P Q
P3 - third phalanx - coffin bone - pedal bone
Pain
Palmar angle
Paracetamol
Pasture-Associated Laminitis (PAL)
PCOS - PolyCystic Ovarian Syndrome
Pergolide - Prascend, Bova pergolide paste, Pergoquin
Phenylbutazone (Bute)
Physical therapy
Pioglitazone
Pituitary Gland
Platelet-Rich Plasma
POMC - proopiomelanocortin
Prolactin (PRL)
Protein
Proxies
PU/PD - Polyuria/Polydipsia
Pain
Palmar angle
Paracetamol
Pasture-Associated Laminitis (PAL)
PCOS - PolyCystic Ovarian Syndrome
Pergolide - Prascend, Bova pergolide paste, Pergoquin
Phenylbutazone (Bute)
Physical therapy
Pioglitazone
Pituitary Gland
Platelet-Rich Plasma
POMC - proopiomelanocortin
Prolactin (PRL)
Protein
Proxies
PU/PD - Polyuria/Polydipsia
P3 - third phalanx - coffin bone - pedal bone
Not sure what the coffin/pedal bone looks like?
Coffin bone photos - www.all-natural-horse-care.com
P3 photos - www.naturalhorsetrim.com
Bone Remodeling of the Equine Distal Limb - Mark Fischer & Sheri Fischer
Engiles JB; Galantino-Homer HL; Dishowitz MI; McDonald D; Boston R; Hankenson KD
Significant Distal Phalangeal Bone Loss in Equine Laminitis
Poster No. 0553 • ORS 2012 Annual Meeting
Coffin bone photos - www.all-natural-horse-care.com
P3 photos - www.naturalhorsetrim.com
Bone Remodeling of the Equine Distal Limb - Mark Fischer & Sheri Fischer
Engiles JB; Galantino-Homer HL; Dishowitz MI; McDonald D; Boston R; Hankenson KD
Significant Distal Phalangeal Bone Loss in Equine Laminitis
Poster No. 0553 • ORS 2012 Annual Meeting
Pain
Analgesia and anaesthesia - Equine Health Sept/Oct 2013 - see Pain Management for Laminitis p 11
Neuropathic pain in laminitis - Equine Science Update
Behavioural Pain Scoring System
Managing Pain - Marieke de Vries - Animal Health Trust March/April 2012
Recognizing pain in stoic horses - Robin Foster, www.thehorse.com Oct 2015
Pain relief for laminitis
Hopster K, van Eps AW
Pain management for laminitis in the horse
Equine Veterinary Education published online March 2018
Foreman JH, Ruemmler R
Efficacy of intramuscular meperidine hydrochloride versus placebo in experimental foot lameness in horses
Equine Veterinary Journal, 45: 48–53 Published online 05 Dec 2013
Collins SN, Pollitt C, Wylie CE, Matiasek K
Laminitic pain: parallels with pain states in humans and other species
Vet Clin North Am Equine Pract. 2010 Dec;26(3):643-71. doi: 10.1016/j.cveq.2010.08.001
Rietmann TR, Stauffacher M, Bernasconi P, Auer JA, Weishaupt MA
The association between heart rate, heart rate variability, endocrine and behavioural pain measures in horses suffering from laminitis
J Vet Med A Physiol Pathol Clin Med. 2004 Jun;51(5):218-25
Effects of pain
Tennant F
The Physiologic Effects of Pain on the Endocrine System
Pain Ther (2013) 2:75–86
Research
Dalla Costa E, Stucke D, Dai F, Minero M, Leach MC, Lebelt D
Using the Horse Grimace Scale (HGS) to Assess Pain Associated with Acute Laminitis in Horses (Equus caballus)
Animals (Basel). 2016 Aug; 6(8): 47. doi: 10.3390/ani6080047
Neuropathic pain in laminitis - Equine Science Update
Behavioural Pain Scoring System
Managing Pain - Marieke de Vries - Animal Health Trust March/April 2012
Recognizing pain in stoic horses - Robin Foster, www.thehorse.com Oct 2015
Pain relief for laminitis
Hopster K, van Eps AW
Pain management for laminitis in the horse
Equine Veterinary Education published online March 2018
Foreman JH, Ruemmler R
Efficacy of intramuscular meperidine hydrochloride versus placebo in experimental foot lameness in horses
Equine Veterinary Journal, 45: 48–53 Published online 05 Dec 2013
Collins SN, Pollitt C, Wylie CE, Matiasek K
Laminitic pain: parallels with pain states in humans and other species
Vet Clin North Am Equine Pract. 2010 Dec;26(3):643-71. doi: 10.1016/j.cveq.2010.08.001
Rietmann TR, Stauffacher M, Bernasconi P, Auer JA, Weishaupt MA
The association between heart rate, heart rate variability, endocrine and behavioural pain measures in horses suffering from laminitis
J Vet Med A Physiol Pathol Clin Med. 2004 Jun;51(5):218-25
Effects of pain
Tennant F
The Physiologic Effects of Pain on the Endocrine System
Pain Ther (2013) 2:75–86
Research
Dalla Costa E, Stucke D, Dai F, Minero M, Leach MC, Lebelt D
Using the Horse Grimace Scale (HGS) to Assess Pain Associated with Acute Laminitis in Horses (Equus caballus)
Animals (Basel). 2016 Aug; 6(8): 47. doi: 10.3390/ani6080047
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Palmar angle
Ramsey GD, Hunter PJ, Nash MP The effect of hoof angle variations on dorsal lamellar load in the equine hoof Equine Vet J. 2011 Sep;43(5):536-42 (PubMed) "The models in this study predict that raising the palmar angle increases the load on the dorsal laminar junction. Therefore, hoof care interventions that raise the palmar angle in order to reduce the dorsal lamellae load may not achieve this outcome." Case study lowering the palmar angle: Severe Laminitis - The Natural Hoof |
Palmar angle of 19 degrees shown in red
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Paracetamol (acetaminophen)
The use of acetaminophen, known as paracetamol in the UK, for pain relief in horses with laminitis has been suggested and investigated. Acetaminophen reduces pain and fever in humans (it is thought to work by blocking messengers in the brain that tell us we have pain, and by affecting body temperature regulation), but has no significant anti-inflammatory effects. Acetaminophen is metabolized by the liver, is hepatotoxic (toxic to the liver) and can cause serious liver damage in humans (paracetamol overdose is the cause of 20% of liver transplants in Europe).
NSAIDs like Bute (phenylbutazone) and Danilon (Suxibuzone) are commonly used for pain relief, e.g. for lameness and laminitis, in horses, but have side effects associated with their use (these NSAIDs are non-selective COX inhibitors which suppress COX-1, which may contribute to gastrointestinal homeostasis, as well as COX-2 - NSAIDs that inhibit COX-2 while sparing COX-1 may have less side effects). Acetaminophen has a similar pharmacology and toxicology profile to the selective COX-2 inhibitors and in humans does not appear to cause the gastrointestinal and kidney problems seen with non-selective NSAIDs.
In horses, acetaminophen is rapidly absorbed from the proximal small intestine, and highly bioavailable (91%), but absorption is affected by feeding (in humans, giving paracetamol after food has been shown to decrease the maximum concentration and increase the time to maximum concentration).
Mercer MA, McKenzie HC, Davis JL, Wilson KE, Hodgson DR, Cecere TE, McIntosh BJ
Pharmacokinetics and safety of repeated oral dosing of acetaminophen in adult horses
Equine Vet J. 2020 Jan;52(1):120-125. doi: 10.1111/evj.13112. Epub 2019 Apr 16
Over 25 days, 8 healthy adult Thoroughbred geldings were given 20 mg acetaminophen/kg bw, finely ground and mixed with water and corn syrup, by syringe into the mouth, as a single dose (day 1), then after 48 hours blood collection a 7 day washout period they were given the same dose every 12 hours for 14 days (28 doses on day 10 to 23).
Acetaminophen was rapidly absorbed into the blood. After the single dose, plasma acetaminophen concentrations reached a mean peak of 16.61 ug/ml 1.35 hours after administration, with a mean half-life of 2.78 hours. When given every 12 hours for 14 days, the mean peak concentration was 15.85 ug/ml an hour after administration, with a mean half-life of 3.99 hours. Absorption was variable between horses, both for maximum concentration and time to reach maximum concentration. Multiple doses did not show significant drug accumulation.
Blood was tested (CBC, biochemistry and liver profile) before the single dose trial started, before the 14 day twice daily dose trial (although this is not clear from the paper), and on days 7 and 14 of the 14 day trial. NB horses were starved for 12 hours for gastroscopy immediately before the start of the 14 day trial, and 48 hours after the end of the 14 day trial. Blood results are given for day 1 (before the single dose trial) and day 23 (the final day of the 14 day trial), and included reduced platelet count (within normal range), increases in total protein, albumin, ALP, AST (not significant) and CK (all within normal ranges). Calcium was below the reference range at day 1, but increased to within the reference range at day 23. SDH decreased significantly, but was above the reference range on day 1 and day 23. Total bilirubin increased significantly and was above the reference range at day 23, and GGT also increased (but not significantly) from within to above the reference range at day 23. Creatinine and urea, commonly measured markers of kidney function, were either not measured or not reported. The authors suggest that the raised liver enzymes could have been due to the horses grazing on pasture containing Panicum grass (see below), and that the increase in total bilirubin was due to fasting prior to gastroscopy, but the paper appears to describe the biochemistry blood being drawn on the final day of acetaminophen administration, but the gastroscopy being carried out 2 days later, so that does not seem to follow.
Liver biopsies were carried out on 7/8 horses 2 days after the end of the 14 day trial, but not at the start (because of concerns that carrying out a biopsy might cause an inflammatory reaction). Evidence of inflammation (mostly mild leucocytic infiltration in portal triads, a lesion not associated with acetaminophen toxicosis in other species) and some degree of cytopathology was found in all horses, with one horse having irreversible changes. However, no clinical signs of liver dysfunction were seen, and although some liver enzymes were above the laboratory reference ranges, none were significantly elevated. After the research period Panicum grass was found in the grazing that the horses had access to, which could account for the liver inflammation and increased liver enzymes (see
Johnson AL, Divers TJ, Freckleton ML, McKenzie HC, Mitchell E, Cullen JM, McDonough SP
Fall Panicum (Panicum dichotomiflorum) Hepatotoxicosis in Horses and Sheep
J Vet Intern Med 2006;20:1414–1421).
Gastroscopy was carried out immediately before the start of the 14 day trial and 48 hours after the final dose of the 14 day trial. There were no significant changes in gastroscopy score between the start and end of the 14 day trial, although scores did increase very slightly (and the mean squamous mucosa score was 1.92 increasing to 2.01, suggesting some evidence of hyperkeratosis or hyperaemia (grade 1) and some small, single or multifocal lesions (grade 2). Based on human research, the paper suggested that "caution should be exercised when combining acetaminophen with other nonselective COX inhibitors in horses due to potential increased risk for gastrointestinal ulceration, and the addition of a proton pump inhibitor" (e.g. GastroGard) "may be advised when combining acetaminophen with other NSAIDs."
The paper concludes that the research demonstrated the safety of giving 20 mg/kg bw acetaminophen by mouth every 12 hours for 14 days to adult horses, but that further evaluation of the pharmacokinetics of higher doses and/or more frequent doses, plus the phamacodynamics, is necessary to determine the effective therapeutic concentration of acetaminophen for horses. However, it appears that the research could not rule out mild liver inflammation and increases in liver enzymes as a result of giving acetaminophen.
Inexpensive Pain Drug Gets a Boost for Treating Horses - Betsy Lynch February 2022 www.thehorse.com
Foreman 2016
A single 20 mg/kg bw dose of acetaminophen produced reduced lameness for 5 hours and reduced heart rate for 11 hours.
Acetaminophen Could Relieve Laminitis Pain - Erica Larson, www.thehorse.com March 2017
West E, Bardell D, Morgan R, Senior M
Use of acetaminophen (paracetamol) as a short-term adjunctive analgesic in a laminitic pony
Vet Anaesth Analg. 2011 Sep;38(5):521-2. doi: 10.1111/j.1467-2995.2011.00639.x (Full)
Analgesia and anaesthesia - Equine Health Sept/Oct 2013 - see Pain Management for Laminitis p 11
NB in humans paracetamol can be toxic to the liver and kidneys - Life Extension Acetaminophen and NSAID Toxicity
The use of acetaminophen, known as paracetamol in the UK, for pain relief in horses with laminitis has been suggested and investigated. Acetaminophen reduces pain and fever in humans (it is thought to work by blocking messengers in the brain that tell us we have pain, and by affecting body temperature regulation), but has no significant anti-inflammatory effects. Acetaminophen is metabolized by the liver, is hepatotoxic (toxic to the liver) and can cause serious liver damage in humans (paracetamol overdose is the cause of 20% of liver transplants in Europe).
NSAIDs like Bute (phenylbutazone) and Danilon (Suxibuzone) are commonly used for pain relief, e.g. for lameness and laminitis, in horses, but have side effects associated with their use (these NSAIDs are non-selective COX inhibitors which suppress COX-1, which may contribute to gastrointestinal homeostasis, as well as COX-2 - NSAIDs that inhibit COX-2 while sparing COX-1 may have less side effects). Acetaminophen has a similar pharmacology and toxicology profile to the selective COX-2 inhibitors and in humans does not appear to cause the gastrointestinal and kidney problems seen with non-selective NSAIDs.
In horses, acetaminophen is rapidly absorbed from the proximal small intestine, and highly bioavailable (91%), but absorption is affected by feeding (in humans, giving paracetamol after food has been shown to decrease the maximum concentration and increase the time to maximum concentration).
Mercer MA, McKenzie HC, Davis JL, Wilson KE, Hodgson DR, Cecere TE, McIntosh BJ
Pharmacokinetics and safety of repeated oral dosing of acetaminophen in adult horses
Equine Vet J. 2020 Jan;52(1):120-125. doi: 10.1111/evj.13112. Epub 2019 Apr 16
Over 25 days, 8 healthy adult Thoroughbred geldings were given 20 mg acetaminophen/kg bw, finely ground and mixed with water and corn syrup, by syringe into the mouth, as a single dose (day 1), then after 48 hours blood collection a 7 day washout period they were given the same dose every 12 hours for 14 days (28 doses on day 10 to 23).
Acetaminophen was rapidly absorbed into the blood. After the single dose, plasma acetaminophen concentrations reached a mean peak of 16.61 ug/ml 1.35 hours after administration, with a mean half-life of 2.78 hours. When given every 12 hours for 14 days, the mean peak concentration was 15.85 ug/ml an hour after administration, with a mean half-life of 3.99 hours. Absorption was variable between horses, both for maximum concentration and time to reach maximum concentration. Multiple doses did not show significant drug accumulation.
Blood was tested (CBC, biochemistry and liver profile) before the single dose trial started, before the 14 day twice daily dose trial (although this is not clear from the paper), and on days 7 and 14 of the 14 day trial. NB horses were starved for 12 hours for gastroscopy immediately before the start of the 14 day trial, and 48 hours after the end of the 14 day trial. Blood results are given for day 1 (before the single dose trial) and day 23 (the final day of the 14 day trial), and included reduced platelet count (within normal range), increases in total protein, albumin, ALP, AST (not significant) and CK (all within normal ranges). Calcium was below the reference range at day 1, but increased to within the reference range at day 23. SDH decreased significantly, but was above the reference range on day 1 and day 23. Total bilirubin increased significantly and was above the reference range at day 23, and GGT also increased (but not significantly) from within to above the reference range at day 23. Creatinine and urea, commonly measured markers of kidney function, were either not measured or not reported. The authors suggest that the raised liver enzymes could have been due to the horses grazing on pasture containing Panicum grass (see below), and that the increase in total bilirubin was due to fasting prior to gastroscopy, but the paper appears to describe the biochemistry blood being drawn on the final day of acetaminophen administration, but the gastroscopy being carried out 2 days later, so that does not seem to follow.
Liver biopsies were carried out on 7/8 horses 2 days after the end of the 14 day trial, but not at the start (because of concerns that carrying out a biopsy might cause an inflammatory reaction). Evidence of inflammation (mostly mild leucocytic infiltration in portal triads, a lesion not associated with acetaminophen toxicosis in other species) and some degree of cytopathology was found in all horses, with one horse having irreversible changes. However, no clinical signs of liver dysfunction were seen, and although some liver enzymes were above the laboratory reference ranges, none were significantly elevated. After the research period Panicum grass was found in the grazing that the horses had access to, which could account for the liver inflammation and increased liver enzymes (see
Johnson AL, Divers TJ, Freckleton ML, McKenzie HC, Mitchell E, Cullen JM, McDonough SP
Fall Panicum (Panicum dichotomiflorum) Hepatotoxicosis in Horses and Sheep
J Vet Intern Med 2006;20:1414–1421).
Gastroscopy was carried out immediately before the start of the 14 day trial and 48 hours after the final dose of the 14 day trial. There were no significant changes in gastroscopy score between the start and end of the 14 day trial, although scores did increase very slightly (and the mean squamous mucosa score was 1.92 increasing to 2.01, suggesting some evidence of hyperkeratosis or hyperaemia (grade 1) and some small, single or multifocal lesions (grade 2). Based on human research, the paper suggested that "caution should be exercised when combining acetaminophen with other nonselective COX inhibitors in horses due to potential increased risk for gastrointestinal ulceration, and the addition of a proton pump inhibitor" (e.g. GastroGard) "may be advised when combining acetaminophen with other NSAIDs."
The paper concludes that the research demonstrated the safety of giving 20 mg/kg bw acetaminophen by mouth every 12 hours for 14 days to adult horses, but that further evaluation of the pharmacokinetics of higher doses and/or more frequent doses, plus the phamacodynamics, is necessary to determine the effective therapeutic concentration of acetaminophen for horses. However, it appears that the research could not rule out mild liver inflammation and increases in liver enzymes as a result of giving acetaminophen.
Inexpensive Pain Drug Gets a Boost for Treating Horses - Betsy Lynch February 2022 www.thehorse.com
Foreman 2016
A single 20 mg/kg bw dose of acetaminophen produced reduced lameness for 5 hours and reduced heart rate for 11 hours.
Acetaminophen Could Relieve Laminitis Pain - Erica Larson, www.thehorse.com March 2017
West E, Bardell D, Morgan R, Senior M
Use of acetaminophen (paracetamol) as a short-term adjunctive analgesic in a laminitic pony
Vet Anaesth Analg. 2011 Sep;38(5):521-2. doi: 10.1111/j.1467-2995.2011.00639.x (Full)
Analgesia and anaesthesia - Equine Health Sept/Oct 2013 - see Pain Management for Laminitis p 11
NB in humans paracetamol can be toxic to the liver and kidneys - Life Extension Acetaminophen and NSAID Toxicity
Pasture Associated Laminitis (PAL)
Pasture Associated Laminitis (PAL) is endocrinopathic laminitis, caused by insulin dysregulation, triggered by sugars and starch in the grass and diet, and seen in horses with EMS and some horses with PPID.
Christopher Pollitt and Gabriel Milinovich write, in chapter 8 of Equine Laminitis 2017 edited by James Belknap, that ingested pasture contains glucose, fructose, sucrose and starch that are digested enzymatically, raise blood sugar levels and trigger the release of insulin. In insulin resistant horses, the consequent high blood insulin levels can cause hoof lamellar pathology and result in pasture-associated laminitis - the most common form of laminitis. Fructans in the grass "do not appreciably raise blood sugar nor trigger the release of insulin." Fructans are fermented by microbes in the hindgut (to volatile fatty acids which are used by the horse as a source of energy).
