Cyclosporine Poor Absorption - What could cause this?

Started by BrookeR, March 26, 2015, 05:36:49 AM

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BrookeR

Hello, Sorry to post on here yet again. Everyone must be getting sick of the sight of all my questions.

Pepper's cyclosporine (neoral) blood test results are in and they aren't very good. Her trough concentrations (12hrs after her last dose) were only around 34 (ng/ml). Our vet said the minimum to achieve immune suppression was around 300.
I also have since read online from a university therapeutic drug monitoring study that they suggest clinical benefits have not been observed when trough concentrations fall below 50ng/ml & they were referring in terms of dermatitis treatment.

So it would seem that the cyclosporine is in too low levels in her body to have any effect on her. I thought this was going to be the case, as I had noticed her chewing at her feet and thought they looked a bit yeast looking inside. I mentioned it to the vet and she checked & confirmed it when we were there today. Lots of yeast was evident in her feet.

She started the cyclosporine on the 4th of this Month and was having 1x50mg tablet per day. We were worried she would get sick and decided to start low for a week to see how she went and then increase the dose. She was on 50mg a day until the 13th, when we put her up to 2x 50mg per day. She has been on 2x 50mg tablets a day until now. After seeing her blood level results our vet wants to increase tomorrow (Friday) to 3x 50mg tablets a day and then on Monday (when the vets are open again) go up to 4x50mg tablets.

We have been giving it to her with food and I know this affects the absorption. But our vet thinks it best to continue giving with food until we get the dose stabilised and then try her without food.

Does anyone have any experience with cyclosporine and have knowledge on what may be causing her poor absorption?
I know every dog is different in their level of absorption, but I am wondering about any other medical conditions that may be affecting it.
Not sure if I have mentioned it before, but we believe that Pepper has IBD, but this has not been conclusively diagnosed.

I also have the horrible thought in the back of my mind about a IMPA relapse.
We reduced her pred from one (20mg) tablet every second day to 1/2 (10mg) a tablet every second day on Tuesday (today is Thursday here). As some of you may have noticed I mentioned in another post I made that she was now limping in her front.
But this has also happened after a crazy amount of running and playing on Monday afternoon and a small amount again on Tuesday afternoon. She is limping always in the same leg, there is no shifting of lameness. This is also the same leg she was limping on a few times for brief periods prior to reducing the pred. This was when we didn't know whether to reduce the pred because of the limp and so did another joint tap. The joint tap showed her front legs had normal levels. Her back legs had increased abnormal cells, but less than initially (when diagnosed) and at a level our specialist said could just be arthritis.

She does not have a temperature, which I have been monitoring closely. She also does not have her head hung down low and the 'walking on egg shells' look that she did when diagnosed. My feelings are that the problems are joint, muscular and ligament related due to the pred use and deteriation of her body during this hard time. I feel (or hope?) that she has just over exerted herself playing on Monday and Tuesday and is feeling the repercussions. Not the IMPA. But with hearing the cyclosporine levels are too low, I am terrified and doubts are creeping in.

How long does it normally take for a relapse to progress?

She had some acupuncture today and chiro/muscle work done. The vet said she was tight throughout her body and her neck was the only muscle in her body that didn't seem weak/stressed. Her muscles loosened up after a bit of work.

She showed pain when the vet checked out all her joints, which is the first time she has shown real pain when her joints have been manipulated. When she was initially diagnosed with IMPA, she never showed any signs of pain when her joints were manipulated. Hence why it too so long for the diagnosis.
Hopefully that means this is different, not the IMPA? Am I clutching at straws? What is everyone elses thoughts?

We have increased her pred back up to the 20mg every second day until we can get her cyclosporine level up higher. I am not willing to go up any further on the steroids, as she has suffered too much from them at this point and I don't think her body could handle it.

Brooke with
Pepper, the English Staffy (IMPA since Dec 2014)
NSW Australia

BrookeR

Her limp has also gotten worse tonight after having the acupuncture today and she is drinking more. I don't have experience with acupuncture, does this sound normal? She also had some chiropractic and muscle manipulation exercises done. I know when I go to the chiro or have remedial massage I feel not the best straight away afterwards and a bit sore with a headache, but it gets better the next day. Hope fully this is the same for her?
Brooke with
Pepper, the English Staffy (IMPA since Dec 2014)
NSW Australia

Clover

It's the chiro and muscle manipulation that can make them sore for a couple of days, not the acupuncture. Being thirstier on the increased pred sounds normal.

