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    • #16993
      Tim Blowfield
      Participant

      A recent report on Trikafta shows the great benefit  but still incomplete benefit of the drug. However it still presenting CF as being just a problem with faulty mucous and sweat. Vertex and others still fails to recognise that the failure of the CFTR Channel has effects has effects in every cell of the body – not just cells of sweat glands and mucous membranes. While organs with mucous membranes such as the lungs, gut and pancreas may be most severely affected, every other cell is affected by retention of Chloride within the cells. Adrenal and Parathyroid Glands, heart and other muscle cells, endothelium (the inner lining cells) in blood vessels may all be affected and issues with these may be seen as CF’ers live longer. Trikafta and other corrector/potentiator drugs may be expected  to improve problems such hypokalaemia which are common in CF’ers. Cardiomyopathy (heart failure) has long been recognised in new born and still born babies but of late is increasingly  recognised in adults. Often CF’ers with heart failure do not respond to the usual drugs as ‘normal’ persons do. ACEI’s & ACB’s, Beta Blockers and Calcium Channel Blockers are all reported to give unacceptable side effects – is that because the intracellular electrolytes are abnormal?

      If Chloride is retained in cells due to failure of the CFTR channel, other electrolytes must either be increased (Cations – eg Calcium, Potassium, etc) or reduced (Anions – bicarbonate). Abnormalities of these electrolytes may well be the reason CF’ers have some weird reactions to many drugs including the heart drugs.

      This side of CF needs much more research and attention without reducing that on the lungs.

    • #16995
      Jenny Livingston
      Keymaster

      Tim, I am always fascinated by the way you talk about these things. You provide a perspective that I haven’t heard discussed elsewhere (at least not in depth). Thanks for sharing, and please continue doing so. There truly is so much we still have to learn and figure out!

    • #17003
      Canadian cf dad
      Participant

      Trikafta still not approved for use in Canada.  Can you believe it?

      • #17004
        Jenny Livingston
        Keymaster

        @the-bearshaw-ca this is something that absolutely blows my mind! I follow the CF Get Loud movement closely and have friends who are advocating strongly to get Trikafta approved. The entire process has been frustrating from afar; I cannot imagine what it’s like for those of you experiencing it firsthand.

      • #17014
        Tim Blowfield
        Participant

        I guess it is because we (my wife is 78 with CF) have had more years to develop problems with slowly developing issues such as cardiomyopathy and Atrial Fibrillation,  Hyperparathyroidism and Adrenal failure. Till I realised that the electrolytes within the cells need to follow the same basic rules of Chemistry re the balance of solutions all these ‘co-morbidities did not make sense. It seemed that Reva was just unlucky that she had so many different seemingly unrelated illnesses with Doctors treating them as unrelated. Even now most doctors still do not see the probable linkage and causation by the Faulty CF gene.

        That is why I am so vocal – why I want our CF Specialist Physicians to see this broader picture of CF and not just concentrate on the Lungs (important as they are). It is why I see inhaled gene therapy as only swabbing the tip of the iceberg. Why I see lung transplants as being only a partial solution to CF.

    • #17007
      Judy Moreland
      Participant

      First of all, please let’s stop using “CF-er.”  We are much more than our disease, and I know we say “diabetic,” “quadriplegic,” “etc, but personally, I really dislike “‘CF-er,”  and I’m not sure “diabetic” is the first adjective used for someone with diabetes.  Would much rather be called a “a person with CF,’ or PWCF.

      Secondly, I don’t understand “every other cell is affected by retention of Chloride within the cells” above.  I must not fully understand CF the way I thought I did because I thought that in CF, the chloride didn’t get into the cells to bind with sodium, form salt, and provide necessary moisture for the cells.  I thought the lack of moisture in the cells caused our problems with thick, sticky mucus.

      Judy Moreland  71 PWCF

       

    • #17009
      Judy Moreland
      Participant

      First of all, please let’s stop using “CF-er.”  We are much more than our disease, and I know we say “diabetic,” “quadriplegic,” “etc, but personally, I really dislike “‘CF-er,”  and I’m not sure “diabetic” is the first adjective used for someone with diabetes.  Would much rather be called a “a person with CF,’ or PWCF.