Pasture Associated Laminitis - Dr Eleanor Kellon April 2019
Menzies-Gow NJ, Harris PA, Elliott J
Prospective cohort study evaluating risk factors for the development of pasture-associated laminitis in the United Kingdom
Equine Vet J. 2017 May;49(3):300-306. doi: 10.1111/evj.12606. Epub 2016 Aug 25
Pasture Associated Laminitis (PAL) is endocrinopathic laminitis, caused by insulin dysregulation, triggered by sugars and starch in the grass and diet, and seen in horses with EMS and some horses with PPID.
Christopher Pollitt and Gabriel Milinovich write, in chapter 8 of Equine Laminitis 2017 edited by James Belknap, that ingested pasture contains glucose, fructose, sucrose and starch that are digested enzymatically, raise blood sugar levels and trigger the release of insulin. In insulin resistant horses, the consequent high blood insulin levels can cause hoof lamellar pathology and result in pasture-associated laminitis - the most common form of laminitis. Fructans in the grass "do not appreciably raise blood sugar nor trigger the release of insulin." Fructans are fermented by microbes in the hindgut (to volatile fatty acids which are used by the horse as a source of energy).
Pasture Associated Laminitis - Dr Eleanor Kellon April 2019
Menzies-Gow NJ, Harris PA, Elliott J
Prospective cohort study evaluating risk factors for the development of pasture-associated laminitis in the United Kingdom
Equine Vet J. 2017 May;49(3):300-306. doi: 10.1111/evj.12606. Epub 2016 Aug 25
PCOS - PolyCystic Ovarian Syndrome
Pergolide - brand names include: Prascend, Bova pergolide paste, Pergoquin, Pergoscend
Need to know
What's the correct dose of Pergolide?
Pharmacokinetics
How stable is pergolide?
How effective is pergolide?
Adverse reactions/Pergolide Veil
How quickly is Pergolide absorbed by horses?
How long does Pergolide remain in the blood?
Pergolide and competing
Does Pergolide affect....?
Research
Pergolide is a dopamine agonist and acts by direct simulation of dopamine receptors (D1 and D2) without requiring metabolic conversion to another form.
Pergolide is an ergot derivative.
Need to know:
Pergolide (Pergolide mesylate) is the recommended treatment for PPID (Cushing's) - licenced for horses as Prascend by Boehringer Ingelheim, Pergoquin by Richter Pharma and Pergoscend by Alfasan Nederland BV, also available as Bova pergolide paste and (in some countries) compounded pergolide.
Do not start at the prescribed dose - work up to the prescribed dose gradually to reduce the incidence of side-effects - See Starting Pergolide/Prascend.
Do not use in lactating mares - pergolide inhibits the release of prolactin (prolactin simulates milk production) - NOAH datasheet for Prascend
Report any adverse effects to Prascend immediately - see Please report adverse reactions to Prascend.
In the UK, Prascend (licenced by Boehringer Ingelheim in 2010) is the only licensed form of Pergolide, but under the veterinary cascade, if Prascend is not suitable for a horse (e.g. a horse needs smaller increments than 0.5 mg or a horse refuses to take Prascend) a vet can prescribe Bova pergolide paste (this must come from a vet). Boehringer Ingelheim's exclusive licence expired in 2020.
VMD datasheet for Prascend
NOAH datasheet for Prascend
SPC for Pergoquin 2021
Pergolide - United States Pharmacopeial Convention
FDA Approval of Prascend 2012
RCP Prascend Decembre 2017 (France)
Datasheets for pergolide use in humans
AAVPT monograph for Pergolide
Permax product information
In the USA Prascend was licenced by the FDA in 2011. At the moment, compounding pharmacies can still supply pergolide.
FDA New Animal Drug Application for Prascend
Pergolide paste available in the UK
A currently unlicensed molasses-flavoured pergolide paste is available in the UK from BOVA UK (only through the horse's vet) for horses that do not respond well to the licensed pergolide treatment. Export from the UK may be possible. See: Pergolide molasses-flavoured paste available in UK
Rendle DI, Frost R, Byrne A
Efficacy of a novel palatable pergolide paste formulation for the treatment of pituitary pars intermedia dysfunction (PPID) in ponies
EVJ Sept 2018 Vol 50, Issue S52 Clinical Research Abstracts of the BEVA Congress September 2018 P 12-13
https://doi.org/10.1111/evj.16_13008
What's the correct dose of Pergolide?
Pharmacokinetics
In humans, pergolide undergoes extensive first-pass hepatic metabolism.
Rendle DI, Doran G, Ireland J, Edwards S
Pharmacokinetics and pharmacodynamics of pergolide mesylate after oral administration in horses with pituitary pars intermedia dysfunction
Domestic Animal Endocrinology Volume 68, July 2019, Pages 135-141. https://doi.org/10.1016/j.domaniend.2019.01.008
Keywords: Dopamine agonist, Endocrine, Equine Cushing's disease, Laminitis
"To reduce the level of fluctuation of ACTH, twice-daily dosing of pergolide may be more appropriate."
Rendle DI, Doran G, Ireland J, Edwards S
Pharmacokinetics and Pharmacodynamics of Oral Pergolide Mesylate In Horses With Pituitary Pars Intermedia Dysfunction
Equine Veterinary Journal Volume 49, Issue S51 September 2017 Page 25
McFarlane D, Banse H, Knych HK, Maxwell LK
Pharmacokinetic and pharmacodynamic properties of pergolide mesylate following long-term administration to horses with pituitary pars intermedia dysfunction
J Vet Pharmacol Ther. 2016 Jun 15. doi: 10.1111/jvp.12339. [Epub ahead of print]
6 horses with PPID were treated with 1 mg Prascend/day for 2 months, then 2 mg Prascend/day for 4 months, then treatment was stopped.
"Pergolide effectively decreased plasma ACTH concentration in aged horses with PPID, with similar pharmacokinetic properties as reported in young horses, including an approximate terminal half-life of 24 h."
Plasma ACTH increased by 50% in 3/6 horses 2 days after stopping treatment and all 6 horses 10 days after stopping treatment.
Pergolide was found (quantifiable) in all 6 horses 2 days after stopping treatment and in none of the horses 10 days after stopping treatment.
"In summary, after discontinuing pergolide treatment, plasma ACTH concentration increased while pergolide was still quantifiable in some horses. Once-daily dosing of pergolide is likely appropriate in most horses with PPID for regulating the plasma ACTH concentration."
Rendle DI, Hughes KJ, Doran GS, Edwards SH
Pharmacokinetics of pergolide after intravenous administration to horses
American Journal of Veterinary Research February 2015, Vol. 76, No. 2, Pages 155-160
Jacobson GA, Pirie A, Edwards S, Hughes KJ, Rendle DI, Davies NW
Determination of pergolide in horse plasma by UPLC-MS/MS for pharmacokinetic applications
J Pharm Biomed Anal. 2014 Jan 24;94C:54-57
Gehring R, Beard LA, Wright A, Coetzee JF, Havel J, Apley MD
Single-Dose Oral Pharmacokinetics of Pergolide Mesylate in Healthy Adult Mares
Vet Ther. 2010 Spring;11(1):E1-8
Abra Wright MSc Thesis 2009
Pharmacokinetics of Pergolide in normal mares
How stable is pergolide?
Stanley SD, DiMaio Knych H
Comparison of Pharmaceutical Equivalence for Compounded Preparations of Pergolide Mesylate
AAEP Proceedings Vol 56 2010
Liquid and dry (capsules/tablets) formulations of 1 mg pergolide were obtained from compounding pharmacies, 2 containers from each pharmacy, with one stored at room temperature and the other refrigerated, and tested on the day of receipt from the pharmacy, and after 15, 30, 45 and 60 days of storage.
Of 14 liquid preparations only 5 met the FDA standard for potency (active dose within +/- 10% of the labelled concentration) when received from the pharmacy, by day 14 only 3/14 were within 90% of labelled dose - only those that had been refrigerated, and all 14 had less than 90% of the labelled concentration of pergolide by day 30.
Of 14 dry preparations, only 7 met the FDA standard for potency when received from the pharmacy, with one powder formulation containing more pergolide than on the label (1.213 mg), and 4/14 containing less than half the amount of pergolide on the label - one powder formulation contained only 0.283 mg.
Dry formulations were much more stable than liquid. Of the 7 products that started at an acceptable potency, all 7 remained acceptable at day 15, 5/7 were acceptable at day 30, 2 were acceptable at day 45 but all were below 90% of labelled concentration by day 60 (other than the product which started at 1.213 mg, which had degraded to acceptable levels at day 45). Looking at all 14 samples, % loss at day 30 ranged from 1% (fridge) to 37% (room temp), and at day 60 from 11% (fridge) to 64% (room temp), with a mean % loss at day 60 of 21% for samples kept in the fridge and 35% for samples kept at room temperature.
There was a large difference in the actual concentration of pergolide in two containers of the same product ordered on the same date from two of the pharmacies - 57% (1.093 and 0.472 mg) and 74% (1.213 and 0.321) difference, with one other pharmacy having a % difference of 13% between the two containers ordered, and all the others having less than 7% difference between the two containers.
The paper concludes that compounded medications should be prepared in state-licensed facilities with strict quality control measures following USP guidelines, and that whenever possible FDA-approved products are preferable because Good Manufacturing Practices have to be followed.
Graphs illustrating the above results - www.prascend.com - Reevaluating Compounding
Shank BR, Ofner CM 3rd
Multitemperature stability and degradation characteristics of pergolide mesylate oral liquid
J Pharm Pract. 2010 Dec;23(6):570-4 (PubMed)
"The time to reach 90% potency (t90) values were calculated to be 43 days and 3 days, respectively, for storage at 25°C and 35°C. Drug concentrations up to ~6 mg/mL can be maintained as a solution at room temperature with this formulation."
Shank BR, Ofner CM 3rd
Stability of Pergolide Mesylate Oral Liquid at Room Temperature
Int J Pharm Compd. 2009 May-June;13(3):254-258 (PubMed)
"After 16 weeks at room temperature, the drug degraded to 71% of its original concentration. The time to reach 90% potency (t90) of pergolide mesylate was calculated to be 6.5 weeks (45 days)."
Davis JL, Kirk LM, Davidson GS, Papich MG
Effects of compounding and storage conditions on stability of pergolide mesylate
J Am Vet Med Assoc. 2009 Feb 1;234(3):385-9 (PubMed)
Pergolide was compounded into a liquid formulation of 1 mg/ml and stored at various temperatures and light conditions for 35 days and tested at days 1, 7, 14, 21 and 35:
-20 degrees C dark – presumably no excessive degradation by day 35
8 degrees C dark – presumably no excessive degradation by day 35
25 degrees C dark – excessive degradation by day 35 but presumably not day 21
37 degrees C dark – excessive degradation by day 21 but presumably not day 14
25 degrees C light – excessive degradation by day 14 but presumably not day 7
"Mean+/-SD concentration of pergolide in the formulation immediately after compounding was 1.05+/-0.086 mg/mL. Samples exposed to light while stored at 25 degrees C had undergone excessive degradation by day 14, samples stored at 37 degrees C had undergone excessive degradation by day 21, and samples stored at 25 degrees C without exposure to light had undergone excessive degradation by day 35."
How effective is pergolide?
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
Keywords: Dopamine agonist, Equine, Parkinson disease animal model, Pituitary pars intermedia adenoma
"The results of this study demonstrate that pergolide, a DA agonist, re-establishes DA and TH levels in the PI of PPID-affected horses."
Tatum RC, McGowan CM, Ireland JL
Efficacy of pergolide for the management of equine pituitary pars intermedia dysfunction: A systematic review
The Veterinary Journal published online 08 October 2020. https://doi.org/10.1016/j.tvjl.2020.105562
A review of published literature including non-randomised uncontrolled field trials (i.e. not good science!) found that "in the vast majority of the included studies, pergolide was reported to provide overall clinical improvement in >75% of cases" (clinical improvement was reported in 40-100% of pergolide-treated PPID cases) - no surprise there, we (The Laminitis Site) see a high rate of improvement in clinical signs in correctly diagnosed PPID cases when pergolide treatment is started. Reported improvements in individual clinical signs varied widely, and ACTH concentrations lowered in 44-74% of cases, with ACTH returning to normal in 28-74% of cases.
Keep in mind that we don't know from this how accurate the diagnosis of PPID was, how advanced the cases, or how well treatment was adapted to clinical signs and blood hormone levels through the year. Often in clinical trials horses are put on a standard dose of pergolide regardless of symptoms and blood results, whereas under the care of an individual owner and vet, a horse may have treatment carefully adapted to best suit the horse's needs.
Adverse reactions/"Pergolide Veil"
"Adverse effects associated with pergolide administration have been reported to be minimal in horses, in comparison to human complications." (Thesis A Wright 2005). However it is not uncommon for a horse to go off its food or show signs of depression when first starting Pergolide at the recommended dose. Tapering up to the recommended dose to avoid these effects, known as the "Pergolide veil", is recommended by ECIRhorse - see Pergolide for lots of information about using Pergolide.
From the NOAH datasheet for Prascend:
"Potential adverse reactions in horses include inappetence, transient anorexia and lethargy, mild central nervous system signs (e.g., mild depression and mild ataxia), diarrhoea and colic. If signs of dose intolerance develop, treatment should be stopped for 2-3 days and then reinstituted at one-half of the previous dose. The total daily dose may be then be titrated back up until the desired clinical effect is achieved, increasing in 0.5 mg increments every 2-4 weeks."
AAEP PROCEEDINGS 2006 Vol 52
Pituitary Pars Intermedia Dysfunction: Challenges of Diagnosis and Treatment
Schott HC
"The most common adverse effect of pergolide, recognized in 5–10% of horses, is a mild decrease in appetite during the first few days after treatment has been initiated. When this problem develops, treatment is stopped for a couple of days and reinstituted at one-half the
previous dose; most horses seem to tolerate this approach."
AAEP PROCEEDINGS 2001 Vol 47
The Michigan Cushing’s Project
Schott HC, Coursen CL, Eberhart SW, Nachreiner RJ, Refsal KR, Ewart SL, Marteniuk JV
"several P(ergolide)-treated horses were reported to have a decrease in appetite during the first week of treatment. Reduction of the dose for a few days seemed helpful in resolving the partial anorexia in these horses.
NB loss of appetite and depression can also be adverse effects of Phenylbutazone (Bute) toxicity:
Myths and Truths About Controlling Pain and Inflammation in Horses
"Gastrointestinal effects are the most important adverse effects of PBZ therapy in horses. Clinical signs include loss of appetite, depression, colic, weight loss, ventral edema, hypoproteinemia (low blood protein), and diarrhea. Hemorrhages and ulcers may occur in the mouth, esophagus, stomach, cecum and right dorsal colon."
Greene SB, Mathews D, Hollingsworth EM, Garbin CP
Behavioral effects of pergolide mesylate on food intake and body weight
Pharmacol Biochem Behav. 1985 Aug;23(2):161-7
Pergolide decreased food intake in rats.
How quickly is Pergolide absorbed by horses?
Rendle DI, Doran G, Ireland J, Edwards S
Pharmacokinetics and Pharmacodynamics of Oral Pergolide Mesylate In Horses With Pituitary Pars Intermedia Dysfunction
Equine Veterinary Journal Volume 49, Issue S51 September 2017 Page 25
"Plasma ACTH concentration reduced significantly within 12 h of the first dose of pergolide with further reductions occurring over the next 10 days."
Abra Wright MSc Thesis 2009
Pharmacokinetics of Pergolide in normal mares
Gehring R, Beard LA, Wright A, Coetzee JF, Havel J, Apley MD
Single-Dose Oral Pharmacokinetics of Pergolide Mesylate in Healthy Adult Mares
Vet Ther. 2010 Spring;11(1):E1-8
Wright/Gehring found that Pergolide was quickly absorbed after giving it orally (it was given after an 8 hour fast to healthy (non-PPID) mares), with the peak blood concentration of Pergolide being reached within 30 minutes in 4/6 horses, and within an hour for all 6 horses. The half-life (the time taken for the concentration of a drug in the blood to decrease by 50%) was 5.86 hours, although this varied considerably between horses.
How long does Pergolide remain in the blood?
Rendle DI, Hughes KJ, Doran GS, Edwards SH
Pharmacokinetics of pergolide after intravenous administration to horses
American Journal of Veterinary Research February 2015, Vol. 76, No. 2, Pages 155-160
In healthy adult horses given 20 μg/kg (10 mg/500 kg horse) pergolide intravenously, the elimination half-life was 5.64 +/- 2.36 hours (measured by high-performance liquid chromatography–tandem mass spectrometry).
Jacobson GA, Pirie A, Edwards S, Hughes KJ, Rendle DI, Davies NW
Determination of pergolide in horse plasma by UPLC-MS/MS for pharmacokinetic applications
J Pharm Biomed Anal. 2014 Jan 24;94C:54-57
An ultra-performance liquid chromatography tandem mass spectrometer assay was developed which was able to determine pergolide in plasma 48 hours after giving a horse a single 10 mg dose of pergolide. The maximum concentration measured was 0.40 ng/ml, and the limit of quantification was 0.006 ng/ml.
Abra Wright's 2009 research (above) also used a UPLC-MS/MS assay, but with a limit of quantification of 0.5 ng/ml. After 6 horses were given ~ 5 mg of pergolide, pergolide was detected in the blood at 3 hrs but not at 4 hrs in 1 horse, at 4 hrs but not 5 hrs in 1 horse, at 8 hrs but not 12 hrs in 3 horses, and at 12 hrs but not 24 hrs in 1 horse. Note the level of detection was much less sensitive in this study.
Alfasan Nederland B.V.
What's the correct dose of Pergolide?
Pharmacokinetics
How stable is pergolide?
How effective is pergolide?
Adverse reactions/Pergolide Veil
How quickly is Pergolide absorbed by horses?
How long does Pergolide remain in the blood?
Pergolide and competing
Does Pergolide affect....?
Research
Pergolide is a dopamine agonist and acts by direct simulation of dopamine receptors (D1 and D2) without requiring metabolic conversion to another form.
Pergolide is an ergot derivative.
Need to know:
Pergolide (Pergolide mesylate) is the recommended treatment for PPID (Cushing's) - licenced for horses as Prascend by Boehringer Ingelheim, Pergoquin by Richter Pharma and Pergoscend by Alfasan Nederland BV, also available as Bova pergolide paste and (in some countries) compounded pergolide.
Do not start at the prescribed dose - work up to the prescribed dose gradually to reduce the incidence of side-effects - See Starting Pergolide/Prascend.
Do not use in lactating mares - pergolide inhibits the release of prolactin (prolactin simulates milk production) - NOAH datasheet for Prascend
Report any adverse effects to Prascend immediately - see Please report adverse reactions to Prascend.
In the UK, Prascend (licenced by Boehringer Ingelheim in 2010) is the only licensed form of Pergolide, but under the veterinary cascade, if Prascend is not suitable for a horse (e.g. a horse needs smaller increments than 0.5 mg or a horse refuses to take Prascend) a vet can prescribe Bova pergolide paste (this must come from a vet). Boehringer Ingelheim's exclusive licence expired in 2020.
