It appears that if one has PD or prodromal PD and suffers from allergies, fexofenadine (Allegra) might be the antihistamine of choice. ncbi.nlm.nih.gov/pmc/articl...
"Previous studies suggested that histamine is involved in the pathogenesis of PD. PD patients have significantly higher blood histamine levels than normal controls [12]. In postmortem brain samples from patients with PD, histamine concentrations are significantly elevated compared to age-matched controls [13]. Histamine induces microglia activation and dopaminergic neuronal cell death via H1 receptor [14]. Endogenous histamine also accelerates the degeneration of dopaminergic neurons via its H1 receptor in 6-hydroxydopmaine (6-OHDA) lesioned rats [15], suggesting that the histamine system may be a target against PD."
"A clinical pharmacology-based drug repositioning strategy is a useful approach for identifying new drugs for PD."
"In the present study, we analyzed claims data obtained from the National Health Insurance Service (NHIS), which covers a significant portion of the South Korean population, to investigate the association between antihistamines, a class of drugs commonly used to treat allergic symptoms by blocking H1 receptor, and PD in a real-world setting. The selected antihistamine was administered to mice, and its effects and mechanisms of action were studied using behavioral assessments and RNA-seq analysis."
"In several animal models, including the 6-OHDA, PFF injection, and C. elegans models, fexofenadine ameliorated PD-related pathologies. RNA-seq analysis and the subsequent experiments suggested that fexofenadine is effective in PD via inhibition of peripheral immune cell infiltration into the brain."
"Fexofenadine shows promise for the treatment of PD, identified through clinical data and validated in diverse animal models."
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Park Bear, I really don't like to get too excited about any one study, but the fact that the epidemiology results were bolstered by results in animal models is promising. And of course this comes on the heels of the AI prediction that antihistamines could be useful in PD; ncbi.nlm.nih.gov/pmc/articl... Interestingly, levocetirizine was one of the highest ranked candidates in that prediction, and in this study the P values on the LEDD chart were virtually identical for fexofenadine and levocetirizine.
Anecdotally....my SOwRBD has been taking levocetirizine for seasonal allergies for a couple of months and has not had an RBD event in that time. Coincidental? Who knows, but I think we'll keep it in the stack for now.
Hey PB, I found a study that sounds like it could have been a follow-up to the AI predictive study (because it concentrates on Ebastine and Levocetirizine) but it was actually published before that one. At any rate, this paper demonstrates the ability of these two antihistamines to act as adjuvants to levo/carbidopa, which makes them potentially useful for wearing off syndrome. Would be interested to know what you think of it. ncbi.nlm.nih.gov/pmc/articl...
"Ebastine and levocetirizine administered in combination with the standard drug showed a remarkable reduction in histamine levels, which gave better results as compared to when they were administered solely."
I had to dig to find this nugget at the end of the study text: "Catalepsy in mice was induced by the administration of haloperidol in all groups except the control group, via (i.p.) route, 30 min following the standard and test drugs."
So sadly this is a pre-treatment study which is not a valid model of Parkinson's. It is possible that the meds that tested the best are indeed the best candidates but cannot really be sure from this study.
I don't believe they talk about the fexofenadine dosage taken by the patients who were studied, unless there's some supplemental info I haven't seen. But they did say that when they conducted a study in mice, they based the dosage on an equivalent human dosage of 120 mg/day.
"Administering fexofenadine to mice at 20 mg/kg/day via oral gavage was determined on assuming a human prescription dose of 120 mg/day and calculating the animal equivalent dose [19] and several references that demonstrated effective outcome in mice [20–22]."
Really glad you brought this up. It's the anticholinergic property of some antihistamines that's responsible for the associated increase in dementia. I was under the impression only 1st generation (older) antihistamines are anticholinergic, but apparently that's not the case;
"In vivo, five antihistamines showed anticholinergic activity: cyproheptadine>promethazine>desloratadine>loratadine>diphenhydramine. The remaining antihistamines had no significant effect at i.v. infusion doses up to 50 imol/kg. Cetirizine and fexofenadine did not antagonize cholinergic responses in either model."