      Secondly, I don’t understand “every other cell is affected by retention of Chloride within the cells” above.  I must not fully understand CF the way I thought I did because I thought that in CF, the chloride didn’t get into the cells to bind with sodium, form salt, and provide necessary moisture for the cells.  I thought the lack of moisture in the cells caused our problems with thick, sticky mucus.

      Judy Moreland  71 PWCF

       

      • #17013
        Tim Blowfield
        Participant

        Sorry Judy, please accept my apology. It was a convenient term I used without thinking it would cause you grief. Thanks for pointing it out.

        We are certainly much more than our CF. What I wish to convey is that CF does affect much more than just our lungs, indeed much more than lungs, gut and Pancreas. It affects every cell in the body – some more than others – often presenting symptoms that are dismissed as co-morbidities or not CF but really are CF caused. Such may well explain why PWCF often have weird reactions to a number of drugs – such as my wife’s reaction to most heart failure drugs. It may explain why PWCF often have issues with Potassium (Hypokalaemia) and Adrenal issues (even though the Adrenal Gland cells do not produce mucous).

        As PWCF get older we can expect to see issues with other organs. We can expect to see issues in persons who have had lung transplants. Changing over the lungs has no effect on the CF in every other cell of the body.

        How do we get our Doctors to see CF in this wider context while not ignoring the Lungs?

        • #17102
          Judy Moreland
          Participant

          Thank you, Tim.  I have disliked “CF-er” for years.  Appreciate your apology.

        • #17109
          Paul met Debbie
          Participant

          Hi Tim,

          I concur with you that cftr defects have influence in many parts and processes in the body and not only in lungs and guts. We should however also consider that there are many entirely different types of chloride channels and they perform different functions in different cells of the body. Cftr is only one of them. So I gather a cftr defect does (fortunately) not imply that chloride transport in the cells is compromised everywhere.

    • #17010
      Judy Moreland
      Participant

      Didn’t mean to submit twice.  I didn’t think it went through the first time.  Sorry.

      Judy Moreland

       

    • #17006
      Canadian cf dad
      Participant

      Opps.. forum would not accept the facts in Canada.  Perhaps you could email me and i could share some information with you?  [email protected]

    • #17005
      Canadian cf dad
      Participant

      Thanks you for that Jenny:).  Our prime minister, Justin Trudeau, is a poser, more concerned with his appearance and world stage  presence and reputation vs taking care of health care in Canada.  if international pressure was put on him confronting him with his inaction re trikafta and the cf population in Canada, he would react and he would take action.  Problem is, who do we contact in the US and how do we motivate them to send a letter to the Prime Minister, calling him out for the unnessary cf deaths occuring during his watch?

      Emails for Trudeau:   [email protected]  [email protected]

      email for Federal Minister of Health: [email protected]

      Any thoughts?

      • #17022
        Jenny Livingston
        Keymaster

        I got your email. Thanks for the additional information. I’ve previously written letters on behalf of my Canadian friends with CF, and I’ve seen a pretty big social media movement taking place. But we can always do more! You mentioned getting the attention of US government officials to help put pressure on Trudeau, which seems like a great idea! But I must admit, I am not sure how to go about doing that. I don’t personally have any contacts who would make that easier. Several times throughout the years, I’ve called and written officials at multiple levels of government in the hope of calling attention to issues in our own country and healthcare system, but it is extremely difficult to get any response or concern from them. *sigh*

        I do think it’s a great idea to encourage our global community to write letters and raise their voices together online. If you want to post a new forum topic with the information you shared above (with the email addresses of Trudeau and the Minister of Health), please feel free to do so! Then, it’ll be in a place all forum members can see it and take part if they wish.

        Also, are you aware of the CF Get Loud movement? They do SO MUCH work and advocacy! Here is their website: CF GET LOUD

    • #17107
      Tim Blowfield
      Participant

      I have tried to insert a diagram I have that shows this more clearly but have failed.- can’t get it to show.

       

    • #17015
      Paul met Debbie
      Participant

      Judy, it’s my understanding that the chloride cannot leave the airway cells so there is a shortage of it outside the cells, in the area of the cells surface where the mucus lining is formed. Because of this shortage of chloride, there is too little sodium-chloride (salt) in that area to bind water (sodiumchloride attracts water), The mucus lining then is built from mucus that is not fluid enough, contains not enough water. Perhaps this link provides some illustration https://www.cff.org/Research/Research-Into-the-Disease/Research-into-CF-Complications/Mucus/

      This problem is where the modern modulators like trikafta do their work, they restore the channel function to increase transport of chloride from the inside of the airway cells to the lining outside, where it can bind to sodium and attract water.

