Peptides In Veterinary Medicine

October 01, 2021
Peptides for veterinary medicine

Peptides In Veterinary Medicine

Bachem offers a choice of generic peptides for use as active ingredients in veterinary medicine, amongst them gonadorelin and gonadorelin agonists and antagonists. For a compilation of our peptide APIs please see page 20. Our offer is complemented by the corresponding peptides in research quality to be found on page 23-25.

Additionally, we provide the anesthetics etomidate and propofol as non-peptide generic APIs for the veterinary practice, please see page 21.

Introduction

A considerable number of peptides applied as therapeutics or diagnostics in humans is also used for various indications in veterinary medicine. Peptides are relatively expensive drugs which, in most cases, can’t be applied orally, but these shortcomings are often outweighed by their advantages.

Peptide-based drugs are especially indicated for treating animals used in food production, as they are highly active compounds which require only very small doses. Additionally, they are metabolized more readily than organic compounds, which reduces the risk of contamination of the milk, eggs, or meat of the treated animal by the unmetabolized pharmaceutical and/ or its degradation products.

Peptide Therapeutics

Administration of synthetic peptides as therapeutics or diagnostics is well-established in human medicine. A few of them have also found use for comparable indications in veterinary medicine.

There is also a vast market for peptide drugs in the treatment of companion animals and horses. Pets can suffer from most diseases of civilization that affect humans. Accordingly, diabetes has become a growing problem with dogs and cats in recent years due to their increasing life expectancy in combination with obesity and lack of exercise. At the same time, owners are more willing to pay for medication and therapies to increase the length and quality of life of their diseased pets.

This also holds true for companion animals suffering from cancer and other life-threatening diseases. Synthetic peptides have also gained importance as diagnostics, especially in the case of small animals, which creates a further growing market for these compounds. Nevertheless, reproduction management is the most important and best established area of usage for peptide drugs in veterinary medicine and animal husbandry. Synthetic peptide hormones and analogs are employed to stimulate and facilitate breeding as well as to prevent unwanted offspring.

Livestock as well as companion animals are treated with LHRH (GnRH, gonadorelin) and its agonists and antagonists to regulate fertility and reproduction as well as to treat disorders of the reproductive tract. A number of LHRH analogs have been applied in the regulation of reproduction in animals:

 

  • Alarelin
  • Azagly-Nafarelin
  • Buserelin
  • Deslorelin
  • Fertirelin
  • Goserelin
  • Lecirelin
  • Leuprolide
  • Lutrelin
  • Nafarelin
  • Peforelin
  • Triptorelin

Gonadotropin-Releasing Hormone (GnRH, LHRH) and Analogs

Besides GnRH, deslorelin, leuprolide, and buserelin are probably the most often commonly prescribed synthetic peptides in veterinary medicine and livestock breeding. GnRH agonists are metabolized more slowly than the native hormone which allows for the use of much lower doses and thus reduces treatment costs. For example, the activity of buserelin was shown to be 100 to 200 times higher than the activity of GnRH, and fertirelin was 2.5 to 10 times more active than the natural peptide.

In female dogs, a single dose of buserelin during heat will induce ovulation. In cows, a postinseminal application will assist the corpus luteum, and administration coinciding with insemination will delay ovulation, which alternatively can be induced by an injection of fertirelin 10 to 17 days postpartum. Repetitive injections of buserelin in mares will effect the onset of heat or ovulation, whereas in rabbits, a single injection of a GnRH analog induces ovulation and increases the conception rate.

Buserelin and fertirelin have also been used in ewes. Overdosage of these highly active peptides can have a detrimental effect on ovarian response. Deslorelin is administered as an injection or implant to induce a reversible infertility in pets, especially in males. These implants can postpone the estrus of bitches for more than 2 years and have found use in the reproduction management of extensive cattle farming. Long-term release formulations of leuprolide have been shown to postpone puberty and reversibly suppressed reproductive function in male and female dogs for periods exceeding 1 year.