VMD datasheet for Prascend
NOAH datasheet for Prascend
SPC for Pergoquin 2021
Pergolide - United States Pharmacopeial Convention
FDA Approval of Prascend 2012
RCP Prascend Decembre 2017 (France)
Datasheets for pergolide use in humans
AAVPT monograph for Pergolide
Permax product information
In the USA Prascend was licenced by the FDA in 2011. At the moment, compounding pharmacies can still supply pergolide.
FDA New Animal Drug Application for Prascend
Pergolide paste available in the UK
A currently unlicensed molasses-flavoured pergolide paste is available in the UK from BOVA UK (only through the horse's vet) for horses that do not respond well to the licensed pergolide treatment. Export from the UK may be possible. See: Pergolide molasses-flavoured paste available in UK
Rendle DI, Frost R, Byrne A
Efficacy of a novel palatable pergolide paste formulation for the treatment of pituitary pars intermedia dysfunction (PPID) in ponies
EVJ Sept 2018 Vol 50, Issue S52 Clinical Research Abstracts of the BEVA Congress September 2018 P 12-13
https://doi.org/10.1111/evj.16_13008
What's the correct dose of Pergolide?
Pharmacokinetics
In humans, pergolide undergoes extensive first-pass hepatic metabolism.
Rendle DI, Doran G, Ireland J, Edwards S
Pharmacokinetics and pharmacodynamics of pergolide mesylate after oral administration in horses with pituitary pars intermedia dysfunction
Domestic Animal Endocrinology Volume 68, July 2019, Pages 135-141. https://doi.org/10.1016/j.domaniend.2019.01.008
Keywords: Dopamine agonist, Endocrine, Equine Cushing's disease, Laminitis
"To reduce the level of fluctuation of ACTH, twice-daily dosing of pergolide may be more appropriate."
Rendle DI, Doran G, Ireland J, Edwards S
Pharmacokinetics and Pharmacodynamics of Oral Pergolide Mesylate In Horses With Pituitary Pars Intermedia Dysfunction
Equine Veterinary Journal Volume 49, Issue S51 September 2017 Page 25
McFarlane D, Banse H, Knych HK, Maxwell LK
Pharmacokinetic and pharmacodynamic properties of pergolide mesylate following long-term administration to horses with pituitary pars intermedia dysfunction
J Vet Pharmacol Ther. 2016 Jun 15. doi: 10.1111/jvp.12339. [Epub ahead of print]
6 horses with PPID were treated with 1 mg Prascend/day for 2 months, then 2 mg Prascend/day for 4 months, then treatment was stopped.
"Pergolide effectively decreased plasma ACTH concentration in aged horses with PPID, with similar pharmacokinetic properties as reported in young horses, including an approximate terminal half-life of 24 h."
Plasma ACTH increased by 50% in 3/6 horses 2 days after stopping treatment and all 6 horses 10 days after stopping treatment.
Pergolide was found (quantifiable) in all 6 horses 2 days after stopping treatment and in none of the horses 10 days after stopping treatment.
"In summary, after discontinuing pergolide treatment, plasma ACTH concentration increased while pergolide was still quantifiable in some horses. Once-daily dosing of pergolide is likely appropriate in most horses with PPID for regulating the plasma ACTH concentration."
Rendle DI, Hughes KJ, Doran GS, Edwards SH
Pharmacokinetics of pergolide after intravenous administration to horses
American Journal of Veterinary Research February 2015, Vol. 76, No. 2, Pages 155-160
Jacobson GA, Pirie A, Edwards S, Hughes KJ, Rendle DI, Davies NW
Determination of pergolide in horse plasma by UPLC-MS/MS for pharmacokinetic applications
J Pharm Biomed Anal. 2014 Jan 24;94C:54-57
Gehring R, Beard LA, Wright A, Coetzee JF, Havel J, Apley MD
Single-Dose Oral Pharmacokinetics of Pergolide Mesylate in Healthy Adult Mares
Vet Ther. 2010 Spring;11(1):E1-8
Abra Wright MSc Thesis 2009
Pharmacokinetics of Pergolide in normal mares
How stable is pergolide?
Stanley SD, DiMaio Knych H
Comparison of Pharmaceutical Equivalence for Compounded Preparations of Pergolide Mesylate
AAEP Proceedings Vol 56 2010
Liquid and dry (capsules/tablets) formulations of 1 mg pergolide were obtained from compounding pharmacies, 2 containers from each pharmacy, with one stored at room temperature and the other refrigerated, and tested on the day of receipt from the pharmacy, and after 15, 30, 45 and 60 days of storage.
Of 14 liquid preparations only 5 met the FDA standard for potency (active dose within +/- 10% of the labelled concentration) when received from the pharmacy, by day 14 only 3/14 were within 90% of labelled dose - only those that had been refrigerated, and all 14 had less than 90% of the labelled concentration of pergolide by day 30.
Of 14 dry preparations, only 7 met the FDA standard for potency when received from the pharmacy, with one powder formulation containing more pergolide than on the label (1.213 mg), and 4/14 containing less than half the amount of pergolide on the label - one powder formulation contained only 0.283 mg.
Dry formulations were much more stable than liquid. Of the 7 products that started at an acceptable potency, all 7 remained acceptable at day 15, 5/7 were acceptable at day 30, 2 were acceptable at day 45 but all were below 90% of labelled concentration by day 60 (other than the product which started at 1.213 mg, which had degraded to acceptable levels at day 45). Looking at all 14 samples, % loss at day 30 ranged from 1% (fridge) to 37% (room temp), and at day 60 from 11% (fridge) to 64% (room temp), with a mean % loss at day 60 of 21% for samples kept in the fridge and 35% for samples kept at room temperature.
There was a large difference in the actual concentration of pergolide in two containers of the same product ordered on the same date from two of the pharmacies - 57% (1.093 and 0.472 mg) and 74% (1.213 and 0.321) difference, with one other pharmacy having a % difference of 13% between the two containers ordered, and all the others having less than 7% difference between the two containers.
The paper concludes that compounded medications should be prepared in state-licensed facilities with strict quality control measures following USP guidelines, and that whenever possible FDA-approved products are preferable because Good Manufacturing Practices have to be followed.
Graphs illustrating the above results - www.prascend.com - Reevaluating Compounding
Shank BR, Ofner CM 3rd
Multitemperature stability and degradation characteristics of pergolide mesylate oral liquid
J Pharm Pract. 2010 Dec;23(6):570-4 (PubMed)
"The time to reach 90% potency (t90) values were calculated to be 43 days and 3 days, respectively, for storage at 25°C and 35°C. Drug concentrations up to ~6 mg/mL can be maintained as a solution at room temperature with this formulation."
Shank BR, Ofner CM 3rd
Stability of Pergolide Mesylate Oral Liquid at Room Temperature
Int J Pharm Compd. 2009 May-June;13(3):254-258 (PubMed)
"After 16 weeks at room temperature, the drug degraded to 71% of its original concentration. The time to reach 90% potency (t90) of pergolide mesylate was calculated to be 6.5 weeks (45 days)."
Davis JL, Kirk LM, Davidson GS, Papich MG
Effects of compounding and storage conditions on stability of pergolide mesylate
J Am Vet Med Assoc. 2009 Feb 1;234(3):385-9 (PubMed)
Pergolide was compounded into a liquid formulation of 1 mg/ml and stored at various temperatures and light conditions for 35 days and tested at days 1, 7, 14, 21 and 35:
-20 degrees C dark – presumably no excessive degradation by day 35
8 degrees C dark – presumably no excessive degradation by day 35
25 degrees C dark – excessive degradation by day 35 but presumably not day 21
37 degrees C dark – excessive degradation by day 21 but presumably not day 14
25 degrees C light – excessive degradation by day 14 but presumably not day 7
"Mean+/-SD concentration of pergolide in the formulation immediately after compounding was 1.05+/-0.086 mg/mL. Samples exposed to light while stored at 25 degrees C had undergone excessive degradation by day 14, samples stored at 37 degrees C had undergone excessive degradation by day 21, and samples stored at 25 degrees C without exposure to light had undergone excessive degradation by day 35."
How effective is pergolide?
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
Keywords: Dopamine agonist, Equine, Parkinson disease animal model, Pituitary pars intermedia adenoma
"The results of this study demonstrate that pergolide, a DA agonist, re-establishes DA and TH levels in the PI of PPID-affected horses."
Tatum RC, McGowan CM, Ireland JL
Efficacy of pergolide for the management of equine pituitary pars intermedia dysfunction: A systematic review
The Veterinary Journal published online 08 October 2020. https://doi.org/10.1016/j.tvjl.2020.105562
A review of published literature including non-randomised uncontrolled field trials (i.e. not good science!) found that "in the vast majority of the included studies, pergolide was reported to provide overall clinical improvement in >75% of cases" (clinical improvement was reported in 40-100% of pergolide-treated PPID cases) - no surprise there, we (The Laminitis Site) see a high rate of improvement in clinical signs in correctly diagnosed PPID cases when pergolide treatment is started. Reported improvements in individual clinical signs varied widely, and ACTH concentrations lowered in 44-74% of cases, with ACTH returning to normal in 28-74% of cases.
Keep in mind that we don't know from this how accurate the diagnosis of PPID was, how advanced the cases, or how well treatment was adapted to clinical signs and blood hormone levels through the year. Often in clinical trials horses are put on a standard dose of pergolide regardless of symptoms and blood results, whereas under the care of an individual owner and vet, a horse may have treatment carefully adapted to best suit the horse's needs.
Adverse reactions/"Pergolide Veil"
"Adverse effects associated with pergolide administration have been reported to be minimal in horses, in comparison to human complications." (Thesis A Wright 2005). However it is not uncommon for a horse to go off its food or show signs of depression when first starting Pergolide at the recommended dose. Tapering up to the recommended dose to avoid these effects, known as the "Pergolide veil", is recommended by ECIRhorse - see Pergolide for lots of information about using Pergolide.
From the NOAH datasheet for Prascend:
"Potential adverse reactions in horses include inappetence, transient anorexia and lethargy, mild central nervous system signs (e.g., mild depression and mild ataxia), diarrhoea and colic. If signs of dose intolerance develop, treatment should be stopped for 2-3 days and then reinstituted at one-half of the previous dose. The total daily dose may be then be titrated back up until the desired clinical effect is achieved, increasing in 0.5 mg increments every 2-4 weeks."
AAEP PROCEEDINGS 2006 Vol 52
Pituitary Pars Intermedia Dysfunction: Challenges of Diagnosis and Treatment
Schott HC
"The most common adverse effect of pergolide, recognized in 5–10% of horses, is a mild decrease in appetite during the first few days after treatment has been initiated. When this problem develops, treatment is stopped for a couple of days and reinstituted at one-half the
previous dose; most horses seem to tolerate this approach."
AAEP PROCEEDINGS 2001 Vol 47
The Michigan Cushing’s Project
Schott HC, Coursen CL, Eberhart SW, Nachreiner RJ, Refsal KR, Ewart SL, Marteniuk JV
"several P(ergolide)-treated horses were reported to have a decrease in appetite during the first week of treatment. Reduction of the dose for a few days seemed helpful in resolving the partial anorexia in these horses.
NB loss of appetite and depression can also be adverse effects of Phenylbutazone (Bute) toxicity:
Myths and Truths About Controlling Pain and Inflammation in Horses
"Gastrointestinal effects are the most important adverse effects of PBZ therapy in horses. Clinical signs include loss of appetite, depression, colic, weight loss, ventral edema, hypoproteinemia (low blood protein), and diarrhea. Hemorrhages and ulcers may occur in the mouth, esophagus, stomach, cecum and right dorsal colon."
Greene SB, Mathews D, Hollingsworth EM, Garbin CP
Behavioral effects of pergolide mesylate on food intake and body weight
Pharmacol Biochem Behav. 1985 Aug;23(2):161-7
Pergolide decreased food intake in rats.
How quickly is Pergolide absorbed by horses?
Rendle DI, Doran G, Ireland J, Edwards S
Pharmacokinetics and Pharmacodynamics of Oral Pergolide Mesylate In Horses With Pituitary Pars Intermedia Dysfunction
Equine Veterinary Journal Volume 49, Issue S51 September 2017 Page 25
"Plasma ACTH concentration reduced significantly within 12 h of the first dose of pergolide with further reductions occurring over the next 10 days."
Abra Wright MSc Thesis 2009
Pharmacokinetics of Pergolide in normal mares
Gehring R, Beard LA, Wright A, Coetzee JF, Havel J, Apley MD
Single-Dose Oral Pharmacokinetics of Pergolide Mesylate in Healthy Adult Mares
Vet Ther. 2010 Spring;11(1):E1-8
Wright/Gehring found that Pergolide was quickly absorbed after giving it orally (it was given after an 8 hour fast to healthy (non-PPID) mares), with the peak blood concentration of Pergolide being reached within 30 minutes in 4/6 horses, and within an hour for all 6 horses. The half-life (the time taken for the concentration of a drug in the blood to decrease by 50%) was 5.86 hours, although this varied considerably between horses.
How long does Pergolide remain in the blood?
Rendle DI, Hughes KJ, Doran GS, Edwards SH
Pharmacokinetics of pergolide after intravenous administration to horses
American Journal of Veterinary Research February 2015, Vol. 76, No. 2, Pages 155-160
In healthy adult horses given 20 μg/kg (10 mg/500 kg horse) pergolide intravenously, the elimination half-life was 5.64 +/- 2.36 hours (measured by high-performance liquid chromatography–tandem mass spectrometry).
Jacobson GA, Pirie A, Edwards S, Hughes KJ, Rendle DI, Davies NW
Determination of pergolide in horse plasma by UPLC-MS/MS for pharmacokinetic applications
J Pharm Biomed Anal. 2014 Jan 24;94C:54-57
An ultra-performance liquid chromatography tandem mass spectrometer assay was developed which was able to determine pergolide in plasma 48 hours after giving a horse a single 10 mg dose of pergolide. The maximum concentration measured was 0.40 ng/ml, and the limit of quantification was 0.006 ng/ml.
Abra Wright's 2009 research (above) also used a UPLC-MS/MS assay, but with a limit of quantification of 0.5 ng/ml. After 6 horses were given ~ 5 mg of pergolide, pergolide was detected in the blood at 3 hrs but not at 4 hrs in 1 horse, at 4 hrs but not 5 hrs in 1 horse, at 8 hrs but not 12 hrs in 3 horses, and at 12 hrs but not 24 hrs in 1 horse. Note the level of detection was much less sensitive in this study.
Alfasan Nederland B.V.
|
Pergolide and competing
The FEI classes pergolide as a prohibited substance - controlled medication, meaning that medication must be stopped before and unable to be detected in the blood at a competition. All members of the equestrian community are welcome to submit a suggested change to the Equine Prohibited Substances List - Equine Prohibited Substances List submission form. From 01 December 2018, horses competing in the USA under USEF rules can apply for a Therapeutic Use Exemption (TUE) for pergolide after submitting proof of diagnosis - see USEF Announces New Therapeutic Use Exemption (TUE) Status for Pergolide Administration Effective December 1, 2018. |
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Does pergolide affect....?
Heart:
Research by Heidrun Gehlen et al. published in 2021 found no changes in left ventricular function in a small population of horses diagnosed with PPID and being treated with pergolide:
Gehlen H, Fisch J, Merle R, Trachsel DS.
Preliminary study on the effects of pergolide on left ventricular function in the horses with pituitary pars intermedia dysfunction.
J Vet Sci. 2021 Sep;22(5):e64. doi: 10.4142/jvs.2021.22.e64. PMID: 34553515; PMCID: PMC8460455.
Keywords: Ultrasonography, heart, horses, equine Cushing syndrome, tissue Doppler echocardiography, speckle tracking
Sperm/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
For comment, see PPID and breeding
Research
de Laat Ma, Sillence MN
A review of recent developments in the pharmagological prevention and treatment of endocrinopathic laminitis
Animal Production Science published online 16 June 2020. doi.org/10.1071/AN19491
Miller, Ashton B
Effects of Pituitary Pars Intermedia Dysfuction and Prascend Treatment on Endocrine and Immune function in Senior Horses.
2019 July PhD Dissertations Veterinary Science 41. https://uknowledge.uky.edu/gluck_etds/41
Corrected Freedom of Information Summary NADA Prascend Tablets September 2011
Heart:
Research by Heidrun Gehlen et al. published in 2021 found no changes in left ventricular function in a small population of horses diagnosed with PPID and being treated with pergolide:
Gehlen H, Fisch J, Merle R, Trachsel DS.
Preliminary study on the effects of pergolide on left ventricular function in the horses with pituitary pars intermedia dysfunction.
J Vet Sci. 2021 Sep;22(5):e64. doi: 10.4142/jvs.2021.22.e64. PMID: 34553515; PMCID: PMC8460455.
Keywords: Ultrasonography, heart, horses, equine Cushing syndrome, tissue Doppler echocardiography, speckle tracking
Sperm/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
For comment, see PPID and breeding
Research
de Laat Ma, Sillence MN
A review of recent developments in the pharmagological prevention and treatment of endocrinopathic laminitis
Animal Production Science published online 16 June 2020. doi.org/10.1071/AN19491
Miller, Ashton B
Effects of Pituitary Pars Intermedia Dysfuction and Prascend Treatment on Endocrine and Immune function in Senior Horses.
2019 July PhD Dissertations Veterinary Science 41. https://uknowledge.uky.edu/gluck_etds/41
Corrected Freedom of Information Summary NADA Prascend Tablets September 2011
Phenylbutazone (Bute)
Phenylbutazone (Bute) is a NonSteriodal Anti-Inflammatory Drug (NSAID) used for the relief of acute or chronic mild to moderate pain and inflammation, and to reduce fever (antipyretic). It is frequently prescribed for horses with laminitis, usually in 1g sachets which can be added to feed or mixed with liquid and syringed into the horse's mouth, and also as a paste and solution for injection. Phenylbutazone is the name of the active ingredient, the drug is sold under various brand names including Equipalazone and Pro-Dynam (UK/Europe), Butamed and Butagesic (USA), Deltazone (Aus). Use of Phenylbutazone was considered safe for many years, but is now known to cause toxicities including colic, diarrhoea, gastroduodenal ulceration, right dorsal colitis, renal papillary necrosis, blood abnormalities and liver disease. Use of concurrent medication e.g. omeprazole (Gastrogard) and sucralfate with the aim of preventing gastric ulcers may lead to other intestinal complications and should be done with caution - see below.
