Pergolide is available for horses in the UK as the licensed medicine Prascend, and also as the currently unlicensed Bova pergolide paste.  Although a licensed medicine should be the first choice for treating any medical condition, if another product is more suitable for an individual horse, that product can be used if there is "clinical justification" for doing so, e.g. if not taking the licensed medicine could lead to welfare issues/a decline in a horse's clinical condition.  For example, some horses will not eat Prascend tablets in any form, or may need dosing increments less than the 0.5 mg that Prascend tablets can be split into.  The Bova pergolide paste is dispensed in 0.2 mg increments, and being molasses-flavoured has been found to be readily accepted by horses in trials.

Obtaining Bova pergolide paste in the UK

Under the Cascade, medicines other than licensed medicines can be used if there is a clinical justification for using the unlicensed medicine over a licensed medicine.  Bova paste is not available on prescription - it must be obtained from your vet.

Obtaining Bova pergolide paste in France

To our knowledge, to date (March 2021) the French agency for veterinary medicinal products (ANSES) has not given authorisation for Bova paste to be imported, but we understand there is no reason why this should be the case, and we recommend that owners who feel their horses would benefit from the Bova paste ask their vets to contact ANSES and ask for permission to import the Bova paste, setting out the reasons why Prascend is not suitable and the Bova paste would be more suitable, and emphasizing that it is a welfare issue if this is the case.  Hopefully the more people who request the import of the Bova paste, the more chance there is of a successful outcome.

ANSES can be contacted at:
Agence nationale du médicament vétérinaire
14 Rue Claude Bourgelat
Parc d'Activités de la Grande Marche
CS 70611 - 35306 Fougères France
 www.anses.fr
www.anses.fr/en/content/contact-french-agency-veterinary-medicinal-products

We understand that the person who should be contacted is Aline HANOUET, Regulatory Affairs Officer.
email: aline.hanouet@anses.fr

Once permission is obtained from the French authority, the vet should contact Bova UK with:
Confirmation that it is legal to import the Bova paste into France from the French authority,
Proof of veterinary registration and a link to a website so that Bova can authenticate the vet's registration.

Obtaining Bova pergolide paste in other EU countries

We have been informed that the Bova pergolide paste can be and has been imported into many EU countries - your vet should contact Bova UK to ask about import permissions for your country.  

To order from/contact Bova UK:

Bova Specials UK Ltd
7‑9 Gorst road
London
Park Royal
NW10 6LA
United Kingdom
Phone: +44 20 3034 3100
Fax: +44 20 3784 8754
Email: orders@bova.co.uk
VETS ONLY - order online at bova.co.uk/register

Treating PPID with pergolide:
1.  reduces the clinical signs of PPID, 
2.  may slow progression of the disease,
3.  may help protect against further neuron degeneration.

​PPID currently cannot be cured, but can be treated with daily oral administration of a dopamine agonist, which acts in place of the dopamine that is under-produced by a horse with PPID, signalling the pars intermedia to reduce hormone production, and thereby reducing the clinical signs of PPID.  It isn’t currently known whether treatment with pergolide will prevent or slow the hyperplasia and hypertrophy associated with the excess hormone production of the pars intermedia, but in theory this seems likely.

Pergolide is the dopamine agonist most commonly used and studied for treating horses with PPID.  Pergolide is available as Prascend, as Bova pergolide paste, or as compounded pergolide, depending on your country.

In addition, research by Gille et al. (2002) found that pergolide protects dopamine-producing neurons under conditions of elevated oxidative stress, and Dr McFarlane has theorised that any antioxidant and neuroprotective properties of pergolide could be beneficial in slowing the progression of PPID, suggesting that early treatment with pergolide may be advisable

The initial dose of pergolide recommended is 0.002 mg/kg bodyweight once a day, so 1 mg for a 500 kg horse, but the dose may depend on the stage of the PPID, the season and other factors, and it should be titrated to the lowest effective dose for each individual horse based on response to therapy, whether that is improvement in clinical signs and blood results or signs of intolerance.  Many horses require an increased dose during the seasonal rise, with a subsequent reduction in dose around Christmas.  