Peforelin, which is used in the reproduction management of swine, is a naturally occurring peptide and corresponds to lamprey LHRH III. Peforelin is applied to induce the estrus of the sow after weaning. Depot formulations of triptorelin have been tested in heifers and gilts.

There is a vast market for peptide drugs in the treatment of companion animals and horses.

GnRH agonists such as deslorelin and leuprolide are applied as implants for longterm reproduction management not only in domestic animals. Implants facilitate longterm administration and allow non-surgical sterilization of stray dogs and cats, population control in wildlife, and reproduction management in zoos.

In dairy cattle and camelids, GnRH and GnRH analogs such as buserelin or fertirelin are indicated for the treatment of ovarian cysts. Deslorelin is commonly applied as an implant for treating hyperadrenocorticism in domestic ferrets. Gonadorelin can also be used as a diagnostic in disorders of the reproductive system, e.g. in dogs with hypogonadotropic hypogonadism to differentiate between pituitary and hypothalamic defects.

Anti-GnRH vaccines

As an additional tool for non-surgical spaying, anti-GnRH vaccines were recently developed. The C-terminally elongated peptide hormone is linked to a carrier protein, and the resulting conjugate is applied in combination with an adjuvant to achieve immunization against endogenous LHRH.

A GnRH-keyhole limpet hemocyanin conjugate vaccine has been developed as a contraceptive to control wildlife. Effective after a single vaccination, it has been applied to bison, deer, feral pigs, and others.

In male pigs, the anti-LHRH-vaccine is injected in two doses several weeks before slaughtering to control boar taint. Another anti-LHRH-vaccine has been registered for the treatment of benign prostatic hyperplasia in dogs.

Ovsynch

The synchronization of ovulation in dairy cattle is the most important application of GnRH and analogs in animal husbandry. The Ovsynch protocol using gonadorelin for the controlled induction of ovulation was developed in 1995 by R. Pursley and N. Bello at Michigan State University. The program consists of an initial injection of GnRH followed 7 days later by an injection of prostaglandin F2α(PGF2α).

It can be started at any stage of the estrous cycle. Two days following the PGF2α injection, cows receive a second GnRH injection followed by timed artificial insemination in the next 8 to 24 hours. The efficiency of the synchronization in lactating dairy cows can be further improved by pretreatment with an additional dose of PGF2α (8 days before starting Ovsynch) and GnRH (6 days before starting Ovsynch) (“G6G”, Bello et al., 2006).

Unfortunately, heifers respond only poorly to Ovsynch and artificial insemination, but suitable modifications of the protocol could be developed. Buserelin, fertirelin and other GnRH agonists have also been administered in synchronization schemes. For example, in the recently described Doublesynch scheme, lecirelin has been shown to be especially suitable for primiparous cows.

GnRH in aquaculture

Not all fish species can be bred efficiently by stimulating reproduction with GnRH agonists. Hence, the development of combination products composed of GnRH agonists as (Des-Gly10, D-Arg6, Pro-NHEt9)-salmon GnRH (sGnRH-A), or alarelin (LHRH-A), and dopamine D2 receptor antagonists as pimozine or domperidone meant a breakthrough for fish farming, as they allowed reliable induction and synchronization of ovulation and spawning („Linpe method“).

The synthetic stimulators yield spawn of much higher quality than the pituitary extracts used in controlled fish reproduction. The dopamine antagonist inhibits the synthesis of gonadotropin. The mixture of the ingredients is applied as single dose injection or in pelleted form. The pellets serve as shortterm controlled release implants.

Injectable drugs containing a combination of sGnRHA and domperidone are employed in the controlled hatching of salmon, trout and many other cultured marine and freshwater fish species, as well as in the breeding of ornamental fish. The combination of the dopamine antagonist metoclopramide and LHRH-A in pelleted form assists e.g. in the culturing of freshwater fish as carp, chub and catfish species.