NOAH datasheet for Equipalazone (1g sachets)
Veterinary Medicines Directorate datasheet for Equipalazone (1g oral paste)
(VMD Product Information Database home page)
J Vet Pharmacol Ther. 1986 Mar;9(1):1-25 (PubMed)
Phenylbutazone in the horse: a review
Tobin T, Chay S, Kamerling S, Woods WE, Weckman TJ, Blake JW, Lees P
"Phenylbutazone is an acidic, lipophilic, non-steroidal anti-inflammatory drug (NSAID). It is extensively metabolized in the horse. The metabolites so far identified, oxyphenbutazone, gamma-hydroxyoxyphenbutazone, account for some 25-30% of administered dose over 24 h. The plasma half-life of phenylbutazone and termination of its pharmacological action are determined primarily by its rate of hepatic metabolism. Phenylbutazone acts by inhibiting the cyclooxygenase enzyme system, which is responsible for synthesis of prostanoids such as PGE2. It appears to act on prostaglandin-H synthase and prostacyclin synthase, after conversion by prostaglandin-H synthase to reactive intermediates. It markedly reduces prostanoid-dependent swelling, edema, erythema, and hypersensitivity to pain in inflamed tissues. Its principal use in the horse is for treatment of soft tissue inflammation. Phenylbutazone is highly bound (greater than 98%) to plasma protein. After i.v. injection, blood levels decline with an elimination half-life of 3-10 h. The plasma kinetics of phenylbutazone may be dose dependent, with the plasma half-life increasing as the drug dosage level increases. Plasma residues of the drug at 24 h after a single i.v. dose of 2 g/450 kg average about 0.9 microgram/ml, but considerable variation occurs. If dosing is repeated, the plasma residue accumulates to give mean residual blood levels of approximately 4.5 microgram/ml on Day 5 after 4 days of dosing. Approximately similar blood levels are found after a combination of oral and i.v. dosing. Experiments on large numbers of horses in training have been undertaken to ascertain the population distributions of residual blood levels after such dosing schedules. Absorption of phenylbutazone from the gastrointestinal tract is influenced by the dose administered and the relationship of dosing to feeding. Access to hay can delay the time of peak plasma concentration to 18 h or longer. Under optimal conditions, the bioavailability of oral phenylbutazone is probably in the region of 70%. Paste preparations may be more slowly absorbed than other preparations and yield higher residual plasma levels at 24 h after dosing, but further controlled studies are required. Phenylbutazone is easily detected in the plasma and urine of horses but concentrations in saliva are low. It is quantitated for forensic purposes by HPLC. The variability of this method between laboratories is about +/- 25%. Increasing urinary pH increases the urinary concentration of phenylbutazone and its metabolites up to 200-fold."
Side effects of Bute (Phenylbutazone) use
Phenylbutazone is associated with many serious side effects, including ulcers of the mouth, stomach and intestines, right dorsal colitis and kidney failure, when given in high doses, for a prolonged period or if the horse is dehydrated or has reduced blood volume. Some horses appear to be more sensitive to NSAID toxicity than others, and symptoms of toxicity can appear at lower than recommended doses (The Merck Veterinary Manual).
Adverse effects of NSAIDs - p 479 Equine Sports Medicine & Surgery, Hinchliff, Kaneps & Geor 2013
NSAIDs inhibit COX pathways and reduce prostaglandins, which have protective functions e.g. on blood flow.
The Equine Manual - Higgins & Snyder - Side effects and toxicity of NSAIDs p 267
Side effects of phenylbutazone use include anorexia, depression, colic, hypoproteinemia, diarrhoea, melena, gastrointestinal erosions and ulcers, weight loss, ventral/abdominal oedema, petechial haemorrhage of mucous membranes, renal papillary necrosis, hepatotoxicity, death. The daily maintenance dose should be no more than 4.4 mg/kg bw (2.2 g/day for a 500 kg horse).
Doctors Foster and Smith Pharmacy (2007) Patient Information Sheet Phenylbutazone
"Possible Side Effects
May see signs of oral or gastric ulcers. In adult horses these signs may include decreased appetite, weight loss, mild colic, poor performance, depression, lying down more than normal, diarrhea, accumulation of fluid under the belly, and anemia with signs of pale gums and weakness. In foals may also see teeth grinding, drooling, weakness, and nursing for only short periods of time. Effects related to the kidney may result in changes in drinking or urination habits."
Veterinary Pharmacology and Therapeutics - Riviere and Papich - Chapter 19 p 475
NSAID toxicosis in horses - The Merck Veterinary Manual
Nonsteroidal Anti-Inflammatory Drugs - The Merck Veterinary Manual
"All NSAIDs have the potential to induce adverse reactions, some of which can be life threatening."
"Horses may develop oral, lingual, or colonic ulceration with accompanying signs of colic, weight loss, and diarrhea."
Toxicity of NSAIDs - Mark Sharwood-Walker - Pegasus Health Jan 2013
Myths and Truths About Controlling Pain and Inflammation in Horses
Clinical Pharmacology - Cynthia Webster 2001
Adverse effects of phenylbutazone include bone marrow hypoplasia, hepatotoxicity, renal papillary necrosis, ulcers, thrombophlebitis, decreased iodine uptake, sodium and water retention.
Death may result from high doses of Phenylbutazone:
NB the dose give below was the equivalent of 5 g (or sachets) per day for a 500 kg horse:
Am J Vet Res. 1983 Dec;44(12):2277-9 (PubMed)
Effects of toxic doses of phenylbutazone in ponies
MacAllister CG
"Toxic doses of phenylbutazone (10 mg/kg of body weight) were administered to 10 ponies once daily for 14 days. Clinical signs of toxicosis similar to those seen in other species included CNS depression, anorexia, oral ulcers, and soft feces. Six ponies died in 7 to 20 days; 1 pony was euthanatized during an acute abdominal crisis; and 3 ponies survived the study. At necropsy, the major lesions were oral and gastrointestinal ulcerations and renal changes."
Vet Rec. 1979 Jul 14;105(2):26-30 (PubMed)
Phenylbutazone toxicity in ponies
Snow DH, Bogan JA, Douglas TA, Thompson H
7 out of 8 ponies given 10 mg/kg phenylbutazone orally for 7 to 14 days resulted in clinical signs of toxicity - anorexia, depression, abdominal oedema (water retention). Blood tests showed reduced total protein, reduced calcium and increased urea. 3/8 ponies died from oedema in the large intestine. The ponies all had mouth ulcers.
1 out of 2 ponies given 4 mg/kg phenylbutazone by IV injection for 7 days showed a significant decrease in plasma total protein concentration.
J Am Vet Med Assoc. 1984 Mar 15;184(6):699-703 (PubMed)
Phenylbutazone toxicosis in the horse: a clinical study
Collins LG, Tyler DE
"In a retrospective study of 269 horses that had been treated with phenylbutazone, horses receiving less than or equal to 8.8 mg/kg of body weight/day for less than or equal to 4 days or 2 to 4 mg/kg of body weight/day for up to 50 days remained clinically normal. Anorexia, depression, colic, hypoproteinemia, diarrhea, melena, weight loss, ventral edema, petechial hemorrhages of mucous membranes, oral and gastrointestinal tract erosions and ulcers, renal papillary necrosis, and death were among the complications seen in horses that had received greater than 8.8 mg/kg of body weight/day. In 2 cases, signs suggestive of gastrointestinal-related shock were also evident."
Ponies may be at higher risk of Phenylbutazone toxicity than horses:
Am J Vet Res. 1981 Oct;42(10):1754-9
Phenylbutazone toxicosis in equidae: a biochemical and pathophysiological study
Snow DH, Douglas TA, Thompson H, Parkins JJ, Holmes PH
At dosages of 10 - 12 mg/kg bw for 8 - 10 days, ponies frequently developed clinical signs of toxicosis characterized by hypoproteinemia, protein-losing gastroenteropathy and gastrointestinal ulceration.
Thoroughbred horses given 8.2 mg/kg bw for 13 days appears to be less susceptible to phenylbutazone toxicity, but 4/6 showed a degree of hypoproteinemia.
Young horses, old horses, horses that are systemically ill and/or dehydrated may also be predisposed to the toxic effects of NSAIDs.
NSAIDs commonly cause gastrointestinal ulceration - in the glandular part of the stomach and in both the small and large intestine.
Giving NSAIDs, and Phenylbutazone in particular, by mouth can cause mouth ulcers and ulcers of the oesophagus - "clinical signs of NSAID toxicity include difficulty in mastication due to oral and lingual ulceration, hypersalivation, and signs of pain when swallowing due to esophageal ulceration" - NSAID toxicosis in horses - The Merck Veterinary Manual.
Phenylbutazone binds to hay, and this may result in large concentrations reaching the caecum and colon, where it might damage the gut walls.
Gastrointestinal ulceration may lead to anaemia and low plasma protein levels.
Phenylbutazone may directly injure the blood supply to the intestines.
(Source: Adverse effects of NSAIDs - p 479 Equine Sports Medicine & Surgery, Hinchliff, Kaneps & Geor 2013)
Vet Ther. 2009 Fall;10(3):113-20.
Effects of Top-Dress Formulations of Suxibuzone and Phenylbutazone on Development of Gastric Ulcers in Horses
Andrews FM, Reinemeyer CR, Longhofer SL
This research found no difference in gastric ulcer numbers or severity between horses treated with the recommended dose of phenylbutazone, suxibuzone or nothing for 15 days, when examined by endoscopy - the gastric ulcers found were considered to "be expected with traditional stabling and intermittent feeding patterns". "Phenylbutazone treated horses did not have more severe gastric ulcers than suxibuzone treated horses, indicating that Suxibuzone does not appear to offer an advantage over Phenylbutazone in preventing gastric ulcers when used at recommended label doses. However, ulcers in other regions of the gastrointestinal tract (e.g., right dorsal colon, duodenum) were not evaluated in horses in this study."
Res Vet Sci. 2004 Apr;76(2):145-9
Lower gastric ulcerogenic effect of suxibuzone compared to phenylbutazone when administered orally to horses
Monreal L, Sabaté D, Segura D, Mayós I, Homedes J
5 horses received a high dose of phenylbutazone, 5 received an equivalent dose of saxibuzone, and 5 received a placebo, for 2 weeks. Post mortems on day 18 showed:
1 horse treated with phenylbutazone had clinical signs of NSAID toxicosis.
2 other horses treated with phenylbutazone had small oral ulcers.
Ulcers in the stomach's glandular mucosa were seen in all horses treated with phenylbutazone.
2 horses treated with saxibuzone had small oral ulcers.
2 horses treated with saxibuzone had ulcers in the stomach's glandular mucosa.
Phenylbutazone treated horses had a significant higher ulcerated area, and gastric ulcers were significantly deeper than those in the suxibuzone and placebo groups.
Blood parameters were not statistically different between groups, and no other lesions were found in any tissue.
Conclusion: Suxibuzone causes significantly lower gastric ulcerogenic effect than phenylbutazone when administered orally at equimolecular doses in horses."
The NOAH Compendium warns that:
"Gastrointestinal tract ulceration may be exacerbated by corticosteroids in animals given non-steroidal anti-inflammatory drugs."
Phenylbutazone may compromise gastric mucosal integrity:
J Vet Intern Med. 2012 Nov-Dec;26(6):1494-9
Effects of meloxicam and phenylbutazone on equine gastric mucosal permeability
D'Arcy-Moskwa E, Noble GK, Weston LA, Boston R, Raidal SL
Horses receiving phenylbutazone at 4.4 mg/kg PO q12h day 1, 2.2 mg/kg PO q12h for 4 days, 2.2 mg/kg PO q24h for 9 days had significantly increased gastric permeability to sucrose, evidenced by increased peak serum sucrose concentrations (280-1,580 pg/μL, P = .001) after treatment. "These results suggest that PBZ was associated with greater compromise to gastric mucosal integrity than meloxicam."
Phenylbutazone may cause right dorsal colitis:
Davis JL
Nonsteroidal anti-inflammatory drug associated right dorsal colitis in the horse
Equine Veterinary Education published online 08 Sept 2015
American Journal of Veterinary Research November 2008, Vol. 69, No. 11, Pages 1496-1505
Pathophysiologic effects of phenylbutazone on the right dorsal colon in horses
McConnico RS, Morgan TW, Williams CC, Hubert JD, Moore RM
12 healthy horses were given 8.8 mg/kg bw Phenylbutazone orally for 21 days. 2 horses developed colitis. Prolonged Phenylbutazone administration caused hypoalbuminemia, neutropenia, increased right dorsal colon arterial blood flow, and reduced VFA production. The authors recommended that vets should monitor serum albumin concentrations and neutrophil counts and be extremely cautious when making dosing recommendations for phenylbutazone treatment because of the extreme variability in tolerance within horses. Blood should be tested as early as 3 to 5 days after starting treatment, and the dose should be decreased as soon as possible.
J Vet Intern Med. 1990 Sep-Oct;4(5):247-53
Right dorsal colitis
Karcher LF, Dill SG, Anderson WI, King JM
"Moderate to severe ulcerative colitis of the right dorsal colon was diagnosed by necropsy or by exploratory celiotomy and biopsy in 13 horses with a primary clinical complaint of either colic, diarrhea, or weight loss. Clinical signs varied from acute fulminating diarrhea (possibly with fever), colic, dehydration, endotoxic shock and death, to a chronic condition manifested by mild intermittent colic up to several months in duration, and weight loss with or without mild diarrhea. In a large percentage of the horses, those affected had been hypovolemic and received nonsteroidal anti-inflammatory drugs (NSAID) or had received inappropriately high doses of phenylbutazone before the onset of illness. Experimental treatment of two horses with high doses of a phenylbutazone oral paste preparation (6 gm once daily for 5 days) and limitation of their water intake to approximately one half of maintenance requirement (for 5 days) resulted in reproduction of ulcerative colitis involving only the right dorsal colon, which was apparent at necropsy examination 11 and 15 days after initiation of drug use. It was concluded that localized ulcerative lesions in the right dorsal colon may be a previously unreported manifestation of toxicity due to the administration of NSAID."
NSAIDS may cause renal failure:
NSAIDS can cause acute renal failure when high doses are given or the horse is dehydrated.
Renal failure in horses: What can we do? (Proceedings)
Harold Schott II Aug 2009 CVC in Kansas City proceedings
NSAIDs should not be given concurrently with drugs or substances that may be nephrotoxic (toxic to the kidneys). Nephrotoxic substances include:
Aminoglycoside antibiotics, e.g. streptomycin, gentamicin - Aminoglycosides, The Merck Veterinary Manual
Tetracycline antibiotics, e.g. oxytetracycline - Tetracyclines, The Merck Veterinary Manual
Heavy metals, e.g. arsenic, mercury
Vitamins D or K3
Plants such as onions, red maple leaves, acorns.
Phenylbutazone may be toxic to the liver:
Cholestatic and parenchymal hepatoxicity have been related to phenylbutazone use. NSAIDs are extensively metabolized in the liver, and drug-induced damage to the liver can lead to cumulation and further toxicity. (Source The Equine Manual - Higgins & Snyder - Side effects and toxicity of NSAIDs p 267).
In humans, NSAIDs are predominantly cleared by hepatic metabolism. Elevation of liver enzymes, especially AST and ALT, can occur with all NSAIDs. Idiosyncratic severe hepatitis has been reported with phenylbutazone use. Source: Rheumatology Secrets edited by Sterling G. West 2002.
NSAIDs may exacerbate bleeding:
Although not frequently observed, NSAIDs impair platelet adhesion and can lead to or exacerbate bleeding. Source: Adverse effects of NSAIDs - p 479 Equine Sports Medicine & Surgery, Hinchliff, Kaneps & Geor 2013
Phenylbutazone may cause aplastic anaemia:
Phenylbutazone toxicity may cause bone marrow suppression.
"Phenylbutazone and chloramphenicol have been reported as causes of aplasia" - Liphook Equine Hospital - Investigating Anaemia
"Aplastic anemia is also sometimes associated with ... the use of certain drugs, including ... phenylbutazone" - Wikipedia - Aplastic anemia
"Phenylbutazone has been incriminated as a cause of aplastic anemia" - Schalm's Veterinary Hematology Sixth Edition edited by DJ Weiss & KJ Wardrop citing
Dunavan ML, Murray ES
Clinical evidence of phenylbutazone induced hypoplastic anemia
In Proceeding of the International Symposium of Equine Hematology, AAEP 1:282-285 1975
NSAIDs may impair bone, tendon and ligament healing:
NSAIDs Help Pain But Not Bone Healing - S Oke - www.thehorse.com 2010
"NSAIDs, when given at high doses and for long durations, negatively impact bone healing."
Vet Comp Orthop Traumatol. 2010;23(6):385-92
Non-steroidal anti-inflammatory drugs inhibit bone healing: a review
Barry S
Am J Vet Res. 2000 May;61(5):537-43
Effects of phenylbutazone on bone activity and formation in horses
Rohde C, Anderson DE, Bertone AL, Weisbrode SE
"PBZ (phenylbutazone) decreased MAR (mineral apposition rate) in cortical bone and appeared to decrease healing rate of cortical defects in horses."
Inflamm Res. 2005 Sep;54(9):358-66 (PubMed)
Effects of cyclooxygenase inhibition on bone, tendon, and ligament healing
Radi ZA, Khan NK
"we provide a critical review of available data on the role of PGs and the effect of COX inhibitors on bone, tendon, and ligament repair. Collectively, this assessment suggests potential involvement of PGs in the healing process of these tissues via modulation by non-selective NSAIDs and selective COX-2 inhibitors."
Phenylbutazone may cause joint collagen loss during treatment (at 1 g 2 x day (500 kg horse)).
Vet J. 2014 Jul;201(1):51-6
In vivo effects of phenylbutazone on inflammation and cartilage-derived biomarkers in equine joints with acute synovitis
de Grauw JC, van Loon JP, van de Lest CH, Brunott A, van Weeren PR
"Although PBZ is clinically effective in treating acute synovitis, it does not limit inflammation-induced cartilage catabolism and may transiently reduce collagen anabolism as evidenced by SF markers."
Am J Vet Res. 2001 Dec;62(12):1916-21 (PubMed)
Effects of oral administration of phenylbutazone to horses on in vitro articular cartilage metabolism
Beluche LA, Bertone AL, Anderson DE, Rohde C
"Oral administration of phenylbutazone for 14 days significantly decreased proteoglycan synthesis in articular culture explants from healthy horses to a degree similar to that induced by in vitro exposure to IL-1beta. Phenylbutazone should be used judiciously in athletic horses with osteoarthritis, because chronic administration may suppress proteoglycan synthesis and potentiate cartilage damage."
Phenylbutazone may have a negative effect on wound healing:
Veterinary Pharmacology and Therapeutics - Riviere and Papich p 480 - one conference report suggested a negative effect of phenylbutazone on wound healing in the horse.
"Though most NSAID are thought to be safe in wound healing, recent work suggests that agents selective for COX-2 inhibition may slow wound healing." - The Merck Veterinary Manual - Factors that interfere with wound healing.
Phenylbutazone affects thyroid hormones:
Phenylbutazone decreases T4 thyroid hormone levels:
Sojka JE, Johnson MA, Bottoms GD
Serum triiodothyronine, total thyroxine, and free thyroxine concentrations in horses
Am J Vet Res. 1993 Jan;54(1):52-5
"Phenylbutazone given at a dosage of 4.4 mg/kg every 24 hours, for 7 days did significantly decrease resting T4 and fT4 concentrations, but did not significantly affect T3 concentrations in horses."
The Equine Manual - Higgins & Snyder 2013 p 652 Phenylbutazone is highly protein bound and can displace thyroid hormone from carrier proteins, leading to increased amounts of free thyroid hormone and consequent inhibition of the hypothalamus-pituitary-thyroid axis.
Phenylbutazone and pregnancy
NSAIDs and Pregnancy - Trisha Dowling, thehorse.com, December 2006
Phenylbutazone may be more toxic than other NSAIDs:
J Am Vet Med Assoc. 1993 Jan 1;202 (1):71-7
Comparison of adverse effects of phenylbutazone, flunixin meglumine, and ketoprofen in horses
MacAllister CG, Morgan SJ, Borne AT, Pollet R
Danilon (suxibuzone) may be a reasonable alternative to phenylbutazone:
Res Vet Sci. 2004 Apr;76(2):145-9
Lower gastric ulcerogenic effect of suxibuzone compared to phenylbutazone when administered orally to horses
Monreal L, Sabaté D, Segura D, Mayós I, Homedes J
"SBZ causes significantly lower gastric ulcerogenic effect than PBZ when administered orally at equimolecular doses in horses."
