And what does it do with the horse?
There is scarcely a medication that is currently as contentious in equine therapy as Prascend. For some, it is the ultimate wonder drug that should be administered to every horse with metabolic issues, as it seemingly makes concerns like laminitis and similar conditions vanish magically.
On the other hand, there are just as many horse owners and therapists who denounce it, as several horses have experienced severe side effects or exhibited no response whatsoever to the costly medication.
Therefore, it is imperative to delve deeper into the matter at hand.
The name Prascend is the brand name by which the medication is marketed by its manufacturer, Boehringer Ingelheim Vetmedica GmbH. It is based on the active ingredient (or former drug name) pergolide, which was originally utilised in the treatment of Parkinson’s disease in humans.
Pergolide
Pergolide is a medicinal substance derived from the alkaloids of the ergot fungus. The ergot fungus (Claviceps spp.) is a cereal fungus that has a particular affinity for infesting rye, though it can also affect other sweet grasses.
Its name is derived from the impact its constituents have on the uterus, which, when administered in small doses, can induce labor or abortion.
Ergotism, the poisoning caused by the ingestion of grain infected with ergot, has been documented in our part of the world since the Middle Ages. This form of poisoning results in significant constriction of blood vessels, leading to circulatory disorders affecting the heart, kidneys, and limbs. Consequently, limb necrosis, kidney failure, and even cardiac arrest can occur. The most recent major outbreak of ergot poisoning was recorded in 1926/27, claiming the lives of approximately 11,000 individuals.
Pergolide (1), also known as 8ß-(methylthiomethyl)-6-propylergoline according to chemical nomenclature, functions as a dopamine agonist within the body. In other words, it can deceive dopamine receptors into believing it is dopamine and subsequently activate them (2). However, it falls under the category of “dirty drugs,” which means it not only selectively binds to dopamine receptors but also to other receptors. Such “dirty drugs” pose challenges to pharmacologists, as their effects are difficult to study and control due to the lack of specificity.
As a result, excellent effects as well as fatal side effects can be observed, depending on the predisposition of the patient.
metabolic imbalances caused by living conditions and/or feeding practices.
© Christian Musat / Adobe Stock
Consequently, since 2007, pergolide has gradually been withdrawn from the market in several countries due to its side effects in humans, ranging from dyskinesia (movement disturbances) to hallucinations and fibrotic damage to the heart valves (3,4,5).
In Europe, pergolide, which was marketed under various trade names in different countries, was ultimately removed from the market in 2011.
Dopamine – a versatile neurotransmitter
Dopamine is a neurotransmitter, a chemical messenger that transmits signals between nerve cells. It is primarily known for inducing a sense of “self-reward” within certain neuronal circuits. This is why it is often referred to as the “happiness hormone” and is believed to be the driving force behind inner motivation.
Individuals with Parkinson’s disease experience a deficiency of dopamine in specific areas of the brain, leading to symptoms such as muscle rigidity, tremors, and, as the disease progresses, a gradual slowing down of movements culminating in complete paralysis (akinesia). By stimulating the dopamine receptors, the progression of the disease can be slowed down.
However, dopamine also exerts other effects on the body, particularly within the autonomic nervous system, which regulates various internal organs. It plays a crucial role in controlling blood flow to vital organs and significantly impacts kidney function, enhancing their performance. Dopamine also influences hormone balance and inhibits the release of prolactin from the pituitary gland, among other functions. The body produces dopamine from the amino acid tyrosine, which, in horses, falls under the category of non-essential amino acids, meaning the organism can synthesise it internally and does not necessarily rely on dietary intake.
In the 1980s, the initial studies on “Cushing’s disease” in horses explored the role of dopamine or dopamine agonists (6). This was followed by experimental trials in the 1990s, administering pergolide to horses displaying Cushing’s symptoms (7).
Cushing’s and insulin resistence
Simultaneously, studies were published suggesting a frequent co-occurrence of Cushing’s disease and insulin resistance, with a suspected connection between the two or a recommendation to prioritise the treatment of Cushing’s symptoms over insulin resistance (8). Regrettably, this approach was not further pursued in veterinary medicine, despite the fact that most horses diagnosed with Cushing’s disease also exhibit insulin resistance and often respond well to treatment with a significant improvement in Cushing’s symptoms.
Connections between Cushing’s symptoms and thyroid disorders were also noted as early as the early 2000s (9). However, despite the potential for a deeper understanding of the disease, this avenue of research was not further pursued.
Until the early 2000s, there were only a few publications exploring the possible treatment of horses with Cushing’s symptoms using pergolide. However, case reports during that time consistently demonstrated that pergolide could lower ACTH levels (10).
(10) Concurrently, the first studies on the effects of monk’s pepper, also called chasteberry, in horses with Cushing’s symptoms emerged. These studies indicated that monk’s pepper had no influence on ACTH levels (11,12). Nonetheless, it still enjoys popularity, particularly among alternative therapists, in attempts to treat horses with Cushing’s symptoms.
After 2007, there was a noticeable increase in studies investigating pergolide in connection with Cushing’s disease in horses. Eventually, in 2011, pergolide was removed from the market in Europe due to its side effects. In its place, Boehringer Ingelheim, the manufacturer, obtained approval in 2010 for the same active ingredient (pergolide mesylate) under the trade name Prascend(R) as a veterinary medicinal product for the treatment of equine Cushing’s syndrome.
Cushing’s diagnosis
Prior to this, veterinarians had to reclassify pergolide for use in horses in their practice. Shortly after the launch of Prascend, Boehringer Ingelheim began targeted veterinarian training on Equine Cushing’s Syndrome and everyday diagnostics using the ACTH value. They also offered a free ACTH test for horse owners.