Some horses go off their food or become depressed when starting treatment with pergolide, but when introduced gradually, ideally starting with 0.2-0.25 mg and slowly increasing to the recommended dose, side effects are minimised.  Giving pergolide at different times to bucket feeds has helped some horses overcome inappetence.

The Bova pergolide paste is molasses flavoured but does not contain molasses, and comes in a tube with 0.2 mg pergolide increments, making it particularly suitable for ponies on small doses and for gradually increasing the dose when first starting pergolide or making changes e.g. for the seasonal rise.  In the UK Prascend is the only licenced treatment that can be obtained with a vet's prescription from pharmacies, but for horses that won't take Prascend or that would be better suited to smaller increments, the Bova pergolide paste can be obtained from vets under the VMD cascade rules.

The video below shows how to administer the Bova pergolide paste.

Evidence that treatment with pergolide is effective 

Fortin JS, Benskey MJ, Lookingland KJ, Petterson JS, Howey EB, Goudreau JL, Schott II HC
Restoring pars intermedia dopamine concentrations and tyrosine hydroxylase expression levels with pergolide: evidence from horses with pituitary pars intermedia dysfunction. 
BMC Vet Res September 2020 16, 356. https://doi.org/10.1186/s12917-020-02565-3
​Dopamine agonist, Equine, Parkinson disease animal model, Pituitary pars intermedia adenoma

Conclusions: "The results of this study demonstrate that pergolide, a DA agonist, re-establishes DA and TH levels in the PI of PPID-affected horses."
​

Written 23 June 2012 and posted on The Laminitis Site Forum.

The FDA NADA for Prascend September 2011
suggests that a review of literature supports a starting dose of 2 mcg/kg with a dose range of 2-4 mcg/kg once daily (2 mcg/kg = 1mg for a 500 kg horse, 4 mcg/kg = 2 mg for a 500 kg horse), but acknowledges that in the literature doses from 0.6 to 10 mcg/kg were used. Whilst many horses do appear to do well on these doses, there are horses on doses of 10 mg+/day (ECIR Group) (TLS note: however, note that although tolerance to pergolide has not been described in horses, tolerance is common with neurotransmitter drugs, i.e. if more than the required dose is given, receptor neurons downregulate, and more of the drug is required to achieve the same effect.  The dose should always be kept at the lowest possible dose).

The USPC 2008 for Pergolide recommends a starting dose of 2 mcg/kg, increasing to 6-10 mcg/kg if no response is seen, and cites research using doses of 3 mg (Sgorbini et al. 2004, Munoz et al. 1996), 1.7-5.5 mcg/kg (Donaldson et al. 2002), 4-5 mg (Williams 1995).

An effectiveness study was carried out using 122 horses aged 10 to 35 diagnosed with PPID by presence of regional hirsutism plus either ACTH 50 pg/ml or more or DST cortisol 1 mcg/dl or more (November  to January). All horses, regardless of their symptoms or diagnostic test results, were started on 2 mcg/kg BW Prascend per day.

There is no mention of the initial dose being tapered, so presume it was introduced at 2 mcg/kg.

At day 90 all horses had diagnostic tests repeated. 42% of the horses still had abnormal results (ACTH > 50 pg/ml, DST cortisol > 1 mcg/dl), and had their dose of Prascend doubled to 4 mcg/kg BW.

Treatment success was based on either an improvement in endocrine testing plus a slight improvement in clinical signs or no improvement in endocrine testing but a reasonable improvement in clinical signs. The clinical signs graded were hirsutism, hyperhidrosis, polyuria/polydipsia, abnormal fat distribution and muscle wasting.

76% were considered treatment successes at day 180 (58% on 2 mcg/kg BW, 42% on 4 mcg/kg BW, following their results at day 90). 8 horses died during the 180 days due to worsening of pre-existing conditions (laminitis, dental disease, septic tenosynovitis) or colic.

32% of horses showed improvement in hirsutism at day 90, 89% at day 180.
27% showed improvement in hyperhidrosis at day 90, 42% at day 180.
31% showed improvement in PU/PD at day 90, 34% at day 180.
21% showed improvement in abnormal fat distribution at day 90, 33% at day 180.
36% showed improvement in muscle wasting at day 90, 46% at day 180.

