Daisy and Her Medication

[Kate H]

I was just going on Clare's latest version of her treatment algorithm (recommendations for vets), which omits mention of frusemide and recommends two other CSF reducing drugs. At the top she says 'Start CSF pressure reducing drugs e.g. cimetidine (Zitac) ... orally 3 times daily' and at the bottom she has a note: 'Because cimetidine reduces stomach acid it may reduce the absorption of other drugs. It is recommended that other drugs are administered at least 2 hours before the administration of cimetidine.'

I would guess that Harley is only on twice a day because he so far only has a pre-syrinx, and Clare always seems to recommend starting drugs low, and the time gap doesn't apply because he's not on other drugs (such as gabapentin).

Kate, Oliver and Aled

[Brian M]

Hello Kate

You know Chestergates ,I wonder what made G.S. prescribe frusemide and not either of the other two which seem a much safer
option to start Daisy with .

[Nicki]

'Because cimetidine reduces stomach acid it may reduce the absorption of other drugs. It is recommended that other drugs are administered at least 2 hours before the administration of cimetidine.'

Thanks Kate - that is a huge problem though, Kayleigh is on Gabapentin three times daily, 7am, 3pm and 11pm. If I have to give that 2 hours before the Cimetidine, it means I have to give her the Cimetidine at 1 am I already take my meds at 11pm and 3am, not sure I can cope with setting the alarm for 1am too! I can only think to give it to her at 3am.

I think perhaps this needs to be checked with Clare? Maybe we can reduce it to twice daily that might be more practical, if the drug will still work like that.


Omeprazole is a concern, in humans there is a risk of bowel cancer with long term usage Pulse therapy is recommended, where you have 4-6 weeks on, 1-2 weeks off. It's not known about long term risk in dogs.
I also found that high doses and long-term use (1 year or longer) may increase the risk of osteoporosis-related fractures of the hip, wrist, or spine.


For Pat and anyone else interested:

My vet contacted Gregg Kortz DVM Diplomate ACVIM - Neurology back in 2007 about the long term use of Omeprazole - at that time he had only be using it for about a year, but had not seen any problems in that time. He kindly sent some a few of the articles on Omeprazole toxicity.


Neuroendocrine cell hyperplasia and neuroendocrine carcinoma of the rodent fundic stomach.
Poynter D, Selway SA.
Glaxo Group Research Ltd., Ware, Herts, U.K.

Certain substances when given orally to rats have effects on the neuroendocrine cells of the fundic stomach. Such compounds also have effects on acid or its secretion, which is to a greater or lesser extent suppressed, with a consequent rise in serum gastrin, followed by an increase in the number of histamine-secreting ECL cells. These changes are seen with the histamine H2 receptor antagonists loxtidine, SKF 93479, ICI 162,846 and ranitidine; with the hypolipidaemic agents clofibrate, ciprofibrate and benzofibrate; with sodium bicarbonate and pentagastrin; and with omeprazole, a potent inhibitor of the parietal cell proton pump mechanism. Changes in the pH of the rat stomach stimulate the neuroendocrine G cells of the pylorus to secrete gastrin, which acts on the ECL cells of the fundus causing the production of histamine, which in turn stimulates the parietal cell. This sequence leads to an excess of circulating gastrin, which is detectable within 5 days. Subsequently increases in the number of ECL cells occur, the hyperplasia being related to hypergastrinaemia and the degree of acid suppression. The hyperplastic response is rapid, being so obvious with loxtidine at 39 days that there is good reason to suppose it could well be detected earlier. Using omeprazole, hyperplasia was found at 28 days after oral doses of 140 mg/kg/day. In order to get an equivalent degree of acid suppression with ranitidine it was necessary to deliver 420 mg/kg/day by subcutaneous infusion using an osmotic minipump, when hyperplasia occurred. Interestingly, only omeprazole produced a hyperplastic response of G cells. Such results reflect the covalent binding of omeprazole to the proton pump as opposed to the competitive binding of ranitidine to the histamine H2 receptor site. In addition to ECL cell hyperplasia there is ample evidence from lifetime studies in rats and mice that neoplasia may result. Neuroendocrine carcinomas (carcinoids) of the rat fundic stomach have been observed with loxtidine, omeprazole, SKF 93479 and ICI 162,846. They are seen late in the 2-year rat studies and are most unlikely to have arisen purely as an extension of the hyperplastic response. It is possible that the prolonged disturbance of gastric homoestasis resulting from achlorhydria result in the production of a carcinogen or carcinogens, in which event it is not too surprising, in view of the neuroendocrine hyperplasia, that the tumours seen are neuroendocrine carcinomas.(ABSTRACT TRUNCATED AT 400 WORDS)