Equine Vet J. 2009 Sep;41(7):700-5
Multicentre, controlled, randomised and blinded field study comparing efficacy of suxibuzone and phenylbutazone in lame horses
Sabaté D, Homedes J, Salichs M, Sust M, Monreal L
Danilon has been shown to have a lower gastric ulcerogenic effect that Bute. In this research, Danilon and Bute showed no significant differences in alleviating lameness in horses, but Danilon was eaten more readily by horses when mixed into feed. The research concluded that Danilon is a good therapeutic alternative to Bute.
However, this research found no difference in gastric ulcer numbers or severity between horses treated with the recommended dose of phenylbutazone, suxibuzone or nothing for 15 days, when examined by endoscopy:
Vet Ther. 2009 Fall;10(3):113-20
Effects of Top-Dress Formulations of Suxibuzone and Phenylbutazone on Development of Gastric Ulcers in Horses
Andrews FM, Reinemeyer CR, Longhofer SL
"Phenylbutazone treated horses did not have more severe gastric ulcers than suxibuzone treated horses, indicating that Suxibuzone does not appear to offer an advantage over Phenylbutazone in preventing gastric ulcers when used at recommended label doses."
Phenylbutazone should not be used in combination with other NSAIDs:
Flood J, Stewart AJ.
Non-Steroidal Anti-Inflammatory Drugs and Associated Toxicities in Horses.
Animals (Basel). 2022 Oct 26;12(21):2939. doi: 10.3390/ani12212939. PMID: 36359062; PMCID: PMC9655344. Open Access.
"Only one NSAID should be administered at one time, as co-administration of NSAIDs (known as ‘stacking’) has an additive effect and may pre-dispose horses to adverse events without any additional analgesic benefit."
Am J Vet Res. 2006 Mar;67(3):398-402
Effects of phenylbutazone alone or in combination with flunixin meglumine on blood protein concentrations in horses
Reed SK, Messer NT, Tessman RK, Keegan KG
Am J Vet Res. 2008 Feb;69(2):167-73
Effectiveness of administration of phenylbutazone alone or concurrent administration of phenylbutazone and flunixin meglumine to alleviate lameness in horses
Keegan KG, Messer NT, Reed SK, Wilson DA, Kramer J
"One horse administered the combination NSAID regimen died of acute necrotizing colitis during the study/"
Phenylbutazone interactions with other medicines:
Omeprazole and Sucralfate have been used at the same time as NSAIDs including phenylbutazone with the aim of reducing the risk of gastric ulcers. Recent research has suggested concurrent use of these medicines might increase other intestinal complications, and until more research has been carried out, caution should be exercised.
Flood J, Stewart AJ.
Non-Steroidal Anti-Inflammatory Drugs and Associated Toxicities in Horses.
Animals (Basel). 2022 Oct 26;12(21):2939. doi: 10.3390/ani12212939. PMID: 36359062; PMCID: PMC9655344.
Citing Bishop et al. 2021 (below) this paper suggests that horses treated with sucralfate at the same time as NSAIDS had a significant increase in right dorsal colon wall thickness, whereas horses treated with omeprazole at the same time as NSAIDs had no changes to right dorsal colon wall thickness, and concludes that further research is needed on drug interactions between sucralfate and omeprazole given at the same time as NSAIDs.
Bishop RC, Kemper AM, Wilkins PA, McCoy AM.
Effect of omeprazole and sucralfate on gastrointestinal injury in a fasting/NSAID model.
Equine Vet J. 2021 Oct 31. doi: 10.1111/evj.13534. Epub ahead of print. PMID: 34719063.
See also:
Comparison of Omeprazole and Sucralfate in Equine Gastric Disease - University of Illinois February 2022
When 14 healthy horses received either omeprazole or sucralfate during a protocol of fasting and flunuxin (NSAID) administration to induce gastric ulcers, equine squamous gastric disease (ESGD) developed or worsened with both treatments. Horses treated with omeprazole had lower ESGD and EGGD scores than horses treated with sucralfate. Horses receiving sucralfate at the same time as flunixin were significantly more likely to have increased right dorsal colon wall thickness, than horses receiving omeprazole. The research concludes that giving sucralfate at the same time as flunixin may be associated with increased risk of large intestinal complications, or perhaps that omepgrazole gives a protective effect against NSAID-associated colitis (a control group with no protective treatment was not used), and that further research is warranted.
Ricord M, Andrews FM, Yñiguez FJM, Keowen M, Garza F Jr, Paul L, Chapman A, Banse HE.
Impact of concurrent treatment with omeprazole on phenylbutazone-induced equine gastric ulcer syndrome (EGUS).
Equine Vet J. 2021 Mar;53(2):356-363. doi: 10.1111/evj.13323. Epub 2020 Aug 18. PMID: 32697849.
22 horses with equine glandular gastric disease (EGGD) and equine squamous gastric disease (ESGD) scores less than or equal to 2 were treated for 7 to 14 days with either phenylbutazone (2.2 grams morning and evening for a 500 kg horse) 8 horses, the same dose of phenylbutazone plus 4 mg/kg once a day omeprazole 8 horses, or control (given Karo Light corn syrup morning and evening) 6 horses.
2/8 horses in the phenylbutazone only group and 6/8 horses in the phenylbutazone plus omeprazole group showed clinical signs of intestinal complications: phenylbutazone only: 1 large colon impaction, 1 small colon impaction; phenylbutazone plus omeprazole: 1 large colon impaction, 1 small colon impaction, 1 colic of undermined cause, 1 diarrhoea, 1 cellulitis and necrotising typhlocolitis and secondary sepsis resulting in death, 1 ulcerative and necrohaemorrhagic enterocolitis with septic peritonitis, leading to euthanasia. At post mortem, the 2 horses that died while being given phenylbutazone plus omeprazole had intestinal inflammation, ulceration and necrosis.
ESGD scores did not change with treatment - phenylbutazone induces primarily EGGD, not ESGD.
Horses treated with phenylbutazone with omeprazole had improvements in EGGD scores.
Conclusions: Administration of omeprazole ameliorated PBZ-induced EGGD, but was associated with an increase in intestinal complications. Caution should be exercised when co-prescribing NSAIDs and omeprazole in horses.
The NOAH Compendium warns that:
"Gastrointestinal tract ulceration may be exacerbated by corticosteroids in animals given non-steroidal anti-inflammatory drugs."
Lees P, Toutain PL
Phenylbutazone in horses and man: Properties relevant to safety of humans consuming horse meat containing phenylbutazone and its metabolites
Equine Veterinary Education, 25: 545–549 (2013)
Phenylbutazone use in humans:
Rheumatology Secrets edited by Sterling G. West 2002 see p 562 onwards.
NOAH datasheet for Equipalazone (1g sachets)
Veterinary Medicines Directorate datasheet for Equipalazone (1g oral paste)
(VMD Product Information Database home page)
J Vet Pharmacol Ther. 1986 Mar;9(1):1-25 (PubMed)
Phenylbutazone in the horse: a review
Tobin T, Chay S, Kamerling S, Woods WE, Weckman TJ, Blake JW, Lees P
"Phenylbutazone is an acidic, lipophilic, non-steroidal anti-inflammatory drug (NSAID). It is extensively metabolized in the horse. The metabolites so far identified, oxyphenbutazone, gamma-hydroxyoxyphenbutazone, account for some 25-30% of administered dose over 24 h. The plasma half-life of phenylbutazone and termination of its pharmacological action are determined primarily by its rate of hepatic metabolism. Phenylbutazone acts by inhibiting the cyclooxygenase enzyme system, which is responsible for synthesis of prostanoids such as PGE2. It appears to act on prostaglandin-H synthase and prostacyclin synthase, after conversion by prostaglandin-H synthase to reactive intermediates. It markedly reduces prostanoid-dependent swelling, edema, erythema, and hypersensitivity to pain in inflamed tissues. Its principal use in the horse is for treatment of soft tissue inflammation. Phenylbutazone is highly bound (greater than 98%) to plasma protein. After i.v. injection, blood levels decline with an elimination half-life of 3-10 h. The plasma kinetics of phenylbutazone may be dose dependent, with the plasma half-life increasing as the drug dosage level increases. Plasma residues of the drug at 24 h after a single i.v. dose of 2 g/450 kg average about 0.9 microgram/ml, but considerable variation occurs. If dosing is repeated, the plasma residue accumulates to give mean residual blood levels of approximately 4.5 microgram/ml on Day 5 after 4 days of dosing. Approximately similar blood levels are found after a combination of oral and i.v. dosing. Experiments on large numbers of horses in training have been undertaken to ascertain the population distributions of residual blood levels after such dosing schedules. Absorption of phenylbutazone from the gastrointestinal tract is influenced by the dose administered and the relationship of dosing to feeding. Access to hay can delay the time of peak plasma concentration to 18 h or longer. Under optimal conditions, the bioavailability of oral phenylbutazone is probably in the region of 70%. Paste preparations may be more slowly absorbed than other preparations and yield higher residual plasma levels at 24 h after dosing, but further controlled studies are required. Phenylbutazone is easily detected in the plasma and urine of horses but concentrations in saliva are low. It is quantitated for forensic purposes by HPLC. The variability of this method between laboratories is about +/- 25%. Increasing urinary pH increases the urinary concentration of phenylbutazone and its metabolites up to 200-fold."
Side effects of Bute (Phenylbutazone) use
Phenylbutazone is associated with many serious side effects, including ulcers of the mouth, stomach and intestines, right dorsal colitis and kidney failure, when given in high doses, for a prolonged period or if the horse is dehydrated or has reduced blood volume. Some horses appear to be more sensitive to NSAID toxicity than others, and symptoms of toxicity can appear at lower than recommended doses (The Merck Veterinary Manual).
Adverse effects of NSAIDs - p 479 Equine Sports Medicine & Surgery, Hinchliff, Kaneps & Geor 2013
NSAIDs inhibit COX pathways and reduce prostaglandins, which have protective functions e.g. on blood flow.
The Equine Manual - Higgins & Snyder - Side effects and toxicity of NSAIDs p 267
Side effects of phenylbutazone use include anorexia, depression, colic, hypoproteinemia, diarrhoea, melena, gastrointestinal erosions and ulcers, weight loss, ventral/abdominal oedema, petechial haemorrhage of mucous membranes, renal papillary necrosis, hepatotoxicity, death. The daily maintenance dose should be no more than 4.4 mg/kg bw (2.2 g/day for a 500 kg horse).
Doctors Foster and Smith Pharmacy (2007) Patient Information Sheet Phenylbutazone
"Possible Side Effects
May see signs of oral or gastric ulcers. In adult horses these signs may include decreased appetite, weight loss, mild colic, poor performance, depression, lying down more than normal, diarrhea, accumulation of fluid under the belly, and anemia with signs of pale gums and weakness. In foals may also see teeth grinding, drooling, weakness, and nursing for only short periods of time. Effects related to the kidney may result in changes in drinking or urination habits."
Veterinary Pharmacology and Therapeutics - Riviere and Papich - Chapter 19 p 475
NSAID toxicosis in horses - The Merck Veterinary Manual
Nonsteroidal Anti-Inflammatory Drugs - The Merck Veterinary Manual
"All NSAIDs have the potential to induce adverse reactions, some of which can be life threatening."
"Horses may develop oral, lingual, or colonic ulceration with accompanying signs of colic, weight loss, and diarrhea."
Toxicity of NSAIDs - Mark Sharwood-Walker - Pegasus Health Jan 2013
Myths and Truths About Controlling Pain and Inflammation in Horses
Clinical Pharmacology - Cynthia Webster 2001
Adverse effects of phenylbutazone include bone marrow hypoplasia, hepatotoxicity, renal papillary necrosis, ulcers, thrombophlebitis, decreased iodine uptake, sodium and water retention.
Death may result from high doses of Phenylbutazone:
NB the dose give below was the equivalent of 5 g (or sachets) per day for a 500 kg horse:
Am J Vet Res. 1983 Dec;44(12):2277-9 (PubMed)
Effects of toxic doses of phenylbutazone in ponies
MacAllister CG
"Toxic doses of phenylbutazone (10 mg/kg of body weight) were administered to 10 ponies once daily for 14 days. Clinical signs of toxicosis similar to those seen in other species included CNS depression, anorexia, oral ulcers, and soft feces. Six ponies died in 7 to 20 days; 1 pony was euthanatized during an acute abdominal crisis; and 3 ponies survived the study. At necropsy, the major lesions were oral and gastrointestinal ulcerations and renal changes."
Vet Rec. 1979 Jul 14;105(2):26-30 (PubMed)
Phenylbutazone toxicity in ponies
Snow DH, Bogan JA, Douglas TA, Thompson H
7 out of 8 ponies given 10 mg/kg phenylbutazone orally for 7 to 14 days resulted in clinical signs of toxicity - anorexia, depression, abdominal oedema (water retention). Blood tests showed reduced total protein, reduced calcium and increased urea. 3/8 ponies died from oedema in the large intestine. The ponies all had mouth ulcers.
1 out of 2 ponies given 4 mg/kg phenylbutazone by IV injection for 7 days showed a significant decrease in plasma total protein concentration.
J Am Vet Med Assoc. 1984 Mar 15;184(6):699-703 (PubMed)
Phenylbutazone toxicosis in the horse: a clinical study
Collins LG, Tyler DE
"In a retrospective study of 269 horses that had been treated with phenylbutazone, horses receiving less than or equal to 8.8 mg/kg of body weight/day for less than or equal to 4 days or 2 to 4 mg/kg of body weight/day for up to 50 days remained clinically normal. Anorexia, depression, colic, hypoproteinemia, diarrhea, melena, weight loss, ventral edema, petechial hemorrhages of mucous membranes, oral and gastrointestinal tract erosions and ulcers, renal papillary necrosis, and death were among the complications seen in horses that had received greater than 8.8 mg/kg of body weight/day. In 2 cases, signs suggestive of gastrointestinal-related shock were also evident."
Ponies may be at higher risk of Phenylbutazone toxicity than horses:
Am J Vet Res. 1981 Oct;42(10):1754-9
Phenylbutazone toxicosis in equidae: a biochemical and pathophysiological study
Snow DH, Douglas TA, Thompson H, Parkins JJ, Holmes PH
At dosages of 10 - 12 mg/kg bw for 8 - 10 days, ponies frequently developed clinical signs of toxicosis characterized by hypoproteinemia, protein-losing gastroenteropathy and gastrointestinal ulceration.
Thoroughbred horses given 8.2 mg/kg bw for 13 days appears to be less susceptible to phenylbutazone toxicity, but 4/6 showed a degree of hypoproteinemia.
Young horses, old horses, horses that are systemically ill and/or dehydrated may also be predisposed to the toxic effects of NSAIDs.
NSAIDs commonly cause gastrointestinal ulceration - in the glandular part of the stomach and in both the small and large intestine.
Giving NSAIDs, and Phenylbutazone in particular, by mouth can cause mouth ulcers and ulcers of the oesophagus - "clinical signs of NSAID toxicity include difficulty in mastication due to oral and lingual ulceration, hypersalivation, and signs of pain when swallowing due to esophageal ulceration" - NSAID toxicosis in horses - The Merck Veterinary Manual.
Phenylbutazone binds to hay, and this may result in large concentrations reaching the caecum and colon, where it might damage the gut walls.
Gastrointestinal ulceration may lead to anaemia and low plasma protein levels.
Phenylbutazone may directly injure the blood supply to the intestines.
(Source: Adverse effects of NSAIDs - p 479 Equine Sports Medicine & Surgery, Hinchliff, Kaneps & Geor 2013)
Vet Ther. 2009 Fall;10(3):113-20.
Effects of Top-Dress Formulations of Suxibuzone and Phenylbutazone on Development of Gastric Ulcers in Horses
Andrews FM, Reinemeyer CR, Longhofer SL
This research found no difference in gastric ulcer numbers or severity between horses treated with the recommended dose of phenylbutazone, suxibuzone or nothing for 15 days, when examined by endoscopy - the gastric ulcers found were considered to "be expected with traditional stabling and intermittent feeding patterns". "Phenylbutazone treated horses did not have more severe gastric ulcers than suxibuzone treated horses, indicating that Suxibuzone does not appear to offer an advantage over Phenylbutazone in preventing gastric ulcers when used at recommended label doses. However, ulcers in other regions of the gastrointestinal tract (e.g., right dorsal colon, duodenum) were not evaluated in horses in this study."
Res Vet Sci. 2004 Apr;76(2):145-9
Lower gastric ulcerogenic effect of suxibuzone compared to phenylbutazone when administered orally to horses
Monreal L, Sabaté D, Segura D, Mayós I, Homedes J
5 horses received a high dose of phenylbutazone, 5 received an equivalent dose of saxibuzone, and 5 received a placebo, for 2 weeks. Post mortems on day 18 showed:
1 horse treated with phenylbutazone had clinical signs of NSAID toxicosis.
2 other horses treated with phenylbutazone had small oral ulcers.
Ulcers in the stomach's glandular mucosa were seen in all horses treated with phenylbutazone.
2 horses treated with saxibuzone had small oral ulcers.
2 horses treated with saxibuzone had ulcers in the stomach's glandular mucosa.
Phenylbutazone treated horses had a significant higher ulcerated area, and gastric ulcers were significantly deeper than those in the suxibuzone and placebo groups.
Blood parameters were not statistically different between groups, and no other lesions were found in any tissue.
Conclusion: Suxibuzone causes significantly lower gastric ulcerogenic effect than phenylbutazone when administered orally at equimolecular doses in horses."
The NOAH Compendium warns that:
"Gastrointestinal tract ulceration may be exacerbated by corticosteroids in animals given non-steroidal anti-inflammatory drugs."
Phenylbutazone may compromise gastric mucosal integrity:
J Vet Intern Med. 2012 Nov-Dec;26(6):1494-9
Effects of meloxicam and phenylbutazone on equine gastric mucosal permeability
D'Arcy-Moskwa E, Noble GK, Weston LA, Boston R, Raidal SL
Horses receiving phenylbutazone at 4.4 mg/kg PO q12h day 1, 2.2 mg/kg PO q12h for 4 days, 2.2 mg/kg PO q24h for 9 days had significantly increased gastric permeability to sucrose, evidenced by increased peak serum sucrose concentrations (280-1,580 pg/μL, P = .001) after treatment. "These results suggest that PBZ was associated with greater compromise to gastric mucosal integrity than meloxicam."
Phenylbutazone may cause right dorsal colitis:
Davis JL
Nonsteroidal anti-inflammatory drug associated right dorsal colitis in the horse
Equine Veterinary Education published online 08 Sept 2015
American Journal of Veterinary Research November 2008, Vol. 69, No. 11, Pages 1496-1505
Pathophysiologic effects of phenylbutazone on the right dorsal colon in horses
McConnico RS, Morgan TW, Williams CC, Hubert JD, Moore RM
12 healthy horses were given 8.8 mg/kg bw Phenylbutazone orally for 21 days. 2 horses developed colitis. Prolonged Phenylbutazone administration caused hypoalbuminemia, neutropenia, increased right dorsal colon arterial blood flow, and reduced VFA production. The authors recommended that vets should monitor serum albumin concentrations and neutrophil counts and be extremely cautious when making dosing recommendations for phenylbutazone treatment because of the extreme variability in tolerance within horses. Blood should be tested as early as 3 to 5 days after starting treatment, and the dose should be decreased as soon as possible.
