Introduction; Hypertension Medication; Nilvadipine

[bladedmind]

Hi, I’m a 67-year-old scholar. I found out I was apoe 4/4 in January. Newbie as of January and lurker since then. I located the Bredesen protocol before finding this board and it turns out I’m already doing more than half of the recommendations.

I’ve been taking the ACE inhibitor benazepril 10 mg/day for about 10 years. With that dose I have good 120/80 blood pressure. In the past few months I’ve been experiencing sporadic minor edemas – slight swelling of upper left lip. I’ve been varying medications and supplements seeking to identify a cause. Last week on different days I’ve had edema on the heel of one hand, the swelling of the right half of my tongue, and on the heel of the other hand, on awakening.

I had fat lip and eyebrow angioedema 45 years ago from ragweed exposure and huge cold urticaria 25 years ago, and I know how sudden and frightening these events can be. And potentially dangerous.

The only suspect substance I haven't varied is the benazapril. I went to the MD on Friday and obtained a Losartan Rx. However, according to notes at rxlist.com notes those who get angioedema from Losartan tend to be those who have had it with ACE inhibitors. Although fewer experience angioedema with the ARB than with the ACE-I. I’m going for a few days without the benazepril to see if the edema events recede, then will slowly ease into losartan.

In researching alternatives I found that the calcium channel blocker Nilvadipine is undergoing stage 3 trials in Europe for Alzheimer’s prevention. A search for Nilvadipine on apoe4 returned no results. I skimmed all apoe4 entries that include the word “hypertension” and found no mention of it (and a favorable mention of losartan). Seems like something people here would be interested in:
http://www.longecity.org/forum/topic/79308-nilvadipine-for-alzheimers-prevention-and-treatment/
http://www.alzforum.org/therapeutics/nilvadipine
google this - site:ncbi.nlm.nih.gov/pubmed nilvadipine Alzheimer's

Nivaldipine is not available in the U.S. And it looks like a similar U.S. drug nicardipine may have no protective effect:

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0065232
http://www.ncbi.nlm.nih.gov/pubmed/25038562

I have a social science Ph.D. but do not know biochemistry and thus interpretations offered on this board are of much use to me. Thanks for any observations!

[Julie G]

Welcome blademind! Sorry to hear about the angioedema- very scary. I know that ACE inhibitors are correlated with angioedema...but I wonder WHY after 10 years you're just now experiencing symptoms? I know it's possible... and even likely, but wonder if you've ruled out other culprits?

Given the pro-inflammatory nature of E4, many of us experience both IgE and non-IgE mediated allergy symptoms. For those of us with highly reactive mast cells; even stress, temperature changes, odors, etc. cause symptoms. I'm wondering if you've been under any big stressors lately that could be contributing? How is your gut health? Working on that has healed allergy symptoms in many of us. For now, keep some H1s nearby to use in case of emergency. Do you have an epi-pen?

I'm sure you know how important it is to keep BP under control for both heart and brain health. While Nilvadapine looks great, availability will most likely be an issue. Out of curiosity, have you tried calcium channel blockers?

I'm largely unfamiliar with anti-hypertensives, but hope other more knowledgeable members will weigh in. Best of luck sorting this out.

[KatieS]

Welcome bladedmind to the forum! I switched from a diuretic to losartan a few months ago, primarily to gain possible AD prevention, since I need an anti-hypertensive anyway. Diuretics slightly increase glucose, which may have contributed to my less than optimal A1c. Some think losartan might increase cerebral blood flow. Here's a recent mice study of multiple positive effects from losartan: http://www.ncbi.nlm.nih.gov/pubmed/24807206

You were on an angiotension inhibitor, which provides good control, and likely the same AD benefit. However, some people have a cough side effect with the inhibitors, so they are switched to a blocker. I hope you do not have this strange edema side effect on the blocker.

Follow your doctor's advise about switching to losartan, (i.e. make sure your doctor is informed that you will be stopping medication and easing into losartan) The pharmacist recommended that I take losartan the first day off the previous medication. As to AD prevention, controlling hypertension is a priority. Also, you are aware of the cardiovascular risk of Apoe4, and as another in seventh decade, we have to be cautious.

[Stavia]

hi Bladedmind and welcome!
Lovely to have you posting.
I am a family medicine doctor in a country far away and can give you my 2 cents worth,
As regards your BP condundrum, a few days or even weeks with a higher BP while sorting out medication is not an issue. Effects of raised BP are slow and take years. So you have no need to panic.
The angio-oedema effects of the ACE-I will take a while to settle. The ARB is worth a go, it is the usual thing to try in this situation. They chances are that you will not cross-react.
The culprit is likely to be the ACE. It is well known to cause angio-oedema.
We are unlikely to have decent trial data on any antihypertensive medication specifically preventing AD in the near future. If I were in your position, I would give the ARB a go, and then if no good, I would swap to a calcium channel blocker. In my country we use felodipine and amlodipine widely. I feel they are all similar (except for the cytochrome pathways and the possible interactions there, this is easily found out by plugging them into any medicines interaction programme). There is good evidence about the positive effects of calcium channel blockers.

[karelena]

Hi

I had the exact same problem with my lisinopril (an ACE inhibitor) after taking it 10 years. Hives in rotating locations then lip swelling (really massive lip swelling, my kids said I looked like a duck!). My doctor said it would be unwise to switch to losartan because of cross reactivity. We started with amlodipine 10 mg but pressures too high so added doxazosin 8 mg (at night) then a low dose metoprolol 25 mg (in the morning). Hydrochlorothiazide 25 mg was continued by itself (I was taking it in a combination pill with the lisinopril). BP is great now, about 110/70. No more hives or swelling since stopping the ACE inhibitor.