      There is another problem as well: ion channels in the cells surface that do the opposite: take sodiumchloride out of the lining and into the cells, are too active. This adds up to the shortage of sodiumchloride on the cells surface.  Research is being done to develop medication to make these re-intake channels less overactive.

    • #17090
      Tim Blowfield
      Participant

      Hi Paul and all,

      Yes it is well known the effect of hat faulty Chloride Channel on the Mucous especially in the lungs.

      The elephant in the room is in what is going on inside the cells. As I have postulated before: Retained Chloride caused high levels of Cations (Na, K , Ca & Mg) within the cells as well as water. Cells may be expected to be overhydrated and respond poorly to diuretics which dehydrate the extracellular space.

      This is most probably the cause of many if not all of the side effects seen when a PWCF start on Trikafta, not only does it increase the salt and water in mucous but it may be expected to reduce cations and water within the bodies cells. Changes in salt and water are well known to affect neurological function. Headaches and many other symptoms are reported. That they subside with time is commonly reported and expected as the body adjusts.

      Restarting at a low dose after a break and gradually increasing may be best for those PWCF who have intolerable side effects.

    • #17095
      Jenny Livingston
      Keymaster

      Tim, stopping and starting on a smaller dose, gradually building up to a full dose is something I’ve seen several people do with varying success. I know of others who have done that and still cannot tolerate even a lowered dose because side effects are too intense. Which is not to say that your postulation is incorrect — I find it both fascinating and logical — but there seems to be such variation in the way people are able to tolerate Trikafta, even after taking a break. It’s all very interesting to me.

    • #17103
      Judy Moreland
      Participant

      Paul and Tim,

      I find this very confusing after thinking all these years that the chloride didn’t get into the cells.  In my memory, I see diagrams showing how some of the new drugs let the chloride right outside the cell go into the cell and some have to bring the chloride to the cell and then inside.  I have R117H in addition to F508, and with the R117H, chloride was close to the cell and needed a push to go into it.

      I appreciate all attempts to make this clearer, but I am still confused.

      As far as other organs affected by CF, I am one of the unfortunate women who were unable to conceive because my reproductive mucus was too thick.

      Judy Moreland

       

    • #17106
      Paul met Debbie
      Participant

      Hi Judy,

      With these diagrams it’s always crucial to determine where the inside (cytoplasm) of the airway cell and the outside (mucus layer) are positioned. Mostly I find diagrams with the inside down, and the outside up. The chloride than travels upwards. But some diagrams are upside down, with the outside (mucus layer) down and the inside of the cell (cytoplasm) up. Then of course the chloride travels down. This can be confusing.

      With the r117h mutation there is some considerable chloride transport function left, up to 75% of normal depending on which variant of r117h you have. In combination with d508 many of these people with CF are with few symptoms and diagnosed late in life.

       

    • #17104
      Tim Blowfield
      Participant

      Very true – there is so very much variability in CF. We understand so little of this chameleon of a problem. I have struggled to understand it just the little I do. The effect of abnormal intracellular electrolytes on cell function has been glimpsed at for a long time but sadly been ignored and put in the “too hard ” basket or seen as irrelevant to the problems caused by thick mucous.

      I postulate that it is fundamental to understanding the plethora of ‘co-morbidities’ that plague PWCF. Problems that are now rearing their ugly heads now that problems of thick mucous  are being controlled.

      I do have issues with Vertex in that they seem not interested in acknowledging and including these issues caused by the intracellular electrolytes despite their fantastic drugs obviously having a profound effect there-in.  Despite their own research showing that Ivacaftor should benefit PWCF with about 120  other mutations they have failed to have those included in the indications for use of Trikafta (at least that is so in Australia). The stupid Australian regulator has also failed to include these despite knowing that they exist (submissions to them having included the USPI’s that list these mutations on pages 7 & 8 (search for Ivacaftor in  [email protected]: FDA-Approved Drugs)

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