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Experience with carbonic anhydrase inhibitors?

Discussion in 'General ME/CFS Discussion' started by anciendaze, Sep 15, 2015.

  1. anciendaze

    anciendaze Senior Member

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    Right from the start, I want to emphasize that I am not recommending treatment or making diagnoses in this post. I am asking for information. People with a number of confusing medical problems end up in the ME/CFS category, and some may have been treated with things that are not in common use. I have been given a number of anticonvulsant drugs on the suspicion that I might have a confusing type of epilepsy without obvious seizures, but I have no experience with the type I'm about to describe.

    This question came to me via a friend who has a solid diagnosis of a rare condition called hypokalemic periodic paralysis (PP). In my limited experience it is rare for ME/CFS patients to have actual paralysis, though there are cases with extreme weakness that may be hard to distinguish from some variants of periodic paralysis. Officially, this is a rare genetic disorder with an incidence of about 1 in 100,000. However, about 1/3 of PP patients do not have any known genetic markers. It is also common for it to appear in young adults who previously had no such illness. This could indicate an infectious origin, or the action of genes which only become active at sexual maturity.

    PP is a channelopathy, with potassium channels most commonly affected. We have considerable reason to suspect disturbances in ion channels and fluid regulation in ME/CFS.

    The FDA recently approved the first drug to treat both hypokalemic and hyperkalemic PP, Keveyis (dichlorphenamide/diclofenamide). This is a sulfonamide which acts as a carbonic anhydraze inhibitor.

    This class of drugs has a long and strange history. Some were synthesized around 1910, but their biological activity was not tested. In the early 1930s work on the first antibiotic, Prontosil, discovered antibacterial action with low human toxicity. Subsequent work showed that the chemical precursor sulfanilamide had better antibacterial activity.

    The medical story of carbonic anhydraze inhibitors mainly concerns use in epilepsy and glaucoma, though idiopathic intracranial hypertension has also been treated with these. Here is a list of some drugs in question: acetazolamide, brinzolamide, dorzolamide, methazolamide, sulthiame/sultiame, topiramate.

    One problem with the new approval is that the recommended treatment now appears to cost $120,000 per year. I suspect insurance will not approve this without evidence from genetic markers, which 1/3 of those diagnosed do not have. Sulthiame/sultiame is similar in biochemical activity, and much cheaper. It has been given to children with an unusual form of epilepsy for years.

    My question is about experience from patients here which might guide research on use of any carbonic anhydraze inhibitors for PP patients, who would not be able to afford the newly introduced drug for PP.
     
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  2. anciendaze

    anciendaze Senior Member

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    Latest news from PP patients is that a pharmacy has quoted them a rate for Keveyis which amounts to $96,000 per month for 2 x 50 mg. pills per day. (Some patients need 4.) If this is the cost of a simple chemical like a sulfonamide, I can't imagine what some drugs which are really difficult to synthesize would cost.

    What's wrong with this picture?

    Also learned that my suggestion about sulthiame/sultiame based on structure and mechanism ties in with experience treating episodic ataxia, which has symptoms overlapping PP. Episodic ataxia is also closer to what some people being treated for ME/CFS have described to me. Even with an incidence of 1 in 100,000 we can expect several thousand patients of this type to be found in a country the size of the U.S. Several thousand more would have true PP.

    At present, patients with serious disabling genetic disorders like these are accidentally collected into a single wastebasket category which could be labeled "patients who are hard to treat" instead of ME/CFS. No one has described a plan to separate these patients from cases for whom psychiatric treatment is considered appropriate, nor is there a clear boundary between ME/CFS and several known serious physiological problems. The present attitude appears to be that you find out when patients have a life-threatening condition by screwing around for months or years, and waiting to see if they die. If they do, you remove them from your research cohort on the grounds they never had ME/CFS/SEID.

    What's wrong with that picture?
     
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  3. adreno

    adreno PR activist

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    There are natural sources of carbonic anhydrase inhibitors:

     
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  4. anciendaze

    anciendaze Senior Member

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    Thanks adreno. The problem with natural sources is that it is hard to control dosage, and some patients are very sensitive to changes in dose.

    The new drug, dichlorphenamide, is said to be 40 times as powerful as acetazolamide. The same chemicals which increase potassium concentrations in some physiological compartments decrease concentration in others. For example, insulin drives carbohydrate metabolism, moving potassium into cells, and lowering concentrations in serum. An overdose of a CA inhibitor can push the patient past the equilibrium point, and into the opposite problem. Both hypokalemic and hyperkalemic PP exist, so it's not always easy to tell which side a patient is on.