My girl has acupuncture every month still and it helps her osteoarthritis so much, it's a godsend. Of course, it also depends on the skill level of the practitioner.

Catherine

Did the vet check out her neck glands? You thought her collar was tighter. Also has Pepper had a haematology and biochemistry blood test recently?

BrookeR

Yes the vet checked her neck glands and said they looked and felt normal. She had no thoughts on why I had to loosen her collar. At least that has put that worry aside in my head at the moment. Her glands there were swollen when she was diagnosed with the impa.

Pepper did weigh more on the scales then the same time last week. I had a bit of trouble getting her to stand still though, because another dog came in right when I put her on the scales. But she appeared almost a kilo heavier. Not sure why, I feed her the same quantities daily. The vet who did the massage /acupuncture on her said that her neck was the only muscle left that was not weak. She was also very gassy our normal vet said, which I had noticed. Perhaps she has put on weight (or muscle) and some in her neck?

They took blood yesterday to check her levels out.  She has been having bloods done monthly and sometimes even more often when something has concerned me. She wasn't due again until the end of next week, but we decided to do it now before increasing the cyclosporine higher.  It will take a few days to come back because our specialist insists it be sent out to an outside lab for more accuracy and consistancy.

Pepper has just got up & had breakfast and still has a limp, but not to the extent it was before bed last night. It's still the same leg too. She's back sleeping again now so I'll have to see what happens as the day progresses. It makes sense with my own experience with remedial massage and chiro that she would feel worse for a while afterwards. Especially when it was her first session. I know they warned me after my first sessions to be tired, possible headaches, sore and even possibly bruised for a while. Hopefully that's all it is, not the impa. I don't know what options we will have if its the impa. I just have to trust my instincts and have faith that it's not. But you just don't know. I'm always second guessing myself with this horrible disease. She cannot handle more steroids now, her body needs some time to recover from them. :(
Brooke with
Pepper, the English Staffy (IMPA since Dec 2014)
NSW Australia

BrookeR

#5
More bad news for pepper :(
Her blood test is back and her alt level (prior to now her alt was always okay it was only her alp that was up) has increased to the borderline of permanent irreversible liver damage. It is 3x4 times normal levels. I am taking her in for another blood test tomorrow morning and stopping all pred. Our vet seems to think she will cope with stopping the pred considering she was down to an every second day dose for the past week and a bit. She is more concerned that her iatrogenic cushings may have become full blown cushings.

We tested her blood prior to starting cyclosporine and her alt level was fine, but now it has gone up for the first time. Her blood level of cyclosporine is extremely low though so our vet doesn't seem to think this could have increased her alt. Perhaps combined with the pred it has? By stopping the pred and considering the cyclosporine levels in her body are well below immune suppressant levels we risk an impa relapse. But there is no other option, I do not want her liver to reach the point of no return.

The one positive to come from today is she has not limped.
She is still hungry and wanting to eat all the time and has no sign of vomiting which the vet said was good in terms of her livers state. She said if this changes over the weekend to take her straight to emergency.

Surely we are going to have to get a break with her soon, it's been such a stressful roller coaster of a battle. I'm starting to feel like we are fighting a loosing battle though. Everywhere we turn we seem to hit a brick wall. But I am not going to give up, she deserves to get better.
I have also found out today that the antibiotic that was prescribed to her (for a urine infection) before she got sick with the impa was a penicillin based one that was not cephalexin, but our vet now (not the vet who prescribed the antibiotic) said was 'too closely related to take a chance with'. Pepper is allergic to Cephalexin and there is a warning window that pops up in her file when opened saying this at the vets. Also I mention it every time she is prescribed any drug, especially when she is prescribed antibiotics. I always ask to make sure it is not related to cephalexin, and I did this this time too. I had been told previously that each time she got exposed to it her reaction would get worse. So this could have triggered the impa in the first place! How could this have happened! I am so annoyed with the vet and also annoyed at myself that I didn't notice and check the antibiotic for myself. It was such a bad time with so much happening I wasn't paying enough attention to what was going on with her.