So it seems fexofenadine and cetirizine are safe in this regard, and I would think levocetirizine is too. Unfortunately for those who prefer Claritin and Clarinex, loratadine and desloratadine appear to be anticholinergic.
Agreed with the anticholinergic properties being of concern . But as news typically comes out many years too late, I’m still a bit cautious about standard antihistamines, in general. I wonder if the more natural ones that work on DAO are safer
I totally understand where you're coming from. I hope you (and others) realize I don't mean to be condoning or promoting the use of antihistamines to treat PD. That's why I suggested that people who's allergies already force them to use medication, might want to choose fexofenadine. Double blind studies need to be done to determine if all PD'ers should be doing so.
My spouse has suffered from allergies from childhood, and used antihistamines a lot over the years. Like you, I had serious reservations about the long term consequences of that, so it was quite reassuring to read that they might actually have had beneficial effects beyond just increasing comfort.
I do believe there's enough evidence that excess histamine isn't good for PD brains to warrant trying to lower levels naturally. Increasing DAO activity is a really good suggestion, but I don't know much about how to do that, other than taking DAO supplements. Beedie Bird also made some good suggestions in this thread.
"My spouse has suffered from allergies from childhood, and used antihistamines a lot over the years. "
Exactly what hubby did-- used CONTAC, since his early 20s when I met him, until 2016, first diagnosed. He is using a nasal spray now, all natural ingredients, "NutriBiotic Sinus Nasal Spray PLUS with Grapefruit Seed Extract and Peppermint." NAC, Quercertin, and umPEA are also on his stack. However, I will have him try Fexofenadine!
Oh boy, I remember Contac from my teenage years. If you had a miserable, feel-like-death cold and took Contac it was like.....cold, what cold? I think it was taken off the market but can't remember why.
Looks like the Contac of my youth contained phenylpropanolamine, a decongestant/appetite suppressant that increases risk of hemorrhagic stroke. In 2005 the FDA declared it unfit for over-the-counter use.
There are 3 "Contac Cold and Flu" versions now. The "daytime" one has a decongestant and acetaminophen but no antihistamine. The "nighttime" versions include chlorpheniramine maleate, a 1st gen antihistamine that has anticholinergic properties and could be expected to cause sleepiness. So your hubby may or may not have been taking an antihistamine, depending on which formula he was taking!
Histamines role in PD and neurodegeneration have been studied for a few years. I think any antihistamine that works on H1 receptors would be beneficial. I take Quercetin daily with each Levodopa dose, due to having histamine intolerance (allergy doctor diagnosis). It does not work on H1 specifically, but does help to break down the overabundance of histamine (and thus inflammation) my body produces. 2nd generation antihistamines make one less sleepy. I prefer Claritin, over Allegra, myself during high allergy season. It seems to be longer lasting.
Per my allergist I also avoid foods that release histamine, unfortunately some very healthy ones are culprits - spinach and bananas. There are also healthy alternatives to over the counter anti-histamines.
From my preferred AI source, Perplexity:
there are several natural sources of histamine and histamine-modulating compounds that could potentially be used therapeutically:
Quercetin: This flavonoid has natural antihistamine properties and can be found in foods like berries, apples, onions, and green tea. It may help reduce allergy symptoms by stabilizing mast cells and inhibiting histamine release.
Vitamin C: Found in citrus fruits, strawberries, broccoli, and other fruits and vegetables. Vitamin C acts as a natural antihistamine and may help reduce allergy symptoms.
Stinging nettle: This herb has been used traditionally as a natural antihistamine and may help relieve allergy symptoms.
Ginger: Contains compounds that can act as histamine blockers and may support the immune system.
Thyme: Rich in vitamin C and other anti-inflammatory compounds that may help block histamine release.