    This is where they get into a problem with the kind of simplistic advice doctors often give. Exercise is generally good, but heavy exercise can produce a setback lasting several days. This intrigues me because it sounds like PEM, though with actual paralysis and other distinctive signs. In the worst cases the patient dies because breathing muscles are paralyzed.

    A patient with complicating factors like diabetes has shown adverse response at measured concentrations about 1000th of the recommended dose of acetazolamide. The general approach in these cases is to dissolve the tablet, or a measured part of a tablet, in liquid. This can then be consumed in small amounts, typically many times a day. If you don't know the concentration of active ingredients in the source material you never know how much is being consumed.

    At the other extreme from the patient described above, we have some who have been on dichlorphenamide in the past, when it was more widely available, and functioned pretty well on twice the current recommended dose. This gives a factor of about 80,000 in known differences between patients.

    I'm still trying to understand how a relatively simple chemical approved and used for common diseases like glaucoma and epilepsy could be available in the past at reasonable price, and now be prohibitively expensive.

    ----

    I keep thinking that some patients now considered to have ME/CFS/SEID must have been given CA inhibitors in the past. I've been the subject of a long list of uncontrolled experiments, and I wonder why nobody ever considered one of the disorders treated with CA inhibitors. There was certainly speculation about epilepsy with "silent seizures", though my EEGs came back clear of problems.

    I'll reiterate my general request to readers. Look over that list of carbonic anhydride inhibitors above, and if you recognize any drugs you have been given, tell us about your experiences.
     
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  5. xrayspex

    xrayspex Senior Member

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    I was just doing a search about Diamox and this class of meds because I suspect I am verging on intracranial hypertension (ICH) headaches. I have gone thru periods over the last 15 years where i suspected it. It usually happens in response to a medication or treatment. IE opiates, ritalin, zantac, and prilosec in the past--did strange things to my heart/blood pressure where I would get awful headache only when in horizontal position usually where would want to pull hair out the pressure was so bad. And of course with CFS/ME I wanted to lie down a lot so was bit of quandry. I havent had many symptoms of it for like 5 years because let go looking to meds for the answers since they usually cause more trouble than worth for me. I did consider trying something like diamox during the worst of it but never took action because I am prone to side effects and it doesn't necessarily sound like an easily metabolized drug.

    But I am thinking about carbonic anhydrase inhibitors again because been getting racing heart at times when waking up in morning or trying to go to sleep at night and at night been getting some of those headaches again, not quite as bad as years back but not good either. I am pretty sure its being triggered by trying frequency specific microcurrent (FSM) treatment. First I want to say I am really impressed with FSM as possible modality to happen chronic pain and fatigue (google it and carol mcmakin to learn more; If I get thru this and find a balance will come back and start a thread, jury still out) but unfortunately it either triggered my heart or autonomic nervous system. I think it happened when I tried a different type that gives off a tangible microcurrent (whereas most FSM, unlike TENs is imperceptible, you dont feel it). It increases ATP and I suspect that is part of the heart of it perhaps for me---maybe there is reason with whatever is wrong with me that my body doesnt want ATP or other things improved....because ironically it sometimes seems that the remedies that are the most powerful and seem to really help also then that have this sort of backlash for me.

    So anyway, I am curious like Anciendaze was if many CFS/ME have tried meds like Diamox as it seems like a worthy one to give a shot (supposed to help ICH). If there are any updates about this treatment would love to hear.

    also I have always had low b/p and did have a tilttable test in cardiology 20 years ago showing neurally mediated hypotension after admin of the med to induce it. I dont think I have had full blown pots much over the years but I wonder if certain treatments that increase heart push me into that territory.
     
    Last edited: May 19, 2017
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  6. xrayspex

    xrayspex Senior Member

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    Adreno, did you have any occasion to want to try to take a carbonic anhydrase inhibitor ?
     
  7. pattismith

    pattismith Senior Member

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    I too suffer from chronic headache, worsened by treatments or supplements.
    I don't have pots, but I havé OI and important muscles issues. I Aldo have grey flies flying on my vision for some weeks or months.
    I decided to start with Diamox to se if it could help with my muscles problems, because impaired voltage gated channels (especially calcium channels) is one of my hypothesis.
    I started two days ago....the result is amazing, it seems to work not only on my muscles but also on my brain !
    Acetazolamide si both effective to improve voltage gated function but as you know it si also used to reduce intra cranial hypertension, so it may well be that I suffer from this condition. The fact it was worsened by Doxycycline and
    by Metronidazole comforts me in this possibility because the first can cause intracranial hypertension and the second can cause neuronal oedema and toxicity.
    I started with a low dose and I am increasing slowly,let ´s hope it will work on the long run !
     