Consequently, there has been a significant increase in the number of “Cushing’s” diagnoses, as even horses without symptoms have been diagnosed with Cushing’s based on the ACTH test and subsequently “treated” with Prascend.
This diagnosis has no scientific basis, as even a healthy horse can exhibit elevated ACTH levels due to circadian rhythms, seasonal changes, or stress. It is scientifically incorrect to conclude the presence of a pituitary adenoma solely based on an increased ACTH level.
A pituitary adenoma leads to a permanently elevated ACTH level, but an elevated ACTH level says nothing about the presence of a pituitary adenoma.
The free “Cushing’s test” provided by the manufacturer of Prascend proved to be a highly effective marketing move, leading to a skyrocketing demand for a condition that had previously occupied a niche in veterinary medicine.
Boehringer Ingelheim’s 2019 financial report reveals that veterinary medicines accounted for approximately 21% of sales, surpassing €4 billion. In 2013, the veterinary medicines segment amounted to just €1.07 billion. Alongside GastroGuard (used to treat stomach ulcers), Prascend stands out as a flagship among equine medicines. The “equine medicines” segment alone witnessed a growth of around 5.7% from 2018 to 2019, primarily driven by Prascend, GastroGuard, and VentiPlus (13). (13)
Prascend ranks high on the list of drugs with undesirable side effects
Shortly after its launch, Prascend claimed the top spot among drugs reported with adverse side effects (14). Commonly mentioned symptoms included inappetence, diarrhea, colic, apathy, and central nervous disturbances. These symptoms frequently arise in horses that have been prescribed Prascend hastily.
One prevailing misconception in treating horses with Cushing’s symptoms or a diagnosis based on the ACTH test using Prascend is the belief that the medication “treats” the tumor, leading to the disappearance of symptoms. This is incorrect.
Studies utilising MRI and subsequent necropsy have shown that the pituitary adenoma continues to grow in size despite Prascend administration (15).
The alleviation of clinical symptoms associated with Cushing’s disease and the decrease in ACTH levels are not attributed to a reduction or disappearance of the tumor, but rather to the effects of Prascend, which have yet to be scientifically investigated.
Since the tumor continues to grow, it can be assumed that horses receiving Prascend for many years and remaining symptomatically stable may not have a pituitary adenoma at all. The space-occupying changes in the skull capsule should have caused neurological deficits long ago.
Prascend for horses
Although Prascend is now widely used in the treatment of horses, whether they exhibit Cushing’s symptoms or not, have elevated ACTH levels or not, and suffer from laminitis or not, there is a lack of reliable clinical studies on the subject.
Analysis of current studies reveals that in some cases, only 40% of horses treated with Prascend show an improvement in the clinical symptoms that led to the diagnosis. A reduction in ACTH levels is observed in 44-74% of horses treated with Prascend (16). Furthermore, there is almost no studies exploring the actual mechanisms of action of Prascend in horses.
In addition to the well-documented dopaminergic effect, it is expected that Prascend also interacts with other receptors, as it falls under the category of “dirty drugs” (17). However, no investigations have been conducted in horses to explore this aspect or its potential side effects. One noteworthy side effect observed in humans is the potential for pergolide, the active ingredient, to cause fibrotic damage to the heart valves, which led to its initial withdrawal from the market. However, no studies on this specific side effect in horses are available thus far.
Considering that many horses are likely misdiagnosed with “Cushing’s”without actually having a pituitary adenoma (since CT/MRI scans are typically not performed, and only the symptom profile or ACTH values are relied upon), and that no improvement in symptoms can be observed in many horses (with side effects often downplayed), it would be prudent to thoroughly examine the effects and side effects of Prascend in horses before indiscriminately distributing this medication.
A good source of income
For the manufacturer and the prescribing veterinarian, Prascend undoubtedly serves as an excellent source of income, as the drug needs to be administered lifelong once initiated. Discontinuation of the medication can lead to a “rebound effect,” where the ACTH levels may rise significantly above the initial levels, potentially triggering severe bouts of laminitis.
With the increasing prescription of Prascend to young horses, the turnover is ensured for years and even decades.
Considering the experiences in human medicine with different groups of medications and their negative long-term effects on individuals and populations, ranging from cortisone creams for neurodermatitis to antibiotics for common colds, one may question why Prascend is recommended so unquestioningly and on such a large scale for horses, without first conducting controlled studies to understand the potential consequences. It is crucial to ascertain what risks may arise from this medication, if any, before unwittingly releasing a Pandora’s box of uncertainties.
Sources:
(1) https://doi.org/10.2165/00023210-199707040-00005
(2) https://doi.org/10.1073/pnas.77.6.3725
(3) https://doi.org/10.4065/77.12.1280
(4) https://doi.org/10.1212/01.WNL.0000083985.00343.F2
(5) https://doi.org/10.1212/01.WNL.0000129842.49926.07
(6) https://doi.org/10.1210/endo-110-4-1430
(7) https://doi.org/10.1136/vr.139.2.41
(8) doi.org/10.1016/S0007-1935(05)80084-3
(9) https://doi.org/10.1016/j.cveq.2007.04.004
(10) https://doi.org/10.2746/042516402776250333
(11) Beech et al.: Comparison of Vitex agnus castus extract and Pergolide in Treatment of Equine Cushing’s Syndrome; AAEP; 2002
(12) Kellon EM: Herbal offers hope for Cushing’s syndrome; Horse J; 2000
(13) Geschäftsberichte Boehringer Ingelheim 2013 und 2019
(14) Palm et a.: Pharmakovigilanzreport Tierarzneimittel, Spontanmeldungen unerwünschter Arzneimittel im Zeitraum 2011 bis 2013; Deutsches Tierärzteblatt; 2014
(15) https://doi.org/10.1111/j.1939-1676.2011.00784.x