Watercress: A potent anti-histamine that can be used in salads or cooked dishes.
Capers: Contain high levels of quercetin, which has antihistamine properties.
Turmeric: May help prevent histamine release from mast cells.
Probiotics: Certain probiotic strains may help modulate the immune response and reduce histamine-related symptoms.
BeedieBird, your "histamine stack" sounds almost identical to ours. I didn't know about watercress though, so thanks for that. We do also use palmitoylethanolamide, which is another mast cell stabilizer. It's used a lot in neuropathic pain syndromes and also has neuroprotective properties. Some here use it for that reason alone. This is a fairly easy-to read review on the subject; mdpi.com/2218-273X/12/5/667
"In the brain, PEA is produced “on demand” by neurons, microglia, and astrocytes, and thus plays a pleiotropic and pro-homeostatic role, when faced with external stressors provoking inflammation. PEA exerts a local anti-injury function by down-modulating mast cell activation and protecting neurons from excitotoxicity [15,16,17]."
Palmitoylethanolamide is often combined with luteolin for a synergistic effect. Luteolin is also an anti-allergic; ncbi.nlm.nih.gov/pmc/articl...
I forgot to add....as a result of Fumaniron bringing up the antihistamine/dementia connection, I learned Claritin is anticholinergic! Allegra and Zyrtec appear not to be.
Yes, true. Anticholinergics (benadryl is included) not the best when it comes to cognitive impairment. I take CDP choline daily which enhances cholinergic activity in the brain.
No I read of another report that said antihistamines might help with T or might help prevent tinnitus, I assume because the action of histamine is blunted. I don't really have any way of knowing for certain one way or another in either direction. The whole area of tinnitus is a big fat mystery! And I have so many potential confounds in my personal case anyway I can hardly have any confidence about my experience.
Loratadine is one of those that does not pass the blood-brain barrier, which is why it is not drowsy, and also means it doesn't get into the brain so it doesn't seem to me likely to have any effect on mentation, and that would include cognition. So I'm going to look into it definitely, since I have to be on an antihistamine all the time anyway. As long as it controls my chronic skin itching.
Of course you're right, second generation antihistamines aren't supposed to cross the blood-brain barrier. But there's evidence suggesting the B/B barrier is compromised in PD.
Can you assume if a particular antihistamine doesn't cause somnolence, it isn't making it into the brain? I don't know, but would prefer one without anticholinergic properties just in case. But then, I'm a scaredy-cat.
Marion, you got my curiosity dander up in regard to this BBB/antihistamine stuff. Reading back through the fexofenadine study, they mention it briefly in the final discussion;
"Although we assumed that fexofenadine could not penetrate the CNS, we cannot completely rule out a direct effect of fexofenadine on the CNS. Disruption of the BBB in PD has been reported in animal models and postmortem human brains [51–53]. Therefore, fexofenadine may directly penetrate the brain. Central histaminergic systems have been reported to be altered in the brains of rats lesioned to model PD [54] and in the brains of patients with PD [55]."
I "think" they're raising the possibility that the effects of the drug were not just reduction of peripheral inflammation, but could involve a direct effect on the CNS. Could that then mean that an antihistamine that's super resistant to crossing the BBB would be inferior, as regards use in PD? I went looking for info about that and got bogged down, but I did run across one study I thought might be of interest to you; pubmed.ncbi.nlm.nih.gov/173...
Also, I have a question for you, since your knowledge of pharmacokinetics far exceeds mine. If loratadine/desloratadine have anticholinergic properties, as that study I linked suggests, would it be wise for people with constipation to stay away from them?
Interesting what you dug up, quite interesting. Without measurements as to how much and fenofexadine gets in, you also therefore cannot assume that it is a significant amount or a significant effect... But if some got in, to assume much or any effect, when would have to have some measurable or observable reason for it, like drowsiness. Drowsy nurses are main observable effect of antihistamines in the brain. In fact, sometimes it is in effect one wants, as in help for sleeping, which my wife uses Benadryl for on occasion. . And another one I has to mean where we intentionally put to use the mild CNS depressant effect coming across the blood brain barrier is dramamine.