GnRH antagonists

Whereas the veterinarian can choose from a number of proven, highly active and efficient GnRH agonists, the situation on the antagonist side is not yet satisfactory Third-generation antagonists such as acyline, antarelix, antide (iturelix), and cetrorelix have been used in studies with domestic animals, e.g. to prevent ovulation during proestrus or terminate pregnancy.

Oxytocin and Carbetoxin

Oxytocin and its more stable carba analog carbetocin are administered to induce normal labor and facilitate parturition in livestock (cows, ewes, sows, goats) as well as in pets. In captive birds such as budgerigars or cockatiels, oxytocin and its avian analog vasotocin help to induce oviposition in case of egg binding. Oxytocin, which is produced in the hypothalamus, and synthetic carbetocin act on the smooth musculature of the female reproductive system.

Both peptides induce strong contractions of the estrogenstimulated uterus, but distinctly prolonged and more frequent contractions will result during administration of the analog. Simultaneously, these hormones stimulate the lactating glands to produce milk and deblock the teats for ejection.

Oxytocin and carbetocin are also applied in case of agalactia or reduced milk flow after birth. In cows, carbetocin is administered to prevent a retarded involution of the uterus or in case of abnormal milk ejection. A single injection of carbetocin in dysgalactic sows induces milk flow post partum. If drug overdosage may cause problems oxytocin is preferred over carbetocin due to its shorter half-life.

In large animals, oxytocin is administered to stimulate the expulsion of placenta after parturition in case of prolonged retention. Oxytocin is also applied therapeutically: in mares, it is indicated for the treatment of endometritis following insemination. In cows and swine, it is used to treat mastitis.

  Peptide-based drugs are especially indicated for treating animals used in food production, though regulation of fertility is their most important application.

Only very small doses of these rather expensive, but highly active compounds are required. Peptides are metabolized more readily than many small molecules, which reduces the risk of contamination of the milk, eggs, or meat of the treated animal.

Vasopressin and Desmopressin

Vasopressin (Antidiuretic Hormone, ADH), a peptide hormone secreted by the hypothalamus, acts on the renal tubulus cells. Most mammals produce (Arg8)-Vasopressin (Arg-Vasopressin, AVP), whereas the Lys8 analog is secreted in pigs.

The porcine analog shows only half of the antidiuretic activity of AVP. In higher dosage, vasopressin additionally induces vasoconstriction and stimulates the production of factor VIII and von Willebrand factor. Vasopressin is administered intravenously or subcutaneously as a diagnostic to differentiate between renal and central diabetes insipidus in dogs, cats, horses, and cattle.

AVP can also be used as a therapeutic in the treatment of the central form of the disease. However, due to its short half-life, its stable synthetic analog desmopressin (DDAVP) is the preferred medication in the treatment of dogs and cats suffering from polyurea caused by diabetes insipidus centralis.

Compared to vasopressin, desmopressin shows an improved antidiuretic and a reduced vasoconstrictive activity, it more effectively stimulates factor VIII and von Willebrand factor production.

DDAVP is often applied conjunctivally or nasally in dogs and cats, and has even been administered orally in humans. It is applied intravenously or subcutaneously in dogs for treating moderate cases of von Willebrand’s disease before surgery to avoid hemorrhagia.

In animals with von Willebrand’s disease, desmopressin transiently elevates von Willebrand’s factor and shortens bleeding time. It may be useful in dogs with von Willebrand’s disease permitting surgical procedures or controlling capillary bleeding.

The hemostatic effect in cats has not yet been evaluated. Vasopressin is gaining attention in veterinary emergency medicine as a cardiovascular resuscitation drug in small animal patients and newborn foals.

Glucagon, Peptides in Pancreatic Disorders

Glucagon

Glucagon, as its antagonist insulin, is secreted by the pancreas. The peptide hormone is used as emergency medication in cases of severe hypoglycemia, as it upregulates plasma glucose. Management of bovine fatty liver disease (FLD, Steatosis hepatis) is an important application of this hormone in veterinary medicine. FLD is an accumulation of fat (especially triglycerides) in the liver occurring in cows after calving.