Brooke with
Pepper, the English Staffy (IMPA since Dec 2014)
NSW Australia

BrookeR

#6
I just found info about elevated alt levels as a result of cyclosporine use on the atopica drug sheet written by Novartis and also in Canine and Feline Dermatology Drug Handbook By Sandra N. Koch, Sheila M. F. Torres, Donald C. Plumb.  It says in a study done less than 2% of dogs showed elevated alt levels from use of cyclosporine. I know this is a small amount of dogs, but from experience with Pepper she doesn't follow the 'norm' and Anything is possible.

The increased alt has only happened since starting the cyclosporine and considering she was on the pred for so long prior to starting cyclosporine without having elevated alt levels it could be feasible? I know also her liver could have just got to the point after all this time on the pred that it has caused the damage.
Now I am concerned we should stop the cyclosporine too?? She is no where near immune suppressant levels in her blood anyway and she has not relapsed yet.

Does anyone have any thoughts?  Our vet thinks it's not cyclosporine, but I haven't mentioned the above study to her yet. She is also not going to be there tomorrow when we go to get the bloods done.
Brooke with
Pepper, the English Staffy (IMPA since Dec 2014)
NSW Australia

Clover

Considering the timing, I would think it's very possible it's from the cyclosporine.  :(  Is there any way you can discuss this with her specialist tomorrow? Even if you leave her a message and she calls you back. Perhaps Pepper needs a different secondary drug.

BrookeR

#8
I am going to bring it up with our vet tomorrow. The specialist told me not to ring her directly and that my vet had to, but then she never gets back to them. If her blood shows her levels are worse tomorrow I am going to ring her myself, if she gets annoyed at me so be it. I am concerned that if it is the cyclosporine my vet told me to up her dose today (prior to blood results), so she had an extra 50mg. I am wondering now should I give her any tomorrow morning. She is supposed to have her dose at 6am and my appointment is not until 8.15. I cannot contact anyone now for advice :(
Brooke with
Pepper, the English Staffy (IMPA since Dec 2014)
NSW Australia

Catherine

Just quickly because I have to go out. I can not advise you about stopping the medication but if you feel the medication is being detrimental to Pepper then I certainly would not increase it. Also we used Azathioprine with Preds for our AIHA dog without any problems. I hear of too many side effects with Cyclosporine.

Now with the elevated ALT. I am not sure how much you are talking about but I have recently experienced elevated ALT and GGT and to a lesser degree ALKP with my dog. To cut a long story short I thought it could be because I thought she was Hypothyroid and my vet was pushing towards liver disease. We started her on Soloxine and......the levels all returned to normal. I am not saying that Pepper may have or will/will not get liver disease but I am just saying blood test results may not necessarily be what they seem!

You might like to read this: http://www.idexx.de/pdf/de_de/smallanimal/snap/bileacids/diagnosing-liver-disease.pdf

Jo CIMDA

Hi

I think it is more like Pepper hasn't been on cyclosporin long enough for maximum effect rather than her body is not absorbing it.  It takes at least 4+ weeks to reach any significant effect.   

If you feel you need to take her off cyclosporin why don't you consider combining cyclosporin with ketoconazole or even grapefruit juice.  Both will enhance the effects of cyclosporin and allows the dose to be reduced without losing immunosuppression.  So you can have the full effect of the drug and reduce the unwanted side effects.  There are articles are on the web.

Personally, I wouldn't stop the preds suddenly because Pepper has been on them for so long her adrenal glands might not be up to full function.  If Pepper were mine I would give preds every other day but alternate it with the minimum replacement therapeutic dose (as you would for a dog with no adrenal function - Addison's disease) 0.2-0.3mg/kg per day (BSAVA Small Animal Formulary, 6th Edition) for a week or so.  At least this way you will not risk an adrenal crisis.   It is a very small every other day 'replacement' dose.

There is another drug that might address IMPA and that is lefunomide.  Perhaps your vet could consider this or another drug. 

Every drug is processed by the liver and it can usually take a hammering and still recover when the drugs are lowered.  I think you should ask the specialist's opinion about Peppers liver enzymes.  It might not be as bad as you think.

Good luck

Jo

BrookeR

So we did another blood test yesterday and peps results were higher than before. I had a freak out over night prior to the blood test and decided I wanted to get the specialists opinion on her results before changing her meds. She sees dogs in peppers situation all the time so maybe the figures would not be as bad as my vet was saying. As you have also suggested Jo.