Only 20 horses had ACTH monitored. Mean baseline ACTH was 73.53 pg/ml, decreasing to 51.12 pg/ml at day 90 and 45.08 pg/ml at day 180.
73.53 pg/ml is not a high ACTH level for a horse with PPID so it is perhaps not surprising that these low doses of pergolide appeared to be effective. It would be interesting to see how effective these doses were on horses with much higher ACTH concentrations.

93 horses had DST cortisol monitored. Mean baseline DST cortisol was 3.12 mcg/dl, decreasing to 1.39 mcg/dl at day 90 but then increasing to 1.47 mcg/dl at day 180. (NB if horses were included in the trial in January, 180 days later may have been in July, so going into the seasonal rise this may have affected test results at 180 days).

Mean insulin was 483 pmol/L (69.6 IU/ml) before treatment, decreasing to 319 pmol/L (45.9 IU/ml) but remained above the reference range (300 pmol/L (43.2 IU/ml)).

Although lab dependent, fasting insulin > 20 IU/ml is generally considered indicative of insulin resistant and therefore not normal. The fact that mean insulin remained above the reference range after treatment with Prascend implies that the dose was not sufficient to control insulin dysregulation - a higher dose may have had a greater effect - or that the insulin resistance was not a result of PPID. Controlling insulin dysregulation, and therefore the risk of laminitis, is surely one of the main aims of treating PPID IF the insulin dysregulation is caused by the PPID.

Side effects reported included:
Decreased appetite 33% - decreased appetite at one or more meals, usually transient and occurring during the first month of treatment, but some horses experienced sporadic inappetance throughout the study. Only 2 horses had a temporary reduction in their dose (despite this being suggested in the UK Prascend data sheet).
Lameness 18%
Diarrhea/loose stools 10%. One case of diarrhea was related to Potomac Horse Fever, the other 11 cases were mild and self-limiting.
Colic 10% - 3 of 12 colics were severe (strangulating lipoma, large colon volvulus) and unlikely to be related to treatment with Prascend. The other colics were mild and resolved with treatment.
Lethargy 10%. Lethargy was not reported in any of the horses before starting treatment, despite being a clinical sign of PPID.
Abnormal weight loss 9% - more than half the horses experienced weight loss, but it was only considered abnormal in 9%. 2 of these horses lost between 22 and 45 kg, and 3 lost more than 45 kg. In most cases of weight loss, the losses were noted to be healthy changes in body composition. Perhaps explained by a reduction in insulin resistance?
Laminitis 8% - 3 new cases and 7 pre-existing, recurring cases
Heart murmur 8%
Death 7% - due to worsening of pre-existing conditions (laminitis, dental disease, septic tenosynovitis) or colic.
Tooth disorder 7%
Skin abscess 6%
Musculoskeletal pain 5%
Behaviour change 5% - included kicking, aggression, agitation, nervous behaviour and increased activity. One horse required a temporary reduction in dose due to energetic behaviour.

The study concludes that Prascend is effective for the control of clinical signs associated with PPID, and that adverse reactions include inappetance, weight loss, lethargy and behavioural changes.

No control group was used because of the ethics of not treating horses known to have PPID. However when monitoring the side effects noted, it would surely have been useful to compare the incidence of similar clinical signs in an age/management matched non-PPID group of horses - without this, how can the clinical signs shown be attributed to the Prascend?

A further 180 day study was undertaken to evaluate the safety margin of Prascend using healthy non-PPID horses. 32 healthy horses aged 3 to 10 years were used. Group 1 received no Prascend, group 2 4 mgc/kg BW, group 3 6 mcg/kg BW (1.5 x the suggested dose) and group 4 8 mcg/kg BW (2 x the suggested dose). All horses started at 4 mcg/kg for 14 days, then those on the higher doses were given 6 mcg on day 15 and 8 mcg/kg on day 31.