The disease can be treated efficiently by longterm intravenous infusion of glucagon. Besides stimulating glycogenolysis, gluconeogenesis, and insulin production, the peptide hormone reduces liver triglycerides. Glucagon is also used as a diagnostic in veterinary medicine, especially in dogs (Glucagon stimulation test). Intravenously injected glucagon causes a short rise in the plasma concentration of insulin in healthy dogs.

This will not happen when administrating glucagon to diabetic canines due to their inability to produce the hormone. But instead of measuring the secreted insulin, determination of the amount of the concomitantly formed C-peptide is preferred, as it is not affected by insulin treatment. The measurement is performed 10 minutes after the glucagon injection.

C-Peptide

Canine C-peptide is applied as a diagnostic tool for monitoring diabetes in dogs. This peptide is released together with insulin from a precursor peptide, so its plasma concentration indicates how much insulin is being produced by the pancreas. The extent of β-cell loss can be deduced from the result.

Determining the amount of C-peptide in diabetic animals allows for therapeutic monitoring as one can differentiate between endogenous (produced by the body) and exogenous (injected into the body) insulin. Inappropriate dosage of insulin in dogs with low blood sugar levels results in a low C-peptide level. Whereas type 1 diabetes is quite common in dogs, type 2 diabetes has not been observed yet.

In case of insulin resistance, the increased concentration of C-peptide results from a high activity level of the pancreas β-cells. Abnormally high amounts of C-peptide can indicate the formation of an insulinoma which secretes insulin.

Octreotide and analogs

Octreotide, a synthetic somatostatin analog showing higher activity and increased half-life, was evaluated in the management of insulinomas in dogs. Octreotide is a long-acting inhibitor of pancreatic secretion, which helps to prevent complications after pancreatic surgery. Single photon emission computed tomography (SPECT) applying 111In-pentetreotide allows the detection and localization of canine insulinomas.

Diagnostics

TRH

As in humans, protirelin (TRH) is injected or infused in pet dogs for diagnosing thyroid disorders as hypothyroidism. TRH acts on the anterior pituitary gland. In the case of a healthy pituitary, application of the hormone stimulates the secretion of TSH, which promotes the secretion of triiodothyronine (T3) and thyroxin (T4) from the thyroid gland. T3 and T4 can be measured in plasma later on.

In horses, a TRH test alone or in combination with the dexamethasone suppression test (DST) is performed to diagnose pituitary gland hyperplasia (pituitary pars intermedia dysfunction (PPID) or equine Cushing’s disease (ECD)).

ACTH and cosyntropin (tetracosactide)

Corticotropin (ACTH) and cosyntropin (tetracosactide) are used diagnostically to detect adrenal disorders, especially in dogs, cats, and horses. Both peptides stimulate the adrenal cortex (zona fasciculata) and induce the production of glucocorticoids. The use of cosyntropin is indicated in case of allergic reactions to the natural hormone.

In dogs, blood samples have to be taken preceding the intravenous or intramuscular injection of the peptide to obtain the basal cortisol value, and one hour after the administration.

Canine Cushing’s disease (hyperadrenocorticism, rather common in dogs but occurs rarely in cats) and Addison’s disease (hypoadrenocorticism, in cats and dogs) can both be diagnosed. In case of spontaneous hyperadrenocorticism, the ACTH test is also performed to monitor the effects of medication. In neonatal foals, cosyntropin stimulation is a reliable test for dysfunctions of the hypothalamic-pituitary-adrenal axis.

Ceruletide

Ceruletide (caerulein) has been proposed as a diagnostic of hepatic dysfunctions in dogs. The cholecystokinin (CCK) analog stimulates postprandial serum bile acid, and is a more efficient secretagogue than CCK. As hepatopathy can occur in dogs suffering from severe respiratory diseases, administration of ceruletide as a liver function test should be performed routinely with such patients.