Pharmacology and toxicology of omeprazole--with special reference to the effects on the gastric mucosa.
Carlsson E, Larsson H, Mattsson H, Ryberg B, Sundell G.
Omeprazole is a long acting inhibitor of gastric acid secretion in different species including rat and dog. Due to the long duration of action, steady state inhibition at repeated once daily administration is reaches within 4-5 days in dogs and in about 3 days in rats. Daily dosing at high dose levels results in virtually complete 24-hour inhibition of acid secretion in experimental animals. The elimination of the inhibitory feedback effect of acid on gastrin secretion leads to hypergastrinaemia. Because gastrin has a trophic effect on the oxyntic mucosa, the hypergastrinaemia results in a reversible hypertrophy of the oxyntic mucosa and an increased capacity to produce acid following maximal stimulation with exogenous secretagogues after discontinuing treatment. Despite the increased capacity to produce acid, basal acid secretion seems to be unchanged. The pronounced hypergastrinaemia which occurs during long-term treatment with high doses rapidly normalizes after discontinuing treatment. The hyperplasia of the oxyntic endocrine ECL cells, and the eventual development of gastric ECL cell carcinoids after lifelong treatment of rats with high doses, can also be attributed to the hypergastrinaemia developing after almost complete elimination of gastric acid secretion in these animals.




Toxicological studies on omeprazole.
Ekman L, Hansson E, Havu N, Carlsson E, Lundberg C.
As part of the safety evaluation of the gastric antisecretory drug, omeprazole, toxicological studies have been performed in several species of animals. The acute toxicity after oral administration to rodents was low. The oral LD50 value was above 4 g/kg. The general toxicity after repeated administration has been studied in rats and dogs. No clinical signs of adverse reactions were seen. Some minor changes in hematology parameters were observed. In rats and mice decreases in the erythrocyte count, hematocrit and hemoglobin have occasionally been found at doses of 125 mumol/kg/day and more. Hyperplasia of oxyntic mucosal cells, concomitant with increases in stomach weight, oxyntic mucosal thickness and folding, has been observed in the species investigated, the dog, rat and mouse. In addition, slight chief cell atrophy and eosinophilia of the chief cell granules were observed in rats. The oxyntic mucosal effects were reversible upon treatment being discontinued. In the oncogenicity studies, gastric carcinoids occurred in the rat but not in the mouse. Investigations of the carcinoids showed that the vast majority of the endocrine cells could be characterised as ECL-cells. The hyperplasia of oxyntic mucosal cells, including hyperplasia of endocrine ECL-cells and development of gastric carcinoids in rats, is attributable to the pronounced hypergastrinemia produced as a secondary effect of almost complete inhibition of acid secretion by the large doses of omeprazole used in the toxicity studies. In agreement with this hypothesis, the hyperplasia of the oxyntic cells was prevented by antrectomy. The reproduction studies performed in rats and rabbits showed no sign of fetal toxicity or teratogenic effect. The results of the short-term mutagenicity tests, Ames test, the micronucleus test in mice and the mouse lymphoma test were all negative.




A review of the effects of long-term acid inhibition in animals.
Carlsson E.
Gastrointestinal Research, AB Hässle, Mölndal, Sweden.

Studies with H2-receptor antagonists have revealed a trophic effect on the gastric mucosa - an effect which has been ascribed to hypergastrinaemia secondary to acid inhibition. Such hyperplasia of oxyntic mucosal cells has also been demonstrated in chronic toxicity studies following profound, long-standing inhibition of gastric acid secretion with omeprazole. The central role of gastrin in this effect was clearly demonstrated in the omeprazole studies, as antrectomy prevented this effect in both rats and dogs. The hyperplasia was fully reversible in both species. The close correlation between serum gastrin and hyperplasia of enterochromaffin-like (ECL) cells in the rat oxyntic mucosa has been demonstrated in a large number of experiments using different means to induce hypergastrinaemia, including administration of exogenous gastrin, treatment with antisecretory drugs and partial fundectomy. The hyperplasia of ECL cells was fully reversible even after 1 year of sustained gastric acid inhibition following treatment with a high dose of omeprazole. Marked long-standing hypergastrinaemia explains the findings of gastric ECL cell carcinoids in the life-long rat toxicity studies with both omeprazole and other inhibitors of gastric acid secretion.