Effects noted.
One horse had mild colic on day 3 although in the 6 mcg/kg group, on day 3 it was receiving 4 mcg/kg.
One 6 mcg/kg horse has mildly icteric sclera (jaundiced eyes) and GGT of 74 U/L on day 90, returning to normal by day 90/180. One control horse had GGT of 73 on day 60.
Prascend treated groups had lower mean heart rates and higher mean temperatures than the control group. The heart rates all remained within normal range. The temperatures all remained below 101.5F.

The study concludes that Prascend is safe when administered at a dose of up to 4 mcg/kg once daily. But as no adverse affects were reported in the higher dose groups, surely this study shows that Prascend is safe when administered at a dose of up to 8 mcg/kg in healthy horses?

Are trials on healthy horses relevant to horses with PPID?

A leading researcher suggested that he would not assume that PPID horses would be more tolerant of pergolide than normal horses, and that it is just as likely that the absence of endogenous dopamine might result in hypersensitivity of dopaminergic nerve terminals and make PPID cases even more sensitive to dopamine agonists - we simply don't know.

Pergolide is not a new treatment for PPID in horses. It has been used since at least 1982 (Orth et al.) at recorded doses up to 10 mcg/kg without reported adverse effects. Owners currently have their horses on higher doses than 10 mcg/kg. In his August 2011 webinar for Prascend Diagnostic Challenges in Equine Endocrine Disease, Andy Durham said that different horses need different doses, it can be a question of playing around with the dose and carrying out further diagnostic testing to see if the pergolide is working. He said that he currently had horses on anything from 1-2 mg/day up to 8 mg/day.

ONE FREE ACTH RETEST A YEAR IS OFFERED TO OWNERS OF HORSES IN THE UK THAT ARE REGISTERED ON THE CARE ABOUT CUSHING'S SITE:
"COMPLIMENTARY ACTH MONITORING TEST
One of the member benefits of Care About Cushing’s is that you will be emailed one complementary monitoring ACTH voucher code* every year. Please log in and complete a diary entry for your horse including their treatment dose and most recent ACTH test result to trigger a monitoring code email.
If you are already registered with Care About Cushing's, log in and complete a diary entry for your horse to check its eligibility for a complimentary monitoring test.
*one voucher code per horse annually. Laboratory fees only. Visit, blood sampling and interpretation fees may still be applied by your vet."
​https://careaboutcushings.co.uk/voucher/request

Do all horses with PPID have an increased risk of laminitis?

No.  The laminitis associated with PPID is endocrine laminitis, due to insulin dysregulation (insulin resistance and/or hyperinsulinaemia).  Horses with PPID may or may not have insulin dysregulation (ID).  If they do not have ID, their laminitis risk is considered to be normal.

Mastro LM, Adams AA, Urschel KL
​Pituitary pars intermedia dysfunction does not necessarily impair insulin sensitivity in old horses
Domest Anim Endocrinol. 2015 Jan;50:14-25. doi: 10.1016/j.domaniend.2014.07.003. Epub 2014 Aug 1
"The results from this study provide evidence that PPID is not always associated with impairments in insulin sensitivity."

Mastro Laurel M 2013 University of Kentucky MSc thesis
The effect of Pituitary Pars Intermedia Dysfunction on Protein Metabolism and Insulin Sensitivity in Aged Horses

Does treatment with pergolide improve laminitis in horses with PPID?

Knowles EJ
Does pergolide therapy prevent laminitis in horses diagnosed with pituitary pars intermedia dysfunction?
Equine Veterinary Education May 2019 Vol 31,5 pp 278-280.  Published online 24 Feb 2018. https://doi.org/10.1111/eve.12903

Knowles EJ
In horses with PPID and laminitis, does treatment with pergolide improve clinical signs of laminitis?  
EBVM Conference 2014

​Miller MA, Moore GE, Bertin FR, Kritchevsky JE
What's New in Old Horses? Postmortem Diagnoses in Mature and Aged Equids
Vet Pathol. 2016 Mar;53(2):390-8. doi: 10.1177/0300985815608674. Epub 2015 Oct 12
Of 241 equids aged 15 years or more at autopsy, 12.9% had disease of the pituitary gland as the cause of death or euthanasia.  "PPID was the most common specific diagnosis, based on the postmortem presence of hyperplasia or adenoma, and was the reason for euthanasia in 47.7% of 65 equids with PPID. The most common nonpituitary causes for death or euthanasia in equids with PPID were colic, lameness, cancer, and spinal cord disease. Coexisting conditions in equids with PPID that were not considered the basis for euthanasia included neoplasms, infections, lameness, and recurrent airway obstruction."