J Vet Intern Med. 1990 Sep-Oct;4(5):247-53
Right dorsal colitis
Karcher LF, Dill SG, Anderson WI, King JM
"Moderate to severe ulcerative colitis of the right dorsal colon was diagnosed by necropsy or by exploratory celiotomy and biopsy in 13 horses with a primary clinical complaint of either colic, diarrhea, or weight loss. Clinical signs varied from acute fulminating diarrhea (possibly with fever), colic, dehydration, endotoxic shock and death, to a chronic condition manifested by mild intermittent colic up to several months in duration, and weight loss with or without mild diarrhea. In a large percentage of the horses, those affected had been hypovolemic and received nonsteroidal anti-inflammatory drugs (NSAID) or had received inappropriately high doses of phenylbutazone before the onset of illness. Experimental treatment of two horses with high doses of a phenylbutazone oral paste preparation (6 gm once daily for 5 days) and limitation of their water intake to approximately one half of maintenance requirement (for 5 days) resulted in reproduction of ulcerative colitis involving only the right dorsal colon, which was apparent at necropsy examination 11 and 15 days after initiation of drug use. It was concluded that localized ulcerative lesions in the right dorsal colon may be a previously unreported manifestation of toxicity due to the administration of NSAID."
NSAIDS may cause renal failure:
NSAIDS can cause acute renal failure when high doses are given or the horse is dehydrated.
Renal failure in horses: What can we do? (Proceedings)
Harold Schott II Aug 2009 CVC in Kansas City proceedings
NSAIDs should not be given concurrently with drugs or substances that may be nephrotoxic (toxic to the kidneys). Nephrotoxic substances include:
Aminoglycoside antibiotics, e.g. streptomycin, gentamicin - Aminoglycosides, The Merck Veterinary Manual
Tetracycline antibiotics, e.g. oxytetracycline - Tetracyclines, The Merck Veterinary Manual
Heavy metals, e.g. arsenic, mercury
Vitamins D or K3
Plants such as onions, red maple leaves, acorns.
Phenylbutazone may be toxic to the liver:
Cholestatic and parenchymal hepatoxicity have been related to phenylbutazone use. NSAIDs are extensively metabolized in the liver, and drug-induced damage to the liver can lead to cumulation and further toxicity. (Source The Equine Manual - Higgins & Snyder - Side effects and toxicity of NSAIDs p 267).
In humans, NSAIDs are predominantly cleared by hepatic metabolism. Elevation of liver enzymes, especially AST and ALT, can occur with all NSAIDs. Idiosyncratic severe hepatitis has been reported with phenylbutazone use. Source: Rheumatology Secrets edited by Sterling G. West 2002.
NSAIDs may exacerbate bleeding:
Although not frequently observed, NSAIDs impair platelet adhesion and can lead to or exacerbate bleeding. Source: Adverse effects of NSAIDs - p 479 Equine Sports Medicine & Surgery, Hinchliff, Kaneps & Geor 2013
Phenylbutazone may cause aplastic anaemia:
Phenylbutazone toxicity may cause bone marrow suppression.
"Phenylbutazone and chloramphenicol have been reported as causes of aplasia" - Liphook Equine Hospital - Investigating Anaemia
"Aplastic anemia is also sometimes associated with ... the use of certain drugs, including ... phenylbutazone" - Wikipedia - Aplastic anemia
"Phenylbutazone has been incriminated as a cause of aplastic anemia" - Schalm's Veterinary Hematology Sixth Edition edited by DJ Weiss & KJ Wardrop citing
Dunavan ML, Murray ES
Clinical evidence of phenylbutazone induced hypoplastic anemia
In Proceeding of the International Symposium of Equine Hematology, AAEP 1:282-285 1975
NSAIDs may impair bone, tendon and ligament healing:
NSAIDs Help Pain But Not Bone Healing - S Oke - www.thehorse.com 2010
"NSAIDs, when given at high doses and for long durations, negatively impact bone healing."
Vet Comp Orthop Traumatol. 2010;23(6):385-92
Non-steroidal anti-inflammatory drugs inhibit bone healing: a review
Barry S
Am J Vet Res. 2000 May;61(5):537-43
Effects of phenylbutazone on bone activity and formation in horses
Rohde C, Anderson DE, Bertone AL, Weisbrode SE
"PBZ (phenylbutazone) decreased MAR (mineral apposition rate) in cortical bone and appeared to decrease healing rate of cortical defects in horses."
Inflamm Res. 2005 Sep;54(9):358-66 (PubMed)
Effects of cyclooxygenase inhibition on bone, tendon, and ligament healing
Radi ZA, Khan NK
"we provide a critical review of available data on the role of PGs and the effect of COX inhibitors on bone, tendon, and ligament repair. Collectively, this assessment suggests potential involvement of PGs in the healing process of these tissues via modulation by non-selective NSAIDs and selective COX-2 inhibitors."
Phenylbutazone may cause joint collagen loss during treatment (at 1 g 2 x day (500 kg horse)).
Vet J. 2014 Jul;201(1):51-6
In vivo effects of phenylbutazone on inflammation and cartilage-derived biomarkers in equine joints with acute synovitis
de Grauw JC, van Loon JP, van de Lest CH, Brunott A, van Weeren PR
"Although PBZ is clinically effective in treating acute synovitis, it does not limit inflammation-induced cartilage catabolism and may transiently reduce collagen anabolism as evidenced by SF markers."
Am J Vet Res. 2001 Dec;62(12):1916-21 (PubMed)
Effects of oral administration of phenylbutazone to horses on in vitro articular cartilage metabolism
Beluche LA, Bertone AL, Anderson DE, Rohde C
"Oral administration of phenylbutazone for 14 days significantly decreased proteoglycan synthesis in articular culture explants from healthy horses to a degree similar to that induced by in vitro exposure to IL-1beta. Phenylbutazone should be used judiciously in athletic horses with osteoarthritis, because chronic administration may suppress proteoglycan synthesis and potentiate cartilage damage."
Phenylbutazone may have a negative effect on wound healing:
Veterinary Pharmacology and Therapeutics - Riviere and Papich p 480 - one conference report suggested a negative effect of phenylbutazone on wound healing in the horse.
"Though most NSAID are thought to be safe in wound healing, recent work suggests that agents selective for COX-2 inhibition may slow wound healing." - The Merck Veterinary Manual - Factors that interfere with wound healing.
Phenylbutazone affects thyroid hormones:
Phenylbutazone decreases T4 thyroid hormone levels:
Sojka JE, Johnson MA, Bottoms GD
Serum triiodothyronine, total thyroxine, and free thyroxine concentrations in horses
Am J Vet Res. 1993 Jan;54(1):52-5
"Phenylbutazone given at a dosage of 4.4 mg/kg every 24 hours, for 7 days did significantly decrease resting T4 and fT4 concentrations, but did not significantly affect T3 concentrations in horses."
The Equine Manual - Higgins & Snyder 2013 p 652 Phenylbutazone is highly protein bound and can displace thyroid hormone from carrier proteins, leading to increased amounts of free thyroid hormone and consequent inhibition of the hypothalamus-pituitary-thyroid axis.
Phenylbutazone and pregnancy
NSAIDs and Pregnancy - Trisha Dowling, thehorse.com, December 2006
Phenylbutazone may be more toxic than other NSAIDs:
J Am Vet Med Assoc. 1993 Jan 1;202 (1):71-7
Comparison of adverse effects of phenylbutazone, flunixin meglumine, and ketoprofen in horses
MacAllister CG, Morgan SJ, Borne AT, Pollet R
Danilon (suxibuzone) may be a reasonable alternative to phenylbutazone:
Res Vet Sci. 2004 Apr;76(2):145-9
Lower gastric ulcerogenic effect of suxibuzone compared to phenylbutazone when administered orally to horses
Monreal L, Sabaté D, Segura D, Mayós I, Homedes J
"SBZ causes significantly lower gastric ulcerogenic effect than PBZ when administered orally at equimolecular doses in horses."
Equine Vet J. 2009 Sep;41(7):700-5
Multicentre, controlled, randomised and blinded field study comparing efficacy of suxibuzone and phenylbutazone in lame horses
Sabaté D, Homedes J, Salichs M, Sust M, Monreal L
Danilon has been shown to have a lower gastric ulcerogenic effect that Bute. In this research, Danilon and Bute showed no significant differences in alleviating lameness in horses, but Danilon was eaten more readily by horses when mixed into feed. The research concluded that Danilon is a good therapeutic alternative to Bute.
However, this research found no difference in gastric ulcer numbers or severity between horses treated with the recommended dose of phenylbutazone, suxibuzone or nothing for 15 days, when examined by endoscopy:
Vet Ther. 2009 Fall;10(3):113-20
Effects of Top-Dress Formulations of Suxibuzone and Phenylbutazone on Development of Gastric Ulcers in Horses
Andrews FM, Reinemeyer CR, Longhofer SL
"Phenylbutazone treated horses did not have more severe gastric ulcers than suxibuzone treated horses, indicating that Suxibuzone does not appear to offer an advantage over Phenylbutazone in preventing gastric ulcers when used at recommended label doses."
Phenylbutazone should not be used in combination with other NSAIDs:
Flood J, Stewart AJ.
Non-Steroidal Anti-Inflammatory Drugs and Associated Toxicities in Horses.
Animals (Basel). 2022 Oct 26;12(21):2939. doi: 10.3390/ani12212939. PMID: 36359062; PMCID: PMC9655344. Open Access.
"Only one NSAID should be administered at one time, as co-administration of NSAIDs (known as ‘stacking’) has an additive effect and may pre-dispose horses to adverse events without any additional analgesic benefit."
Am J Vet Res. 2006 Mar;67(3):398-402
Effects of phenylbutazone alone or in combination with flunixin meglumine on blood protein concentrations in horses
Reed SK, Messer NT, Tessman RK, Keegan KG
Am J Vet Res. 2008 Feb;69(2):167-73
Effectiveness of administration of phenylbutazone alone or concurrent administration of phenylbutazone and flunixin meglumine to alleviate lameness in horses
Keegan KG, Messer NT, Reed SK, Wilson DA, Kramer J
"One horse administered the combination NSAID regimen died of acute necrotizing colitis during the study/"
Phenylbutazone interactions with other medicines:
Omeprazole and Sucralfate have been used at the same time as NSAIDs including phenylbutazone with the aim of reducing the risk of gastric ulcers. Recent research has suggested concurrent use of these medicines might increase other intestinal complications, and until more research has been carried out, caution should be exercised.
Flood J, Stewart AJ.
Non-Steroidal Anti-Inflammatory Drugs and Associated Toxicities in Horses.
Animals (Basel). 2022 Oct 26;12(21):2939. doi: 10.3390/ani12212939. PMID: 36359062; PMCID: PMC9655344.
Citing Bishop et al. 2021 (below) this paper suggests that horses treated with sucralfate at the same time as NSAIDS had a significant increase in right dorsal colon wall thickness, whereas horses treated with omeprazole at the same time as NSAIDs had no changes to right dorsal colon wall thickness, and concludes that further research is needed on drug interactions between sucralfate and omeprazole given at the same time as NSAIDs.
Bishop RC, Kemper AM, Wilkins PA, McCoy AM.
Effect of omeprazole and sucralfate on gastrointestinal injury in a fasting/NSAID model.
Equine Vet J. 2021 Oct 31. doi: 10.1111/evj.13534. Epub ahead of print. PMID: 34719063.
See also:
Comparison of Omeprazole and Sucralfate in Equine Gastric Disease - University of Illinois February 2022
When 14 healthy horses received either omeprazole or sucralfate during a protocol of fasting and flunuxin (NSAID) administration to induce gastric ulcers, equine squamous gastric disease (ESGD) developed or worsened with both treatments. Horses treated with omeprazole had lower ESGD and EGGD scores than horses treated with sucralfate. Horses receiving sucralfate at the same time as flunixin were significantly more likely to have increased right dorsal colon wall thickness, than horses receiving omeprazole. The research concludes that giving sucralfate at the same time as flunixin may be associated with increased risk of large intestinal complications, or perhaps that omepgrazole gives a protective effect against NSAID-associated colitis (a control group with no protective treatment was not used), and that further research is warranted.
Ricord M, Andrews FM, Yñiguez FJM, Keowen M, Garza F Jr, Paul L, Chapman A, Banse HE.
Impact of concurrent treatment with omeprazole on phenylbutazone-induced equine gastric ulcer syndrome (EGUS).
Equine Vet J. 2021 Mar;53(2):356-363. doi: 10.1111/evj.13323. Epub 2020 Aug 18. PMID: 32697849.
22 horses with equine glandular gastric disease (EGGD) and equine squamous gastric disease (ESGD) scores less than or equal to 2 were treated for 7 to 14 days with either phenylbutazone (2.2 grams morning and evening for a 500 kg horse) 8 horses, the same dose of phenylbutazone plus 4 mg/kg once a day omeprazole 8 horses, or control (given Karo Light corn syrup morning and evening) 6 horses.
2/8 horses in the phenylbutazone only group and 6/8 horses in the phenylbutazone plus omeprazole group showed clinical signs of intestinal complications: phenylbutazone only: 1 large colon impaction, 1 small colon impaction; phenylbutazone plus omeprazole: 1 large colon impaction, 1 small colon impaction, 1 colic of undermined cause, 1 diarrhoea, 1 cellulitis and necrotising typhlocolitis and secondary sepsis resulting in death, 1 ulcerative and necrohaemorrhagic enterocolitis with septic peritonitis, leading to euthanasia. At post mortem, the 2 horses that died while being given phenylbutazone plus omeprazole had intestinal inflammation, ulceration and necrosis.
ESGD scores did not change with treatment - phenylbutazone induces primarily EGGD, not ESGD.
Horses treated with phenylbutazone with omeprazole had improvements in EGGD scores.
Conclusions: Administration of omeprazole ameliorated PBZ-induced EGGD, but was associated with an increase in intestinal complications. Caution should be exercised when co-prescribing NSAIDs and omeprazole in horses.
The NOAH Compendium warns that:
"Gastrointestinal tract ulceration may be exacerbated by corticosteroids in animals given non-steroidal anti-inflammatory drugs."
Lees P, Toutain PL
Phenylbutazone in horses and man: Properties relevant to safety of humans consuming horse meat containing phenylbutazone and its metabolites
Equine Veterinary Education, 25: 545–549 (2013)
Phenylbutazone use in humans:
Rheumatology Secrets edited by Sterling G. West 2002 see p 562 onwards.
Physical therapy
Physical therapy is an important part of laminitis rehabilitation, particularly when horses have had long-term chronic laminitis. Therapies may include physiotherapy, TTouch, massage, stretching and once able, returning to exercise.
TTouch for laminitics - Danielle Dibbens/The Laminitis Site
Foreleg Stretches for Navicular Rehab and Toe Loading - Ute Miethe
Using front leg stretches to guide lowering the heels/palmar angle
Some trimmers suggest that stretching the forelegs forward to check for flexibility can help indicate whether a horse is ready to have high heels lowered (on club feet or following laminitis with a high palmar angle). With the horse ideally warmed up (e.g. after a period of walk or trot if able), stand in front of the horse and gently ask the horse to bring a front foot forward, lifting the leg with your hands behind the knee or lower leg and sliding your hands down the leg to hold the leg at the foot (without particularly pulling the leg forward or forcing the horse to straighten the knee). Offer the horse the opportunity to stretch the leg forward and straighten the knee/leg. If the horse does not want to stretch he will keep the knee bent and pull back away from you/the stretch. You can also try placing the front foot on a hoof stand if that is easier for you and/or your horse.
If the horse is happy to stretch the leg forwards and straighten the knee, the heels/palmar angle can probably be lowered carefully (several small trims may be required). If the horse does not want to stretch/straighten the knee, be cautious about lowering the heel - lower the heels no lower than the existing sole plane (not the live/ideal sole plane), and bring breakover back as much as possible to help the horse to swing through the stride and stretch the legs out when moving.
Physical therapy is an important part of laminitis rehabilitation, particularly when horses have had long-term chronic laminitis. Therapies may include physiotherapy, TTouch, massage, stretching and once able, returning to exercise.
TTouch for laminitics - Danielle Dibbens/The Laminitis Site
Foreleg Stretches for Navicular Rehab and Toe Loading - Ute Miethe
Using front leg stretches to guide lowering the heels/palmar angle
Some trimmers suggest that stretching the forelegs forward to check for flexibility can help indicate whether a horse is ready to have high heels lowered (on club feet or following laminitis with a high palmar angle). With the horse ideally warmed up (e.g. after a period of walk or trot if able), stand in front of the horse and gently ask the horse to bring a front foot forward, lifting the leg with your hands behind the knee or lower leg and sliding your hands down the leg to hold the leg at the foot (without particularly pulling the leg forward or forcing the horse to straighten the knee). Offer the horse the opportunity to stretch the leg forward and straighten the knee/leg. If the horse does not want to stretch he will keep the knee bent and pull back away from you/the stretch. You can also try placing the front foot on a hoof stand if that is easier for you and/or your horse.
If the horse is happy to stretch the leg forwards and straighten the knee, the heels/palmar angle can probably be lowered carefully (several small trims may be required). If the horse does not want to stretch/straighten the knee, be cautious about lowering the heel - lower the heels no lower than the existing sole plane (not the live/ideal sole plane), and bring breakover back as much as possible to help the horse to swing through the stride and stretch the legs out when moving.
Pioglitazone
Pioglitazone is a thiazolidinedione drug which is used to improve insulin sensitivity and increase total and HMW adiponectin in humans.
Legere R, Taylor DR, Bello K, Parker C, Judd RL, Wooldridge AA
Short-Term Pioglitazone in Equids Increases High Molecular Weight Adiponectin Concentrations and Decreases Insulin Response to Oral Sugar
ECEIM 2018/ACVIM 2018
Horses and ponies, some considered healthy and some considered to have insulin dysregulation (ID) if their OST insulin > 65 uIU/ml at 60 mins, were treated with 2 mg/kg Pioglitazone by mouth once daily for 28 days. Serum HMW adiponectin was measured on days 0, 14 and 28, and OSTs carried out on days 0 and 28. Insulin at 90 and 120 minutes (but not 60 minutes?) was lower in normal ponies and ID equids after Pioglitazone treatment, but there was no significant difference in horses. HMW adiponectin was significantly higher after treatment in all groups.
However, controls were not used and time of year is not given (according to the poster) - could time of year or management changes explain the differences seen?
Wearn JM, Crisman MV, Davis JL, Geor RJ, Hodgson DR, Suagee JK, Ashraf-Khorassani M, McCutcheon LJ
Pharmacokinetics of pioglitazone after multiple oral dose administration in horses
J Vet Pharmacol Ther. 2011 Jun;34(3):252-8. doi: 10.1111/j.1365-2885.2010.01217.x. PMID: 21492190 (Full paper: DeepDyve)
Healthy horses were given 1 mg/kg pioglitazone hydrochloride once a day for 11 days. Apparent elimination half-life was over 9 hours. "This study showed that in healthy horses, pioglitazone administered at a daily oral dose of 1 mg/kg results in plasma concentrations and total drug exposure approximating, but slightly below, those considered therapeutic in humans."
Pioglitazone is a thiazolidinedione drug which is used to improve insulin sensitivity and increase total and HMW adiponectin in humans.