The specialist had told me not to ring her directly, but my normal vet wasn't going to be back until Monday and our vet never could get a response from her. So I knew I was going to get in trouble ringing, but when faced with possible permanent liver damage (as per what my vet had told me) I decided that was more important.

Well... I got absolutely blasted by the specialist for ringing, I haven't been spoken too so rudely before. I know she is a busy person, but I am only concerned about my girl. Is that so bad? It's the only time I've rang her, it's not like I am ringing her everyday.
After she blasted me, she rang back a couple of hours later more calm and said that peppers results were nothing that she could see to be conerned about. She said they were consistent with what she normally sees for dogs on the drugs that she is on. She said that you cannot pay too much attention to the alp and alt s etc when on the preds. My worry is if you don't pay attention how do you know when you are approaching permanent liver damage?  And why after all his time on pred and now we are reducing it but have upped the cyclosporine has her alt only now started going up quickly?

She has told me to continue weaning the pred and start upping her cyclosporine. I am still very worried, but I guess I have to trust her and do what she says otherwise she will stop helping us.
She has said that we may be able to start having phone consults and just get the tests run at my vet. So I don't get conflicting advice. I am happy with this, but don't want to annoy my vet and still want them in the loop in case we have trouble.


There has been no more limping. She has a very dry mouth though. You can hear her tongue grinding in her mouth sometimes. She has been sleeping deep at night and snoring louder than normal since on the cyclosporine . Since I have increased the cyclosporine by another 50mg a day (yesterday and today) she has been very lethargic.
She is still eating, with no vomitting or diarrhoea. But she has her sad face back and is very sleepy and sad looking. She is more hesitant to follow me around whereas normally she trots along behind me everywhere.
I haven't heard lethargy as a side effect of cyclosporine? Could the increasing alt/alps make her tired.
All she wants to do is sleep. She was much more perked up on Saturday morning when I didn't give her any pred or cyclosporine until I heard from the specialist. As soon as i did give it to her at lunch time she got sad and tired. Which has got worse each time I have given her more?
Brooke with
Pepper, the English Staffy (IMPA since Dec 2014)
NSW Australia

BrookeR

The only other thing that was different that i forgot to mention was that I gave her denosyl which she has never had before. But surely that couldnt do anything?

Today she has slept all day and was having trouble getting up and hesitant to jump. She had her 2x50mg of cyclosporine this morning at 7.30 and then denosyl at 11.
She was her worst at about 2-3pm. By 4 o'clock she was up and barking and walking around again. She is due to have more cyclosporine tonight. I'm worried now that her symptoms after lunch today were similar to that of her impa when diagnosed. Head low, sunken arched back. sad face reluctance to walk and jump. No temp though. Im preying it's not that coming back. She seems okay now I guess I will see what happens when I give her more cyclosporine tonight (it's only 50mg). I'm thinking I won't give her anymore denosyl tomorrow either and see what happens. If it's the impa it should come on again regardless of whether I give her the cyclosporine. So if she struggles again with tonight's (50mg) dose and tomorrow mornings (100mg) then I guess I can try make an appointment with the specialist to stop the cyclosporine and see what happens. She does not have enough in her system to be helping her with the impa. So if it's impa it will happen again. But if it's the cyclosporine doing (or denosyl) it shouldn't happen again?
Brooke with
Pepper, the English Staffy (IMPA since Dec 2014)
NSW Australia

Jo CIMDA

Hi

I doubt the raised liver enzymes will be having any obvious detrimental clinical affect, so I wouldn't worry about that.  You need to give the cyclosporin time to reach its full potential.  I think the specialist should be able to control herself better and realise that you are the 'customer' and without people like you, who care for their animals and are prepared to spend a great deal of money, she wouldn't be in business.  You need her but she also needs you.

I am sure these drugs make the dogs feel awful at times and this is why the clinical signs seem to wax and wane. There's nothing you can do about it at this time but hope you can start to reduce the drugs as soon as possible. 

Jo

Penel CIMDA moderator

Sorry that you had such a bad experience with the specialist.  People that work as veterinary specialists should be good with people as well, after all it is the owners who are describing the changes in the animal.  Many of us have been there.  You learn to develop a thick skin, or you find another vet or specialist.
I was extremely lucky with several amazing specialists here in the UK.  They have been deeply empathetic and kind to both my pets and to us as well. 
Penel
(SLE, Surrey - UK)
Forum Owner
CIMDA