But now I'm on 4 medications instead of 2. I wonder if I should increase the dose of one to try to eliminate at least one, or if it is better to have more meds at lower doses? Right now I'm happy BP is good so probably will not change the meds unless there is new evidence that one or more is bad for AD or IR or lipids.
K

[Stavia]

Hi Karelena! {waves}
We favour multiple small drugs at lower doses rather than less at higher doses because the side effect profile tends to be better with the former. If you really wanted to drop one I would recommend targeting dropping the betablocker and increasing the doxazosin. I usually go to 8mg doxazosin bd in such a situation. But if you are tolerating the beta-blocker stick with it, its a pretty good class of drugs. You are unlikely to be able to get decent BPS with only two meds without going to maximum doses of your beta blocker. And I wouldn't recommend that in a young active person. I like the amlodipine, the ca channel blockers have very favourable outcomes and appear to be pretty innocuous in terms of adverse effects.

[bladedmind]

Julie Gee, Kitano, Stavia, karalena, thanks for your generous and learned observations. I’ve read many of your other comments and know who you are. Your replies reduce uncertainty and are quite useful to me in other ways. I did find several medical publications reporting cases of edema from ACE inhibitors after years of uneventful use. Of course the idea that the benazepril is related to my edemas is only a hypothesis; I want to lay off the benazepril to test the hypothesis. I’ve tried varying all other routines I can think of. My first 24 hours of abstinence is already helping my lungs. I had completely adapted to a constant cough (which seemed to invite respiratory infections - who knows), but I’ve already gone from shallow hackings to fewer and more productive coughs.

I had consulted apoe4 and suggested the losartan to my FP MD as a replacement.

Julie Gee is right I should get an epi-pen; I hauled one everywhere for 10 years in my cold-urticaria phase. I have only mild hypertension without medication, and Stavia’s comments are welcome: my intuition was that I could take a week or two off, but I didn’t know that it would take a while for the edema events to recede (that will inform my research design). Also, karalena confirms what I read on rxlist, that those with edema with ACE inhibitor are more likely than the average person to have the same problem with an ARB. Karelena, I had duck lips when I was 20, quite awkward on a date! Back then they called it neurotic angioedema, as if it comes from bad thoughts.

I wonder why no discussion of Nilvadipine on the board? There are several reports on the internet about it, ultimately originating from the company though, and I try to be wary of hype. Phase three trials are complete in December 2017. I know there are no single bullets for AD; and I do understand that an ACE inhibitor or an ARB are also advised for AD prevention.

Just found this: Kennelly S, Abdullah L, Kenny RA, Mathura V, Luis CA, Mouzon B, Crawford F, Mullan M, Lawlor B. Apolipoprotein E genotype-specific short-term cognitive benefits of treatment with the antihypertensive nilvadipine in Alzheimer's patients-an open-label trial. Int J Geriatr Psychiatry. 2011 May 10; PubMed.

I’ll continue to monitor and learn from this discussion and develop ideas to solve my problem. Thanks again.

[Stavia]

Bladed, dunno why we missed this, since its in phase III already. My thoughts are - I wonder if its a class effect (which is likely), what is its proposed mechanism of action (I see they believe it targets amyloid) and how will they tease our BP control effects from actual antiamyloid effects?
Thanks so much for bringing this to the forum!

Byw, what is your actual area of scholarship? I'm curious. I like to get to know people and their context.

[karelena]

Stavia {waves} to you too! I am so happy to have this community and I am loving that you have consolidated a ton of research for the newbies like me in great detail on another thread. So glad for you and all the others here!

[Tincup]

Here is a pitch for the non-drug solution. Biophysicist Richard Moore MD PhD's book "The High Blood Pressure Solution" http://www.amazon.com/High-Blood-Pressure-Solution-Scientifically/dp/0892819758 suggests 1) constructing a diet that is 4:1 on intake for potassium:sodium. This will signal the kidney to excrete sodium or 2) reduce insulin as low insulin also signals the kidney to excrete sodium. This effect is so profound that the "best practice" suggestion for those starting a very low carb diet (think the "induction" phase of the Atkins diet) supplement with 5g/day of sodium (see Volek & Phinney's books http://www.artandscienceoflowcarb.com/# )

On p 270 of the 1993 version of Moore (recently moved and the later edition is hiding from me), he notes "...very low-calorie diets will decrease blood pressure in only 3 to 4 days..." "There is now much evidence that insulin promotes retention of sodium by the kidney, and this may be a major contributor to hypertension..."

In her intro, Stavia suggests keeping fasting insulin <5 https://www.apoe4.info/forums/viewtopic.php?f=33&t=1418#p15620.

Russ posted about the Newcastle University approach reversing T2 diabetes in 2 months https://www.apoe4.info/forums/viewtopic.php?f=6&t=1022&p=14798&hilit=diet#p14798

In this newsletter, the author discusses this approach, referenced as the Newcastle Diet http://www.yourhealthbase.com/archives/ihn252.pdf http://www.yourhealthbase.com/archives/ihn251.pdf http://www.yourhealthbase.com/archives/ihn250.pdf

I recently notice my own fasting glucose creeping up, so adopted a version of this approach (I don't have a blood pressure problem). I've been fasting 22 hours/day, eating about 1,000 calories/day 60 g carbs of which 30 are fiber (still a big Walhs/Gundry salad), 50 g of protein from eggs & shrimp and the rest from EVOO & avocados. I still payed attention to trying to get as much nutrition as possible from the caloric restriction. Took a few days, but my fasting sugars are now in the 70's and my ketones are around 3 mmol/L.

Anyways, get your IR under control with "perfect" fasting insulin and glucose and your blood pressure issues are likely to improve.