Legere R, Taylor DR, Bello K, Parker C, Judd RL, Wooldridge AA
Short-Term Pioglitazone in Equids Increases High Molecular Weight Adiponectin Concentrations and Decreases Insulin Response to Oral Sugar
ECEIM 2018/ACVIM 2018
Horses and ponies, some considered healthy and some considered to have insulin dysregulation (ID) if their OST insulin > 65 uIU/ml at 60 mins, were treated with 2 mg/kg Pioglitazone by mouth once daily for 28 days. Serum HMW adiponectin was measured on days 0, 14 and 28, and OSTs carried out on days 0 and 28. Insulin at 90 and 120 minutes (but not 60 minutes?) was lower in normal ponies and ID equids after Pioglitazone treatment, but there was no significant difference in horses. HMW adiponectin was significantly higher after treatment in all groups.
However, controls were not used and time of year is not given (according to the poster) - could time of year or management changes explain the differences seen?
Wearn JM, Crisman MV, Davis JL, Geor RJ, Hodgson DR, Suagee JK, Ashraf-Khorassani M, McCutcheon LJ
Pharmacokinetics of pioglitazone after multiple oral dose administration in horses
J Vet Pharmacol Ther. 2011 Jun;34(3):252-8. doi: 10.1111/j.1365-2885.2010.01217.x. PMID: 21492190 (Full paper: DeepDyve)
Healthy horses were given 1 mg/kg pioglitazone hydrochloride once a day for 11 days. Apparent elimination half-life was over 9 hours. "This study showed that in healthy horses, pioglitazone administered at a daily oral dose of 1 mg/kg results in plasma concentrations and total drug exposure approximating, but slightly below, those considered therapeutic in humans."
Pituitary gland
See also Hypothalamus/Hypothalamic-Pituitary Gland Axis
The pituitary gland (or hypophysis), often called the master gland, lies directly beneath the hypothalamus at the base of the brain and consists of two distinct parts:
1. the anterior pituitary or adenohypophysis, a fleshy lobe consisting of endocrine cells - the secretion of anterior pituitary hormones is controlled by releasing and inhibiting factors secreted by neurons in the hypothalamus. The anterior pituitary is composed of:
2. the posterior pituitary or neurohypophysis or pars nervosa - an extension of the hypothalamus consisting of neural tissue. Stores and releases arginine vasopressin (anti-diuretic hormone) and oxytocin, under the control of neurons in the hypothalamus.
For an explanation of the normal equine hypothalamic-pituitary-adrenal axis, see p2 onwards:
Effects of PPID, season, and pasture diet on blood ACTH and metabolite concentrations in horses - Sarah Elliott 2010
For an introduction to the physiology of the pituitary gland and its functions in humans, see:
The hypothalamus and pituitary gland - Colorado State University
Pease AP, Schott HC 2nd, Howey EB, Patterson JS
Computed tomographic findings in the pituitary gland and brain of horses with pituitary pars intermedia dysfunction
J Vet Intern Med. 2011 Sep-Oct;25(5):1144-51 (PubMed)
"On initial examination, pituitary glands of PPID-affected horses were larger in height (P < .01) and width (P < .01) than controls, but the difference in length was not significant (P = .06). After 6 months of pergolide treatment of PPID-affected horses, pituitary gland length increased (P < .05), but height and width were not different from pretreatment values."
"CT is a useful imaging modality to determine pituitary gland size of PPID-affected horses,and CT measurements are similar to gross pathologic measurements."
Keenan DM, Alexander S, Irvine C, Veldhuis JD
Quantifying Nonlinear Interactions within the Hypothalamo-Pituitary-Adrenal Axis in the Conscious Horse
Endocrinology. Apr 2009; 150(4): 1941–1951
van der Kolk JH, Heinrichs M, van Amerongen JD, Stooker RC, in de Wal LJ, van den Ingh TS
Evaluation of pituitary gland anatomy and histopathologic findings in clinically normal horses and horses and ponies with pituitary pars intermedia adenoma
Am J Vet Res. 2004 Dec;65(12):1701-7. (PubMed)
Brain Research Bulletin Volume 54, Issue 6, April 2001, Pages 587–593
The mammalian pituitary intermediate lobe: an update on innervation and regulation
Salanda LC
Okada T, Shimomuro T, Oikawa M, Nambo Y, Kiso Y, Morikawa Y, Liptrap RM, Yamashiro S, Little PB, Sasaki F
Immunocytochemical localization of adrenocorticotropic hormone-immunoreactive cells of the pars intermedia in thoroughbreds
Am J Vet Res. 1997 Aug;58(8):920-4 (PubMed)
The pituitary gland (or hypophysis), often called the master gland, lies directly beneath the hypothalamus at the base of the brain and consists of two distinct parts:
1. the anterior pituitary or adenohypophysis, a fleshy lobe consisting of endocrine cells - the secretion of anterior pituitary hormones is controlled by releasing and inhibiting factors secreted by neurons in the hypothalamus. The anterior pituitary is composed of:
- pars distalis - produces, stores and secretes hormones including growth hormone (GH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), thyroid-stimulating hormone (TSH), prolactin, beta-endorphin and adrenocorticotropic hormone (ACTH).
- pars intermedia - consists only of melanotrope cells which produce POMC derived peptides including ACTH, alpha-MSH, beta-MSH, CLIP and beta-endorphin under the inhibitory control of dopamine from the periventricular nucleus of the hypothalamus.
- pars tuberalis - dense in melatonin receptors which read daily melatonin concentrations to control the seasonal output of reproductive hormones.
2. the posterior pituitary or neurohypophysis or pars nervosa - an extension of the hypothalamus consisting of neural tissue. Stores and releases arginine vasopressin (anti-diuretic hormone) and oxytocin, under the control of neurons in the hypothalamus.
For an explanation of the normal equine hypothalamic-pituitary-adrenal axis, see p2 onwards:
Effects of PPID, season, and pasture diet on blood ACTH and metabolite concentrations in horses - Sarah Elliott 2010
For an introduction to the physiology of the pituitary gland and its functions in humans, see:
The hypothalamus and pituitary gland - Colorado State University
Pease AP, Schott HC 2nd, Howey EB, Patterson JS
Computed tomographic findings in the pituitary gland and brain of horses with pituitary pars intermedia dysfunction
J Vet Intern Med. 2011 Sep-Oct;25(5):1144-51 (PubMed)
"On initial examination, pituitary glands of PPID-affected horses were larger in height (P < .01) and width (P < .01) than controls, but the difference in length was not significant (P = .06). After 6 months of pergolide treatment of PPID-affected horses, pituitary gland length increased (P < .05), but height and width were not different from pretreatment values."
"CT is a useful imaging modality to determine pituitary gland size of PPID-affected horses,and CT measurements are similar to gross pathologic measurements."
Keenan DM, Alexander S, Irvine C, Veldhuis JD
Quantifying Nonlinear Interactions within the Hypothalamo-Pituitary-Adrenal Axis in the Conscious Horse
Endocrinology. Apr 2009; 150(4): 1941–1951
van der Kolk JH, Heinrichs M, van Amerongen JD, Stooker RC, in de Wal LJ, van den Ingh TS
Evaluation of pituitary gland anatomy and histopathologic findings in clinically normal horses and horses and ponies with pituitary pars intermedia adenoma
Am J Vet Res. 2004 Dec;65(12):1701-7. (PubMed)
Brain Research Bulletin Volume 54, Issue 6, April 2001, Pages 587–593
The mammalian pituitary intermediate lobe: an update on innervation and regulation
Salanda LC
Okada T, Shimomuro T, Oikawa M, Nambo Y, Kiso Y, Morikawa Y, Liptrap RM, Yamashiro S, Little PB, Sasaki F
Immunocytochemical localization of adrenocorticotropic hormone-immunoreactive cells of the pars intermedia in thoroughbreds
Am J Vet Res. 1997 Aug;58(8):920-4 (PubMed)
Platelet-Rich Plasma (PRP)
Carmona JU, Gómez WA, López C
Could Platelet-Rich Plasma Be a Clinical Treatment for Horses With Laminitis?
JEVS February 2018 Vol 61, Pages 46–57
Carmona JU, Gómez WA, López C
Could Platelet-Rich Plasma Be a Clinical Treatment for Horses With Laminitis?
JEVS February 2018 Vol 61, Pages 46–57
POMC - proopiomelanocortin
POMC is a hormone precursor protein produced by the pars distalis and the pars intermedia (in the pituitary gland).
In the corticotropes of the pars distalis, the majority of POMC is converted to ACTH, and also beta-lipotropic hormone, gamma-lipotropic hormone and beta-endorphin. In the melanotropes of the pars intermedia, POMC is converted to melanocyte-stimulating hormones (including α-MSH), β-endorphin, CLIP, ACTH and beta-lipotropic hormone. ACTH production in the pars intermedia is minimal in the healthy horse.
Dopamine inhibits the release of POMC derived peptides in a healthy horse, therefore the reduction in dopamine in horses with PPID leads to increased levels of these hormones.
Alpha-MSH plays a role in metabolism, obesity, inflammation, stress. It has broad anti-inflammatory effects, including decreased production of cytokines. It causes an anorexic response and feeling of satiety. It impairs neutrophil function (including oxidative burst, chemotaxis, adhesion).
Beta-endorphin is a potent endogenous opiod receptor agonist with roles in analgesia and reduction of pain-associated inflammation.
CLIP "is the cleavage product generated from the c-terminal portion of ACTH". We do not know much about CLIP, it is cleaved into Beta-cell tropin, and both CLIP and Beta-cell tropin have been shown to stimulate the release of insulin from rat pancreas cells.
Carmalt JL, Mortazavi S, McOnie RC, Allen AL, Unniappan S
Profiles of proopiomelanocortin and encoded peptides, and their processing enzymes in equine pituitary pars intermedia dysfunction
PLoS ONE Jan 2018 13(1): e0190796. https://doi.org/10.1371/journal
PPID is characterized by hyperplasia of the pars intermedia melanotrophs of the pituitary gland, and increased production of POMC. POMC is cleaved (divided) by PC1 (prohormone convertase 1) to produce ACTH. ACTH is cleaved by PC2 to produce alpha-MSH and CLIP.
This study found that PC1 and PC2 are upregulated (increased) in the pituitary gland of horses with PPID, that POMC mRNA expression is elevated, and that abnormally high POMC derived hormones are released into the blood from the pituitary gland in horses with PPID. The "results conclude a defect in ACTH precursor and its processing enzymes in PPID."
McFarlane D
Review of Current Understanding of Pituitary Pars Intermedia Dysfunction
AAEP 2013
Vet Clin North Am Equine Pract. 2011 Apr;27(1):1-17
Hypothalamic-pituitary gland axis function and dysfunction in horses
Hurcombe SD
Br Vet J. 1993 Mar-Apr;149(2):139-53 (PubMed)
Equine Cushing's disease
Love S
"In the horse, adenomata of the pairs intermedia of the pituitary gland have been associated with the distinct clinical entity of Cushing's disease which arises largely as a result of excessive secretion of adrenocorticotropin (ACTH) or other proopiomelanocortin (POMC) peptides. Pars intermedia peptide secretion is under dopaminergic control and compounds such as pergolide or bromocriptine, which are dopamine agonists, can palliate the clinical signs. A variety of endocrinological abnormalities, relevant to both pathogenesis and diagnosis, may be demonstrated in equine Cushing's disease, including hyperadrenocorticism, peripheral insulin resistance and excessive POMC-peptide secretion from the pituitary gland. Preliminary studies on carbohydrate metabolism suggest that quantification of insulin activity may be a useful prognostic index in cases of equine Cushing's disease, and that insulin therapy of secondary diabetes mellitus may be indicated in some cases."
Wilson MG, Nicholson WE, Holscher MA, Sherrell BJ, Mount CD, Orth DN
Proopiolipomelanocortin peptides in normal pituitary, pituitary tumor, and plasma of normal and Cushing's horses
Endocrinology. 1982 Mar;110(3):941-54 (PubMed)
"Using RIAs for six regions within proopiolipomelanocortin (proOLMC), gel filtration, and electrophoresis, we studied pituitary peptides in a normal horse and one with Cushing's disease caused by a pars intermedia adenoma. Almost all immunoreactive (IR) ACTH (78%) was 4,500 mol wt (4.5K) ACTH in normal pars distalis, but it was almost 100% corticotropin-like intermediate lobe peptide (CLIP) in normal pars intermedia. alpha MSH and beta MSH were found mainly in pars intermedia: equal concentrations of the beta MSH precursors, beta-lipotropin (beta LPH) and gamma LPH, were found in pars distalis. Most IR-beta-endorphin (IR-beta END) was found as beta END in pars intermedia, but roughly equal concentrations of beta END and its precursor, beta LPH, were found in pars distalis. A 33K molecule containing IR-ACTH, IR-gamma 3MSH, and IR-beta END, presumed to be proOLMC, and a variety of 15-27K presumed biosynthetic intermediates were found in both normal pars distalis and pars intermedia. The pars intermedia adenoma causing Cushing's syndrome contained high IR-peptide concentrations. Several differences in precursors were noted, including the presence of three larger presumed precursors (38.5K, 47K, and 63K) that had both ACTH and beta END immunoreactivities and both deletions and additions of 15-27K intermediates. The Cushing's horse's plasma peptides reflected tumor concentrations; 4.5K ACTH was modestly elevated, but the concentrations of CLIP, alpha MSH, beta MSH, gamma LPH, and beta END were dramatically increased. About 20% of plasma IR-ACTH and 5% of IR-beta MSH and IR-beta END were found as high molecular weight forms. Normal processing of horse proOLMC appears to be similar to that in other species, but may be altered in pars intermedia tumors of horses with Cushing's disease, the plasma of which contains disproportionately increased concentrations of pars intermedia proOLMC peptides."
Research in other species
Millington WR 1988
Dopaminergic regulation of the biosynthetic activity of individual melanotropes in the rat pituitary intermediate lobe a morphometric analysis by light and electron microscopy and in situ hybridization
Endocrinology
In the corticotropes of the pars distalis, the majority of POMC is converted to ACTH, and also beta-lipotropic hormone, gamma-lipotropic hormone and beta-endorphin. In the melanotropes of the pars intermedia, POMC is converted to melanocyte-stimulating hormones (including α-MSH), β-endorphin, CLIP, ACTH and beta-lipotropic hormone. ACTH production in the pars intermedia is minimal in the healthy horse.
Dopamine inhibits the release of POMC derived peptides in a healthy horse, therefore the reduction in dopamine in horses with PPID leads to increased levels of these hormones.
Alpha-MSH plays a role in metabolism, obesity, inflammation, stress. It has broad anti-inflammatory effects, including decreased production of cytokines. It causes an anorexic response and feeling of satiety. It impairs neutrophil function (including oxidative burst, chemotaxis, adhesion).
Beta-endorphin is a potent endogenous opiod receptor agonist with roles in analgesia and reduction of pain-associated inflammation.
CLIP "is the cleavage product generated from the c-terminal portion of ACTH". We do not know much about CLIP, it is cleaved into Beta-cell tropin, and both CLIP and Beta-cell tropin have been shown to stimulate the release of insulin from rat pancreas cells.
Carmalt JL, Mortazavi S, McOnie RC, Allen AL, Unniappan S
Profiles of proopiomelanocortin and encoded peptides, and their processing enzymes in equine pituitary pars intermedia dysfunction
PLoS ONE Jan 2018 13(1): e0190796. https://doi.org/10.1371/journal
PPID is characterized by hyperplasia of the pars intermedia melanotrophs of the pituitary gland, and increased production of POMC. POMC is cleaved (divided) by PC1 (prohormone convertase 1) to produce ACTH. ACTH is cleaved by PC2 to produce alpha-MSH and CLIP.
This study found that PC1 and PC2 are upregulated (increased) in the pituitary gland of horses with PPID, that POMC mRNA expression is elevated, and that abnormally high POMC derived hormones are released into the blood from the pituitary gland in horses with PPID. The "results conclude a defect in ACTH precursor and its processing enzymes in PPID."
McFarlane D
Review of Current Understanding of Pituitary Pars Intermedia Dysfunction
AAEP 2013
Vet Clin North Am Equine Pract. 2011 Apr;27(1):1-17
Hypothalamic-pituitary gland axis function and dysfunction in horses
Hurcombe SD
Br Vet J. 1993 Mar-Apr;149(2):139-53 (PubMed)
Equine Cushing's disease
Love S
"In the horse, adenomata of the pairs intermedia of the pituitary gland have been associated with the distinct clinical entity of Cushing's disease which arises largely as a result of excessive secretion of adrenocorticotropin (ACTH) or other proopiomelanocortin (POMC) peptides. Pars intermedia peptide secretion is under dopaminergic control and compounds such as pergolide or bromocriptine, which are dopamine agonists, can palliate the clinical signs. A variety of endocrinological abnormalities, relevant to both pathogenesis and diagnosis, may be demonstrated in equine Cushing's disease, including hyperadrenocorticism, peripheral insulin resistance and excessive POMC-peptide secretion from the pituitary gland. Preliminary studies on carbohydrate metabolism suggest that quantification of insulin activity may be a useful prognostic index in cases of equine Cushing's disease, and that insulin therapy of secondary diabetes mellitus may be indicated in some cases."
Wilson MG, Nicholson WE, Holscher MA, Sherrell BJ, Mount CD, Orth DN
Proopiolipomelanocortin peptides in normal pituitary, pituitary tumor, and plasma of normal and Cushing's horses
Endocrinology. 1982 Mar;110(3):941-54 (PubMed)
"Using RIAs for six regions within proopiolipomelanocortin (proOLMC), gel filtration, and electrophoresis, we studied pituitary peptides in a normal horse and one with Cushing's disease caused by a pars intermedia adenoma. Almost all immunoreactive (IR) ACTH (78%) was 4,500 mol wt (4.5K) ACTH in normal pars distalis, but it was almost 100% corticotropin-like intermediate lobe peptide (CLIP) in normal pars intermedia. alpha MSH and beta MSH were found mainly in pars intermedia: equal concentrations of the beta MSH precursors, beta-lipotropin (beta LPH) and gamma LPH, were found in pars distalis. Most IR-beta-endorphin (IR-beta END) was found as beta END in pars intermedia, but roughly equal concentrations of beta END and its precursor, beta LPH, were found in pars distalis. A 33K molecule containing IR-ACTH, IR-gamma 3MSH, and IR-beta END, presumed to be proOLMC, and a variety of 15-27K presumed biosynthetic intermediates were found in both normal pars distalis and pars intermedia. The pars intermedia adenoma causing Cushing's syndrome contained high IR-peptide concentrations. Several differences in precursors were noted, including the presence of three larger presumed precursors (38.5K, 47K, and 63K) that had both ACTH and beta END immunoreactivities and both deletions and additions of 15-27K intermediates. The Cushing's horse's plasma peptides reflected tumor concentrations; 4.5K ACTH was modestly elevated, but the concentrations of CLIP, alpha MSH, beta MSH, gamma LPH, and beta END were dramatically increased. About 20% of plasma IR-ACTH and 5% of IR-beta MSH and IR-beta END were found as high molecular weight forms. Normal processing of horse proOLMC appears to be similar to that in other species, but may be altered in pars intermedia tumors of horses with Cushing's disease, the plasma of which contains disproportionately increased concentrations of pars intermedia proOLMC peptides."