Prospective Peptide Drugs

Peptide drugs

Peptide drugs such as exenatide or teriparatide, which have been successfully established in human medicine, can likely also be applied to treat similar medical conditions of companion animals and horses. The somatostatin analogs lanreotide and the recently approved pasireotide also show potential in veterinary medicine, e.g. in the treatment of canine Cushing’s disease or feline hypersomatotropism.

In the management of cancer and development of new (peptide) therapeutics, human patients can profit from the experience gained with afflicted pet dogs and vice versa, as naturally occurring cancers in these species share many features including biological behavior and the response to conventional therapies.

Peptide vaccines

Peptide-based vaccines could be a safer alternative to immunization using the inactivated virus. Peptide vaccines present a number of advantages, as they are easily available (also on large scale), relatively cheap, shelf-stable, chemically well-defined compounds.

A number of studies evaluating synthetic peptides (immunogenic sequences from viral proteins, used in combination with a suitable adjuvant for inoculation) as vaccines against viral diseases affecting livestock such as foot-and-mouth disease or swine fever have been published.

Antimicrobial peptides

An alternative to the antibiotics used in animals involved in food production may come from antimicrobial peptides, which have been described in many organisms. These peptides have a wide spectrum of action.

They can kill gram negative and gram positive bacteria, enveloped viruses, yeasts, and moulds. Several peptides were recently discovered in shrimp and oysters, where they are essential elements of innate defense, in the absence of acquired immunity.

These molecules could advantageously replace antibiotics, since they are less susceptible to cause resistance in the target microorganisms, due to their direct action on membranes, and to their fast degradability, which avoid the accumulation of residues. Application of antibacterial peptides is an attractive option for intensive animal husbandry such as poultry farming and, especially, aquaculture.

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References

LHRH (GnRH) and Analogs

LHRH and LHRH agonists

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T.E. Trigg et al.
A review of advances in the use of the GnRH agonist deslorelin in control of reproduction.
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E.U. Baitlesov et al.
Etiology and pathogenesis of ovarian cysts in cows and possibility of normalizing ovarian function.
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K.P. Brüssow et al.
Luteinizing hormone release after administration of the gonadotropin-releasing hormone agonist Fertilan (goserelin) for synchronization of ovulation in pigs.
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C. Gobello
New GnRH analogs in canine reproduction.
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M.A. Kutzler
Estrus induction and synchronization in canids and felids.
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L.C. Metrione et al.
Preliminary evaluation of deslorelin, a GnRH agonist for contraception of the captive variable flying fox Pteropus hypomelanus.
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Anti-GnRH vaccines

F.R. Dunshea et al.
Vaccination of boars with a GnRH vaccine (Improvac) eliminates boar taint and increases growth performance.
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J.K. Levy et al.
GnRH immunocontraception of male cats.
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L.A. Miller et al.
Contraception of bison by GnRH vaccine: a possible means of decreasing transmission of brucellosis in bison.
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G. Killian et al.
Immunocontraception of Florida feral swine with a single-dose GnRH vaccine.
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Ovsynch

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Synchronization of ovulation in dairy cows using PGF2α and GnRH.
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H. Twagiramungu et al.
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P.S. Baruselli et al.
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A.R. Rabiee et al.
Efficacy of Ovsynch program on reproductive performance in dairy cattle: a metaanalysis.
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N.M. Bello et al.
Optimizing ovulation to first GnRH improved outcomes to each hormonal injection of ovsynch in lactating dairy cows.
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M.G. Colazo et al.
Resynchronization of estrus in beef cattle: Ovarian function, estrus and fertility following progestin treatment and treatments to synchronize ovarian follicular development and estrus.
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W.W. Thatcher and J.E. Santos
Control of ovarian follicular and corpus luteum development for the synchronization of ovulation in cattle.
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J.W. Lauderdale
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T. Osawa et al.
Effect of synchronisation of ovulation on ovarian profile and days open in holstein cows diagnosed as nonpregnant 26 days after timed artificial insemination.
J. Reprod. Devel. 55, 163-169 (2009)