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  8. xrayspex

    xrayspex Senior Member

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    you must be dancin' barefoot Patti ;)
    seriously that sounds really good.....I didnt push to try it because of my poor tolerance of most meds and it sounded a bit complicated to break down. If I did try it would try to find a way to dilute it and try small amount if possible.
    I have had some good results this year with frequency specific microcurrent (FSM) sometimes CBD--but can't do too regularly or get incredibly unnaturally down and negative in my head---and I think yacon root syrup is bizarrely some sort of missing link for me to help me function bit better.....unexpected

    at any rate I digress from the topic....keep us posted on the diamox! I have bouts sometimes of ICH but right now not in too bad of a phase for headaches but get cervical pressure from compression that wax and wane and aggravating. I think the ICH was worse from some meds I used to be on or if I fly or dental infection etc
     
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  9. anciendaze

    anciendaze Senior Member

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  10. pattismith

    pattismith Senior Member

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    yes it's a field that needs far more investigations.
    We still even not know perfectly how Acetazolamide is doing to improve channelopathy....and not all the hypoPP cases are fixed with it.


    I'm not dancing yet, maybe I will be ready for New Eve?:)

    I would be interested to know which meds induced ICH if you can remember

    For me Tetracyclines, Metronidazole and Macrolides were involved.

    Knowing that some viral (EBV) or bacterial infections can trigger ICH as well, I wonder if some infection may be the first trigger, and reaction to meds only agravating factors...:thumbdown:
     
  11. kangaSue

    kangaSue Senior Member

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    A post by @pattismith got me interested in Diamox. I see Dr Diana Driscoll theorizes that for those with Ehlers-Danlos Syndrome (EDS), the cause of their POTS is due to a combination of External Communicating Hydrocephalus, Chronic Cerebrospinal Venus Insufficiency and Mast Cell Disease and recommends treatment of H1 and H2 inhibitors and the carbonic anhydraze inhibitor Diamox (acetazolamide), the latter for POTS by relieving intracranial pressure through a reduction in cerebrospinal fluid production.
    https://slingsandarrowsofoutrageousfortune.wordpress.com/the-driscoll-theory/

    That increased cerebrospinal fluid pressure can occur from the likes of spinal tumours or stenosis or even left renal vein compression would suggest that the likes of Diamox would benefit others not having EDS too and, as pattismith mentions, she doesn't even have POTS so it looks to help with lesser incidence of autonomic dysfunction if that's the cause of OI for her.

    There are some interesting articles about this class of drug being helpful for peripheral neuropathic pain;
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4465580/
    As far back as the '60's, one paper suggests inhibition of carbonic anhydrase with Diamox induces a mild or moderate degree of metabolic acidosis, which has beneficial effects on gastric hyperacidity so could be an alternative for GERD too.
    https://link.springer.com/article/10.1007/BF02232634

    Because Diamox has been to shown to help with issues of neuromyotonia, I would be interested to see if it has any effect on my severe gastroparesis, especially given that Dr Driscoll had this too and resolved it with the above protocol.
     
  12. xrayspex

    xrayspex Senior Member

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    Patti--one of the instigating factors to my metabolic derailment was taking erythomyocin--but I didn't notice at the time any link of increased pressure in my head etc That happened shortly after that when made mistake of having high velocity chiropractic adjustments on a whim after someone said that might help my malaise. I didn't know I had cervical stenosis so that hosed me structurally and then I had problems with a couple bodily systems going on instead of one--before that was pretty hearty and active--since then chronic pain and fatigue--and its been like 28 years :(
    but in past i used opiates in moderation and they are known to increase head pressure and did for me sometimes
    flexeril can if take more than a couple days to where lying down is hard--that is on very diluted dose
    Lyrica and another one in that classish increased pressure, some of the ssris and snris did

    I am thinking about diamox trial again now.....last week I had a home accident where something heavy on a top shelf with a cord hanging off it got tangled on me moving things around in the closet and slammed into the right side of my head. Not good....with history of probable concussions and significant cervical stenosis....am pretty bummed as was in a relatively stable phase before that. NOw the pressure is back and pain etc
    Question: can you picture a form of diamox that would be easy to dilute--going to ask my physician about that--if its a tablet that could be scored ? or liquid etc but I would need to take baby dose of any med I try...genetic and acquired detox limitiations
     
    Last edited: Dec 17, 2017
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  13. xrayspex

    xrayspex Senior Member

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    I just did a search on diamox and it said suicidal ideation can be side effect with anti-epleptics--interesting as that is how I felt on baclofen--not literally suicidal but caused very negative cloudy outlook in teeniest dose--CDB oil can do that to me too--has anyone experienced that or other bothersome side effects with diamox?
     