Research in other species
Millington WR 1988
Dopaminergic regulation of the biosynthetic activity of individual melanotropes in the rat pituitary intermediate lobe a morphometric analysis by light and electron microscopy and in situ hybridization
Endocrinology
Prolactin (PRL)
Need to know: Prolactin is not increased by PPID, but treatment with pergolide affects prolactin concentrations. Prolactin is not diagnostic for PPID.
Prolactin (a hormone) is a single-chain protein made up of 199 amino acids that is secreted by lactotropes in the pars distalis. Plasma prolactin concentrations in the horse have been shown to be highest in the summer, start to decrease at the end of August and are lowest from November to February (in the northern hemisphere).
Prolactin regulates mammary growth and development and lactation, and influences hair growth/haircoat shedding, reproduction and follicular activity.
Hyperprolactinemia has been shown to cause infertility in human males and females, galactorrhea (abnormal lactation), oligomenorrhea (infrequent menstruation) and amenorrhea (loss of menstruation) in females, and hypogonadism (reduced production of sex hormones) in men.
The synthesis and secretion of prolactin is inhibited by dopamine, through an auto-regulatory feedback loop to tuberoinfundibular dopamine neurons.
The release of prolactin is inhibited by dopamine agonists Prascend/pergolide and bromocriptine (NOAH datasheet for Prascend).
Secretion of prolactin is stimulated by TRH and Prostaglandin-F2α, and dopamine antagonists such as sulpiride. Prolactin concentrations have been shown to increase 4 to 6 hours after feeding, and with stress (including twitching) and exercise.
www.ecirhorse.org - physiology of PPID - PPID mares that had enlarged mammary glands and/or were leaking milk were found to have elevated blood prolactin concentrations.
Prolactin blood tests
Using RIA, Cahill et al. 1994 found mean prolactin concentrations ranging from 3.2 to 10.4 ng/ml in lactating mares, with higher concentrations earlier in lactation.
Cahill CM, Van der Kolk H, Goode JA, Hayden TJ.
Development of homologous radioimmunoassays for equine growth hormone and equine prolactin and their application to the detection of circulating levels of hormone in horse plasma.
Reprod Nutr Dev. 1994;34(4):309-28. doi: 10.1051/rnd:19940404. PMID: 7986349.
Using RIA, Roser et al. 1984 found prolactin concentrations ranging from 0.6 to 12.0 ng/ml in stallions, pregnant mares and non-pregnant mares.
Galinelli N, Erdody M, Bamford N, Harris P, Sillence M, Bailey S
Suspected presence of macroprolactin in the plasma of horses and ponies
JEVS May 2021 Vol 100 103471. https://doi.org/10.1016/j.jevs.2021.103471
Roser JF, Chang YS, Papkoff H, Li CH.
Development and characterization of a homologous radioimmunoassay for equine prolactin.
Proc Soc Exp Biol Med. 1984 Apr;175(4):510-7. doi: 10.3181/00379727-175-41829. PMID: 6709647.
Thompson DL, Oberhaus EL,
Prolactin in the Horse: Historical Perspective, Actions and Reactions, and Its Role in Reproduction.
Journal of Equine Veterinary Science 2015, Volume 35, Issue 5, Pages 343-353. https://doi.org/10.1016/j.jevs.2015.03.199. (Full paper: ResearchGate)
Prolactin - R Bowen
Schott II HC, Norby B, Thompson DL
Assessment of Prolactin Concentration as a Screening Test for PPID
International Equine Endocrine Summit Jan 2017
Thompson Jr DL, Oberhaus EL
Prolactin in the Horse: Historical Perspective, Actions and Reactions, and Its Role in Reproduction
Journal of Equine Veterinary Science Volume 35, Issue 5, May 2015, Pages 343–353
Proceedings of the 2015 Equine Science Society Symposium
Lisa C. DiGiovanni
Factors affecting basal and post-exercise prolactin secretion in horses
MSc thesis Louisiana State University 2013
Arginine Vasopressin (AVP) and vasoactive intestinal polypeptide (VIP) did not affect prolactin secretion.
Exercise increased prolactin concentrations.
Treatment with corticosteroid dexamethasone and opioid antagonist naloxone prior to exercise did not reduce the increased prolactin concentrations due to exercise - (neither corticotropin releasing hormone or ACTH appear to be involved in the prolactin response to exercise).
Treatment with cabergoline, a dopamine agonist, abolished the prolactin response even with exercise - it was concluded that cabergoline is a potent inhibitor of prolactin secretion.
Treatment with NSAID flunixin meglumine (which prevents prostaglandin production and secretion) did not reduce the exercise-induced prolactin response.
Treatment with sulpiride, a dopamine antagonist, stimulated prolactin secretion, but did not affect the exercise-induced prolactin response.
Repeatability of Prolactin Responses to Sulpiride in Mares and Geldings and the Effect of Pergolide and Cabergoline
Rebekah Hebert MSc Thesis May 2012
Estradiol interactions with dopamine antagonists in mares: prolactin secretion and reproductive traits
Kristian Kandis Kelley MSc Thesis May 2006
"Thompson et al. (1986) reported that horses have higher prolactin levels during the breeding season, with mares having the highest levels. Mares undergoing transition from the anovulatory season in winter to the breeding season experience increases in several hormones, including prolactin."
J Clin Endocrinol Metab. 1980 Aug;51(2):242-6. (PubMed) HUMAN
Correlation of hyperprolactinemia with altered plasma insulin and glucagon: similarity to effects of late human pregnancy.
Gustafson AB, Banasiak MF, Kalkhoff RK, Hagen TC, Kim HJ.
"These results suggest that elevated plasma PRL concentrations may contribute to the development of hyperinsulinemia and accentuated glucagon suppression in response to glucose"
Protein
Research by Loos et al. has suggested that ingested protein/amino acids might increase insulin levels in horses with insulin dysregulation. This might suggest that protein levels should be carefully assessed to ensure sufficient but not excess protein is fed, or that the protein content of the diet should be divided into several small feeds. Could this explain why laminitis is often seen after horses have been eating spring grass and alfalfa?
Loos CMM, Dorsch SC, Elzinga SE, Brewster-Barnes T, Vanzant ES, Adams AA, Urschel KL.
A high protein meal affects plasma insulin concentrations and amino acid metabolism in horses with equine metabolic syndrome.
Vet J. 2019 Sep;251:105341. doi: 10.1016/j.tvjl.2019.105341. Epub 2019 Jul 20. PMID: 31492392.
Some amino acids are involved in the secretion of insulin. 6 horses with EMS and 6 horses without EMS, matched for age, were fed 2 g/kg bodyweight of a high (31% CP) protein pellet at time 0 and time 30, following an overnight fast, and blood collected for 4 hours. Horses with EMS had a 9 x greater insulin response [but was ESC + starch/NSC controlled for?]. Post-prandial levels of histadine, citrulline, tyrosine, valine, methionine, isoleucine, leucine and ornithine were higher in horses with EMS [how might that happen?].
"These results illustrate that consumption of a high protein meal caused a hyperinsulinemic response and affected amino acid dynamics in horses with EMS. These findings suggest that dietary protein content should be taken into consideration in the management of horses with insulin dysregulation."
Loos, Caroline Margot Marcelle
The impact of insulin dysregulation on protein metabolism in horses
PhD dissertation February 2018 University of Kentucky. https://doi.org/10.13023/ETD.2018.048
Macon, Erica L
Plasma and Muscle Amino Acid Concentrations in Insulin Resistant Compared to Normal Horses in the Fed and Fasted State
MSc thesis May 2017 Middle Tennessee State University
Manfredi, Jane Marie
Identifying breed differences in insulin dynamics, skeletal muscle and adipose tissue histology and gene expression
2016 PhD dissertation Michigan State University
Giving arginine IV (70 mg/kg) caused insulin concentrations to increase significantly from 1 minute until at least 15 minutes after administration.
Sticker LS, Thompson DL Jr, Gentry LR
Pituitary hormone and insulin responses to infusion of amino acids and N-methyl-D,L-aspartate in horses
J Anim Sci. 2001 Mar;79(3):735-44 (full paper available as pdf)
Horses were given:
arginine - increased prolactin; increased insulin only in mares (that also showed signs of colic)
aspartic acid - increased GH
lysine - increased prolactin; increased insulin
glutamic acid - increased GH; increased prolactin
N-methyl-D,L-aspartate (NMA) - increased GH; increased LH in mares and stallions; increased FSH in mares.
Research by Loos et al. has suggested that ingested protein/amino acids might increase insulin levels in horses with insulin dysregulation. This might suggest that protein levels should be carefully assessed to ensure sufficient but not excess protein is fed, or that the protein content of the diet should be divided into several small feeds. Could this explain why laminitis is often seen after horses have been eating spring grass and alfalfa?
Loos CMM, Dorsch SC, Elzinga SE, Brewster-Barnes T, Vanzant ES, Adams AA, Urschel KL.
A high protein meal affects plasma insulin concentrations and amino acid metabolism in horses with equine metabolic syndrome.
Vet J. 2019 Sep;251:105341. doi: 10.1016/j.tvjl.2019.105341. Epub 2019 Jul 20. PMID: 31492392.
Some amino acids are involved in the secretion of insulin. 6 horses with EMS and 6 horses without EMS, matched for age, were fed 2 g/kg bodyweight of a high (31% CP) protein pellet at time 0 and time 30, following an overnight fast, and blood collected for 4 hours. Horses with EMS had a 9 x greater insulin response [but was ESC + starch/NSC controlled for?]. Post-prandial levels of histadine, citrulline, tyrosine, valine, methionine, isoleucine, leucine and ornithine were higher in horses with EMS [how might that happen?].
"These results illustrate that consumption of a high protein meal caused a hyperinsulinemic response and affected amino acid dynamics in horses with EMS. These findings suggest that dietary protein content should be taken into consideration in the management of horses with insulin dysregulation."
Loos, Caroline Margot Marcelle
The impact of insulin dysregulation on protein metabolism in horses
PhD dissertation February 2018 University of Kentucky. https://doi.org/10.13023/ETD.2018.048
Macon, Erica L
Plasma and Muscle Amino Acid Concentrations in Insulin Resistant Compared to Normal Horses in the Fed and Fasted State
MSc thesis May 2017 Middle Tennessee State University
Manfredi, Jane Marie
Identifying breed differences in insulin dynamics, skeletal muscle and adipose tissue histology and gene expression
2016 PhD dissertation Michigan State University
Giving arginine IV (70 mg/kg) caused insulin concentrations to increase significantly from 1 minute until at least 15 minutes after administration.
Sticker LS, Thompson DL Jr, Gentry LR
Pituitary hormone and insulin responses to infusion of amino acids and N-methyl-D,L-aspartate in horses
J Anim Sci. 2001 Mar;79(3):735-44 (full paper available as pdf)
Horses were given:
arginine - increased prolactin; increased insulin only in mares (that also showed signs of colic)
aspartic acid - increased GH
lysine - increased prolactin; increased insulin
glutamic acid - increased GH; increased prolactin
N-methyl-D,L-aspartate (NMA) - increased GH; increased LH in mares and stallions; increased FSH in mares.
Proxies
2 proxy measurements have been suggested to asses insulin sensitivity in horses, the reciprocal of the square root of insulin (RISQI) and the modified insulin to glucose ratio (MIRG). However the proxy values were established on a closely related group of ponies, and many vets (including Dr Nicholas Frank, see below) do not recommend using these proxies, suggesting that a fasting resting insulin concentration of > 20 µIU/ml is a more appropriate cut-off value for diagnostic of hyperinsulinaemia.
Nicholas Frank
Equine Metabolic Syndrome
Veterinary Clinics of North America: Equine Practice - April 2011 (Vol. 27, Issue 1, Pages 73-92)
Guide to Insulin Resistance & Laminitis (2008)– Nicholas Frank, Raymond Geor, Steve Adair p32
The G:I ratio is not recommended because:
it leads to over-diagnosis of IR
it fails to recognise all forms of IR
it fails to recognise differences in laboratory results/normal ranges
glucose is relatively unstable and if the glucose sample has degraded this will lower the ratio
hyperglycaemia will increase the ratio
RISQI is not recommended because the cut-off used is too low (IR is indicated by a RISQI of <0.29, this is the equivalent of 12 µIU/ml).
Lindåse S, Nostell K, Bergsten P, Forslund A, Bröjer J.
Evaluation of fasting plasma insulin and proxy measurements to assess insulin sensitivity in horses.
BMC Vet Res. 2021 Feb 15;17(1):78. doi: 10.1186/s12917-021-02781-5. PMID: 33588833; PMCID: PMC7885592.
"Proxies are mathematical calculations based on fasting glucose and/or insulin concentrations developed to allow prediction of insulin sensitivity (IS) and β-cell response.... Conclusions: All proxies and fasting insulin (FI) provided repeatable estimates of horses’ insulin sensitivity. However, there is no advantage of using proxies instead of FI to estimate IR in the horse. Due to the heteroscedasticity of the data, proxies and FI in general are more suitable for epidemiological studies and larger clinical studies than as a diagnostic tool for measurement of IR in individual horses."
Equine Veterinary Journal Volume 44, Issue 4, pages 444–448, July 2012
Use of proxy measurements of insulin sensitivity and insulin secretory response to distinguish between normal and previously laminitic ponies
Borer KE, Bailey SR, Menzies-Gow NJ, Harris PA, Elliott J
None of the proxies accurately identified individual previously laminitic ponies.
Pratt SE, Siciliano PD, Walston L
Variation of Insulin Sensitivity Estimates in Horses
Journal of Equine Veterinary Science Volume 29, Issue 6 , Pages 507-512, June 2009
Treiber KH, Kronfeld DS, Geor RJ
Insulin Resistance in Equids: Possible Role in Laminitis
The Journal of Nutrition 2006
Treiber KH, Kronfeld DS, Hess TM, Boston RC, Harris PA
Use of proxies and reference quintiles obtained from minimal model analysis for determination of insulin sensitivity and pancreatic beta-cell responsiveness in horses
Am J Vet Res. 2005 Dec;66(12):2114-21 (PubMed)
Q: Are the glucose:insulin ratio and proxies like RISQI useful for diagnosing EMS/IR, or are baseline insulin and glucose results better?
Nicholas Frank
Equine Metabolic Syndrome
Veterinary Clinics of North America: Equine Practice - April 2011 (Vol. 27, Issue 1, Pages 73-92)
Guide to Insulin Resistance & Laminitis (2008)– Nicholas Frank, Raymond Geor, Steve Adair p32
The G:I ratio is not recommended because:
it leads to over-diagnosis of IR
it fails to recognise all forms of IR
it fails to recognise differences in laboratory results/normal ranges
glucose is relatively unstable and if the glucose sample has degraded this will lower the ratio
hyperglycaemia will increase the ratio
RISQI is not recommended because the cut-off used is too low (IR is indicated by a RISQI of <0.29, this is the equivalent of 12 µIU/ml).
Lindåse S, Nostell K, Bergsten P, Forslund A, Bröjer J.
Evaluation of fasting plasma insulin and proxy measurements to assess insulin sensitivity in horses.
BMC Vet Res. 2021 Feb 15;17(1):78. doi: 10.1186/s12917-021-02781-5. PMID: 33588833; PMCID: PMC7885592.
"Proxies are mathematical calculations based on fasting glucose and/or insulin concentrations developed to allow prediction of insulin sensitivity (IS) and β-cell response.... Conclusions: All proxies and fasting insulin (FI) provided repeatable estimates of horses’ insulin sensitivity. However, there is no advantage of using proxies instead of FI to estimate IR in the horse. Due to the heteroscedasticity of the data, proxies and FI in general are more suitable for epidemiological studies and larger clinical studies than as a diagnostic tool for measurement of IR in individual horses."
Equine Veterinary Journal Volume 44, Issue 4, pages 444–448, July 2012
Use of proxy measurements of insulin sensitivity and insulin secretory response to distinguish between normal and previously laminitic ponies
Borer KE, Bailey SR, Menzies-Gow NJ, Harris PA, Elliott J
None of the proxies accurately identified individual previously laminitic ponies.
Pratt SE, Siciliano PD, Walston L
Variation of Insulin Sensitivity Estimates in Horses
Journal of Equine Veterinary Science Volume 29, Issue 6 , Pages 507-512, June 2009
Treiber KH, Kronfeld DS, Geor RJ
Insulin Resistance in Equids: Possible Role in Laminitis
The Journal of Nutrition 2006
Treiber KH, Kronfeld DS, Hess TM, Boston RC, Harris PA
Use of proxies and reference quintiles obtained from minimal model analysis for determination of insulin sensitivity and pancreatic beta-cell responsiveness in horses
Am J Vet Res. 2005 Dec;66(12):2114-21 (PubMed)
Q: Are the glucose:insulin ratio and proxies like RISQI useful for diagnosing EMS/IR, or are baseline insulin and glucose results better?
PU/PD - polyuria and polydipsia
Polyuria (PU) - excess urination - and polydipsia (PD) - excess drinking - can be signs of PPID. A horse is considered to have PU/PD if it produces > 50 ml/kg/day urine and drinks > 100 ml/kg/day - this would be 25 litres of urine and 50 litres of water for a 500 kg horse. However, diet, environmental temperature, exercise and lactation will affect water intake and urine output.
As well as PPID, other common causes of excess drinking and urination include chronic renal failure and psychogenic/primary polydipsia (when a horse drinks too much through boredeom, usually seen in stabled horses), but excessive salt intake, excessive protein intake, diabetes insipidus, diabetes mellitus, hepatic (liver) insufficiency, sepsis and some medicines (e.g. corticosteroids and diuretics) can also be causes.
See: Investigation of polyuria (PU) and polydipsia (PD) - Liphook Equine Hospital Lab Book 2015 .
Indicators of Polyuria and Polydipsia - Liphook Equine Hospital 2016
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In her presentation Is it PPID or is it EMS in 2014, Dianne McFarlane suggested that PU/PD is seen as a clinical sign in horses that have both PPID and EMS
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The reason for PU/PD in horses with PPID is not known for sure, but suggestions include:
Moses ME, Johnson PJ, Messer NT, Wilson DA
Antidiuretic response of a horse affected with pituitary pars intermedia dysfunction to desmopressin acetate
Equine Veterinary Education 2013 25: 111–115
McKenzie EC
Polyuria and polydipsia in horses
Vet Clin North Am Equine Pract. 2007 Dec;23(3):641-53, vii (full paper on ResearchGate)
Polydipsia/polyuria - Vetstream
- Decrease in antidiuretic hormone (arginine vasopressin) due to compression of the pars nervosa by the enlarged pars intermedia,
- hyperglycaemia (above normal glucose) and glucosuria (glucose in the urine) resulting in osmotic diuresis (increased urination). However some researchers suggest that hyperglycaemia and glucosuria do not appear to be that common in horses with PPID, and horses that have not tested hyperglycaemic have shown signs of PU/PD, also horses have been seen to have marked hyperglycaemia without increasing their water intake,
- increased cortisol concentrations increase the glomerular filtration rate (but high cortisol concentrations are not often found in horses with PPID),
- increased cortisol concentrations inhibit the release and/or action of antidiuretic hormone (arginine vasopressin).
Moses ME, Johnson PJ, Messer NT, Wilson DA
Antidiuretic response of a horse affected with pituitary pars intermedia dysfunction to desmopressin acetate
Equine Veterinary Education 2013 25: 111–115
McKenzie EC
Polyuria and polydipsia in horses
Vet Clin North Am Equine Pract. 2007 Dec;23(3):641-53, vii (full paper on ResearchGate)
Polydipsia/polyuria - Vetstream