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Meanwhile, on anticholinergic effects, I suppose that could be a small factor, but more likely effect that would matter would be dry mouth which would make keeping your teeth healthy harder, maybe some dry eyes. Either way, dose matters and antihistamine doses are not large. You find these things out by playing around with the medication in the short-term, whereas what you were talking about with some of those studies are long-term effects, long-term use that is also chronic use, as opposed to periodic or episodic use. You are not going to accumulate much structural changing in your brain at all from episodic use or periodic use, brian doesn't change quite that fast. Anyway, else to constipation from antihistamines, it's easily tested, you just take some for a few weeks and see. Then stop it and see. No harm. It's not like you're taking, say, cyanide.
Significant anticholinergic effects are, on the other hand, a very prominent feature of the old tricyclic antidepressants, because they have very significant anticholinergic effects at the doses necessary to achieve antidepressant benefit, and there yes you would definitely have constipation as a side effect. But you are going to need a prescription for those anyway.
I will say one thing about Zyrtec, though, and that is about rebound itching, I've seen several reports of people saying that if you use it for very long and then stop it, the horrible itching you were using it to help alleviate comes back and is seemingly much more intense than what you used it for. I don't know if that's a temporary effect, but I can tell you major atopic skin and the "atopic triad," skin itching especially and then also exercise asthma, is one seriously debilitating experience and it's constant, and a huge number of people have it.
An interesting little side note, just fun history but not really something to overreact to, is there is one very powerful antihistamine that is sort of in a class by itself, that nobody really mentions anymore doesn't really have much place in conversations that occur around here...thorazine. but honestly in general there's really very very little to be feared with antihistamines.
By the way, this video is really pretty good, the guy's really nice at putting together a nice overall story about antihistamines history. m.youtube.com/watch?v=Q_aEV...
Thanks for posting Rufous2. Antihistamines have been a bit of a head scratcher for me. I had never tried them before (nor any supplements until recently) for a lingering post nasal drip. I tried cetrazine and it cleared up pretty much straight away. Interestingly one day I felt exceptionally great. That was weird I thought 🤔. So eventually I tried to replicate the great day buzz with the Zyrtec again . I sort of 1/2 did once or twice and left it at that although I was intending to revisit the phenomenon. There was some very real effect that’s for sure. So your post has piqued my curiosity again and I have decided to try the Fexofenadine 180mg 😃. My interpretation from the study is that as the data was taken from the health records the dose should just have been daily recommended.
All I was able to determine about dosage is they used the human dosage of 120 mg/day to determine how much to give mice.
""Administering fexofenadine to mice at 20 mg/kg/day via oral gavage was determined on assuming a human prescription dose of 120 mg/day and calculating the animal equivalent dose [19] and several references that demonstrated effective outcome in mice [20–22]."
It seems the commonly recommended dose in people is 60mg twice a day or 180mg once a day.
It's interesting that cetirizine would increase a sense of well-being for you. I wonder if a slight augmenting effect on meds is responsible. Levocetirizine (Xyzal, the active enantiomer of cetirizine) is one of those that was predicted by AI to do this. Or maybe an anti-inflammatory effect is responsible? aacijournal.biomedcentral.c....
An anti-inflammatory effect seems to be a property of several of the 2nd gen antihistamines, fexofenadine in particular. Here are a few of the studies I came across, if anyone's interested;
On an anecdotal note....my dad has suffered for years with post shingles neuralgia. It comes and goes, so I suspected it might be exacerbated by allergies, as he used to suffer terribly with "hayfever." I got him some levocetirizine and it seems to be helping, but I'm going to try him on fexofenadine in the hope it might slow down his disc degeneration in addition to helping his pain. A long shot, but seems safe enough to try.
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