed for giving up! Thanks for the list of an alternative for blood pressure, in case Prazosin doesn´t work for me.