Glover CM, Miller LM, Dybdal NO, Lopez A, Duckett WM, McFarlane D
Extrapituitary and Pituitary Pathological Findings in Horses with Pituitary Pars Intermedia Dysfunction: A Retrospective Study
Journal of Equine Veterinary Science - March 2009 Vol. 29, Issue 3, Pages 146-153
Organs (lungs, kidney, liver, heart, pituitary, thyroid & adrenal glands)from horses with PPID were compared to normal horses. Horses with PPID had changes in liver and adrenal glands, bronchiolitis (lungs), proliferative glomerulopathy (kidney), myocardial lipofuscinosis and fibrosis (heart).

J Am Vet Med Assoc. 2004 Apr 1;224(7):1123-7.
Evaluation of suspected pituitary pars intermedia dysfunction in horses with laminitis.
Donaldson MT, Jorgensen AJ, Beech J.
8 horses suspected of having PPID were euthanised - 5 because of laminitis, 1because of RAO, 1 because of septic tenosynovitis secondary to a foot abscess, and 1 because of ataxia. Post mortem examination of 6 horses revealed: adrenocortical hyperplasia (4/6 ), gastric ulceration (3/6 ), tapeworm infestation (2/6), pulmonary abscess (1/6), jugular vein thrombophlebitis (1/6), carcinoma of the bladder (1/6). NB these findings may have been incidental to the PPID.

Does PPID or treatment for PPID affect breeding?

Stallions
Ujvari S, Gerber V, Sieme H, Fouché N, Burger D
Effect of Pergolide Therapy on Semen Parameters in a Stallion With Pituitary Pars Intermedia Dysfunction
JEVS November 2017 Volume 58, Pages 64–67
This paper, looking at 1 stallion with PPID only, looked at semen collected before (July) and 90 days after (~October) treatment with pergolide (at 0.002 mg/kg bw, so 1 mg for a 500 kg horse).  After 90 days semen volume was lowered, but semen density increased, resulting in an equal total sperm count.  Possible reasons for this might be altered prolactin levels, season (and effect of season on PPID as the sperm examinations took place around the start and end of the seasonal rise), and pergolide.  The study concluded that pergolide may alter semen parameters but this was unlikely to affect fertility, and further research in larger numbers of stallions is needed.

Mares
​See Mares

Liphook Equine Hospital have produced the graph above based on thousands of ACTH tests to show the seasonal rise and fall of ACTH.

Until recently it was suggested that 2 reference ranges should be used to take account of the "seasonal rise" or increase in ACTH between August and October - 47 pg/ml was recommended for the period August to October, and 29 pg/ml the rest of the year.  However, it was recognised that the cut-off was not really going to leap from 29 pg/ml on 31 July to 47 pg/ml on 01 August, and vice versa between 31 October and 01 November.  It has also recently been recognised that the seasonal rise seems to start around the June solstice, and finish by the December solstice, peaking around the September equinox.  After studying thousands of ACTH results, Liphook are now recommending that weekly reference ranges should be used for diagnosing PPID - see Seasonal Changes in ACTH Secretion - A E Durham, Liphook Equine Hospital 2016 (and graph below for weekly cut-offs).  Liphook use Immulite for their ACTH assay.

Note that these reference ranges apply to the UK - geographical location may affect interpretation of results, and of course these week numbers apply to the northern hemisphere.