  14. Ema

    Ema Senior Member

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    Now I'm interested in Diamox again...I've been measuring urine pH and find that I am alkaline stressed during most of the day, specifically in the morning when we should get an acidity wave to help us get going.

    I wonder if Diamox during the day would help shift that pattern? Seems worth a try anyway.

    @xrayspex , the generic tablets I have could easily be cut.
     
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  15. pattismith

    pattismith Senior Member

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    interesting extract from this scientific article:

    "The most devastating phenotype of PDH deficiency presents in the newborn period. The majority of patients are male and critically ill with a severe metabolic acidosis. There is an elevated blood or CSF lactate concentration and associated elevations of pyruvate and alanine. These patients have seizures, failure to thrive, optic atrophy, microcephaly and dysmorphic features. Multiple brain abnormalities have been described, including dysmyelination of the cortex, cystic degeneration of the basal ganglia, ectopic olivary nuclei, hydrocephalus and partial or complete agenesis of the corpus callosum. A less devastating phenotype presents in early infancy. These patients demonstrate the histopathological features of Leigh's syndrome. Other patients affected in infancy survive with a chronic neurodegenerative syndrome manifested by mental retardation, microcephaly, recurrent seizures, spasticity, ataxia and dystonia.

    Mutations involving the E1 α subunit behave clinically like an X-linked dominant condition. These mutations usually are lethal in boys during early infancy. The clinical spectrum in the heterozygous girl is more varied, ranging from a devastating condition in early infancy to a mild chronic encephalopathy with mental retardation. The least symptomatic woman may give birth to affected male and female progeny and pose a significant problem in clinical diagnosis and genetic counseling.

    Treatment is largely symptomatic, and the prognosis ranges from dismal to guarded. Thiamine, lipoic acid, ketogenic diet and physostigmine have been tried in different concentrations and doses with equivocal results. Some patients with periodic ataxia resulting from PDHC deficiency may respond to acetazolamide.
     
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  16. EsetIsadore

    EsetIsadore

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    Could you ask your doctor to prescribe via a compounding pharmacy for you? Then they can customize dose and delivery as well as remove excessive “inactive” ingredients.
     
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  17. EsetIsadore

    EsetIsadore

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    I am so grateful to all of you for this thread of conversation! I don’t have the stamina sufficient to read or to write like I’d like. But I’ll try my best...

    I’ve considered acetazolamide since my neuro-ophthalmologist recommended it to me a year ago for “vestibular-ocular reflex disorder”, as he then called it. Because it’s side effect profile looked too much like my everyday, I didn’t go for it.

    I have Hemiplegic Migraines with Brainstem Aura and Vestibular features (in addition to ME in the more severe range). Acetazolamide can be used for HM treatment. Because of my certainty that oxygen delivery plays one key role for me, its known ability to enhance this captivates me. I experience exacerbation around my menses and am super sensitive to weather shifts, especially when abrupt; it’s been used for menstrual migraine, catemenial epilepsy, and weather sensitive migraine. It can also treat “dancing eyes”, which I have intermittently too.

    Nevertheless, though circumstance has served only to grow my interest, I remain cautious. Amongst other side effects, I’ve read that it can cause low back pain, severe chills, and (of course) dehydration. It also depletes Mg, K, Na, folic acid, and zinc, so I’d need be watchful of these nutrient levels.

    I’ll stay tuned to this conversation! Thank you all so much; this was perfect timing for me, as I see my neurologist next Wednesday and this is much on my mind...
     
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  18. pattismith

    pattismith Senior Member

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    @EsetIsadore
    I'm glad you talked about migraines, I have posted something about it elsewhere, I quoted it for you:

    Of course this is a drug that must be used with caution, but for some of us, it can give dramatical improvment
     
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  19. EsetIsadore

    EsetIsadore

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    Thank you so much for sharing this with me!
     
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  20. pattismith

    pattismith Senior Member

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    .I just wish to add a document about side effects from Acetazolamide use. Diamox can lead to metabolic acidosis, kidney stones, and some other issues.

    (Sodium bicarbonate may increase the kidney stones occurence)
     

    Attached Files:

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