***If anyone is using Omeprazole and wants to continue with it, I have a supply of capsules here which I am happy to send on! [ideally in exchange for a donation to Rupert's Fund but that's not essential!]***

[Kate H]

I think the move away from frusemide is a fairly recent thing, and that not all neurologists are yet convinced that the drawbacks with it outweigh its usefulness. All drugs have side effects and each practitioner has to weigh up whether in their experience the good effect of any drug is worth the uncomfortable side effects or risks. And dogs are individuals - what works well with one doesn't necessarily work as well with another. I know Ulrika Michal at Chestergates has tried one of the other CFS reducers that Clare recommends (can't remember which one it was) and didn't find it particularly useful, so they may be waiting to see what results Clare gets before committing themselves to the change (I expect she'll write a paper about it!).

Kate, Oliver and Aled

PS Nicki, you echoed my thoughts in an earlier post about the nightmare of trying to fit in both gabapentin and Zitac three times a day!!

[Karen and Ruby]

This has all confused me a little bit- I have always given the Zitac alongside Rubys dose of pregabalin although she gets her 2nd dose half way through the day on its own- I'd never heard of not giving it alongside each other.

Charlie also has Zitac but he isn't on anything else so it doesn't matter so much.

I'll have to ask her when Charlie goes back in a few weeks.

I must say it would be a whole lot easier to only give 100mg twice a day as I work full time!!

[Brian M]

Hi Kate

I have fortunatley always been in good health and never missed a days work since a car crash nearly
killed me ,collar bone all my ribs on right ,right leg and right arm in three places ,and have always
had an outlook on life to face problems as and if they arrive, so with my Daisy I am on a very steep
learning curve so any advice and guidance from you ,Nicki ,Pat and many others is more than welcome.

Thank You Ladies .

Ps Never even seen PDE and dont intend to ,that would get me worried and am too much
of a coward .

[Nicki]

Brian, Frusemide was originally the standard treatment for Syringomyelia. It is only recently that I have heard about Simon Swift's concerns [shown on this thread http://www.cavaliertalk.com/forums/s...t=simon+swift]

I found some info about the RAAS if anyone wants to read up

http://en.wikipedia.org/wiki/Renin-angiotensin_system

In brief it increases the volume of fluid in the body, which also increases blood pressure.


Teddy was on Frusemide for quite a few years, he ended up with a grade 5 to 6 heart murmur aged only 6 He was also having liver issues - we suspected due to all the medication. His breeders' lines were normally pretty good for hearts - but I'm now wondering if this was connected to the Frusemide? Need to have a look into this when I'm feeling a bit more awake

[Nicki]

PS Nicki, you echoed my thoughts in an earlier post about the nightmare of trying to fit in both gabapentin and Zitac three times a day!!

Sorry Kate, yes meant to comment on that! Half asleep tonight so it's hard to take all this in

Think I was composing my last post when you posted so have duplicated you a bit

[Brian M]

Nicki

As I posted previously Simon is going to ring me on Monday to sort this out I think he
may have been away to a cardio conference either last week or the week before, and
he said to me he was going to seek majority advice from his colleagues about this point and then
advise me on whether Daisy should take fortekor to counter the RAAS effects that taking frusemide
seems to stimulate or we go back to GS for a change of diuretic. At Daisy's appoitment he made
comments that the frusemide and RAAS problem had not been addressed before so this seems to
be a new line of thought but then we have Pat's learned advice that she was previously aware that frusemide for a
dog with a murmur doesnt seem to be a good idea .
Hopefully I will get an answer on Monday as with anything to do with the girls I am
pretty tenacious and will not rest until we have a definate opinion ,and will post as
soon as I hear .
Rest easy Nicki pls dont get stressed like I did with Australia loosing today all I was
thinking about was the extra cash for the fund if they win but all is not lost yet .

[Brian M]

Hi

Just phoned Simon but he is in consultation ,but we will speak as the day goes on .I have printed off
C. .R guidelines together with the NOAH Zitac information .