A single cut-off value is likely to be unrealistic (i.e. it is unlikely that a horse will definitely be negative for PPID with an ACTH below the suggested cut-off, and positive for PPID with an ACTH above the suggested cut-off), and therefore some interpretation of the blood test results is likely to be required.  Before weekly reference ranges were suggested, when the cut-off from November to July was suggested to be 29 pg/ml, research by David Rendle et al. suggested that horses with ACTH below 19 pg/ml were unlikely to have PPID, and horses with ACTH over 40 pg/ml were likely to have PPID, but that "results of the current study indicate that when an ACTH concentration between 19 and 40 pg/ml is measured, further testing should be considered to increase the accuracy of PPID diagnosis."  A similar grey area may exist around all suggested cut-offs when interpreting ACTH results for diagnosis of PPID.
Rendle DI, Litchfield E, Heller J, Hughes K J
Investigation of rhythms of secretion and repeatability of plasma adrenocorticotropic hormone concentrations in healthy horses and horses with pituitary pars intermedia dysfunction
Equine Veterinary Journal Vol 46, Issue 1, pages 113–117, January 2014 (published online Aug 2013)

Other laboratories suggest different cut-offs for diagnosing PPID, particularly during the seasonal rise.  Cornell AHDC suggests that "Seasonal elevation of ACTH levels occurs from approximately mid-August to mid-October. Samples taken during this time period may have up to 3 times reference levels of ACTH in normal horses."  Their normal cut-off is 35 pg/ml (outside of the seasonal rise), therefore up to 3 times this might mean an ACTH of up to 105 pg/ml might be considered negative for PPID between August and October.  Cornell use Immulite for their ACTH assays.

The assay used by the laboratory will affect results and cut-offs.  Immulite is a chemiluminescent Immunoassay (CIA), and much of the research into PPID uses Immulite, so this may be considered the industry standard.  However, some laboratories use radio immunoassay (RIA).  RIA ACTH results and cut-offs will be higher than CIA.  In an article for Vet Times by David Rendle in 2012, the upper reference range for ACTH measured by CIA outside of the seasonal rise was suggested as 35 pg/ml, compared to 45-50 pg/ml for RIA - see Identifying Horses with PPID - Part 2: Interpreting Results.

Research by Banse et al 2018 suggested that CIA and RIA should not be used interchangeably for measurement of equine ACTH. 
Banse HE, Schultz N, McCue M, Geor R, McFarlane D
Comparison of two methods for measurement of equine adrenocorticotropin
J Vet Diagn Invest. 2018 Mar;30(2):233-237. doi: 10.1177/1040638717752216. Epub 2017 Dec 28 (PubMed)

It is essential that the effect of stress and other factors that can raise ACTH produced as part of a normal stress response from the pars distalis can be eliminated when interpreting ACTH for a diagnosis of PPID, as commercial tests do not differentiate between pars distalis ACTH (normal stress response) and pars intermedia ACTH (due to PPID).  See Does a high ACTH result mean my horse has PPID?

Age may affect the cut-off for diagnosis of PPID.  Horses aged 20 and older, confirmed free of PPID at post mortem, had an average ACTH of 26.4 pg/ml with ACTH results up to 50 pg/ml (CIA), between November and July, suggesting that "A resting plasma ACTH concentration < 50 pg/ml would be considered normal in aged horses", according to this study.  However, the horses were due to be euthanized, so health status may have affected results, and other factors such as geographical location and breed may have an influence.  See 
Dianne McFarlane
Establishment of a Reference Interval for Plasma ACTH Concentration in Aged Horses Dianne McFarlane
p 18 Equine Endocrinology Summit 2017

Clinical signs of PPID must be present for a diagnosis of PPID to be made.  In her webinar Is it PPID or is it EMS? Dianne McFarlane suggested that history and clinical signs are essential for an early diagnosis of PPID, and that a diagnosis should not be made on the basis of diagnostic test results if there are no clinical signs.

For more information about PPID and diagnosis, see: 
Pituitary Pars Intermedia Dysfunction
Recommendations for the Diagnosis and Treatment of Pituitary Pars Intermedia Dysfunction (PPID) 2015
​

​
Is PPID in horses similar to Parkinson's Disease in humans?
"Although the diseases are anatomically distinct, recent evidence suggests the pathogenesis of dopaminergic neuronal damage in PPID may have significant similarities to that of PD."
Ageing Res Rev. 2007 May;6(1):54-63. Epub 2007 Feb 20. PubMed.
Advantages and limitations of the equine disease, pituitary pars intermedia dysfunction as a model of spontaneous dopaminergic neurodegenerative disease. 
McFarlane D.