J. Taponen
Fixed-time artificial insemination in beef cattle.
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Ö.A. Öztürk et al.
Is Doublesynch protocol a new alternative for timed artificial insemination in anestrous dairy cows.
Theriogenology 73, 568-576 (2010)

GnRH in aquaculture

H.R. Lin et al.
Effects of (sGnRH-A) and [D-Arg6, Trp7, Leu8, Pro9NEt]-luteinizing hormone-releasing hormone (LHRH-A), in combination with pimozide or domperidone, on gonadotropin release and ovulation in the Chinese loach and common carp.
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Y. Zohar
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C.R. Kramer et al.
sGnRH-A [(D-Arg6, Pro9 NEt-)LHRH] in combination with domperidone induces gonad reversal in a protogynous fish, the bluehead wrasse, Thalassoma bifasciatum.
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H.R. Lin and R.E. Peter
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C.C. Mylonas and Y. Zohar
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E. Brzuska et al.
The application of [D-Tle6,ProNHEt9]mGnRH (Lecirelin) with the dopaminergic inhibitor metoclopramide to stimulate ovulation in African catfish (Clarias gariepinus).
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V.R. Cerqueira and M.Y. Tsuzuki
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C. Gillet and B. Breton
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GnRH antagonists

A.M. Hinojosa et al.
The effect of a GnRH antagonist on endocrine and seminal parameters in stallions.
Theriogenology 56, 903-912 (2001)
(Antarelix)

H. Ulker et al.
LHRH antagonist decreases LH and progesterone secretion but does not alter length of estrous cycle in heifers.
J. Anim. Sci. 79, 2902-2907 (2001)
(Cetrorelix)

M.J. Evans et al.
Effectiveness of an antagonist to gonadotrophin releasing hormone on the FSH and LH response to GnRH in perifused equine pituitary cells, and in seasonally acyclic mares.
Anim. Reprod. Sci. 73, 37-51 (2002)
(Cetrorelix)

K.M. Pelican et al.
Short term suppression of follicular recruitment and spontaneous ovulation in the cat using levonorgestrel versus a GnRH antagonist.
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(Antide)

Oxytocin and Carbetocin

J.R. Owiny et al.
Effect of pulsatile intravenous oxytocin administration to pregnant sheep over the last third of gestation on fetal ACTH and cortisol responses to hypotension.
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J.W. Lemaster et al.
Effects of administration of oxytocin on embryonic survival in progestogen supplemented cattle.
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T.A.E. Stout et al.
Oxytocin administration prolongs luteal function in cyclic mares.
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S. Gutjahr et al.
Effect of dose and day of treatment on uterine response to oxytocin in mares.
Theriogenology 54, 447-456 (2000)

J. Riedl et al.
Aetiology of reduced milk ejection in cows after transport and the use of a long-acting analogue of oxytocin for prophylaxis.
Vet. Rec. 148, 653-656 (2001)

A.C. Bajcsy et al.
The effect of a single oxytocin or carbetocin treatment on uterine contractility in early postpartum dairy cows.
Theriogenology 65, 400-414 (2006)

D. Mota-Rojas et al.
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A.R. Schramme et al.
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A.J. Barrett et al.
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Vet. Rec. 165, 623-626 (2009)

Vasopressin and Desmopressin

P.A. van Wijk et al.
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Eur. J. Endocrinol. 130, 410-416 (1994)

V. Bizub and L. Leng
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Res. Vet. Sci. 62, 189-190 (1997)

M.B. Callan and U. Giger
Effect of desmopressin acetate administration on primary hemostasis in Doberman Pinschers with type-1 von Willebrand disease as assessed by a point-of-care
instrument.
Am. J. Vet. Res. 63, 1700-1706 (2002)

C.A. Schmittinger et al.
Cardiopulmonary resuscitation with vasopressin in a dog.
Vet. Anaesth. Analg. 32, 112-114 (2005)

A.R. Hollis et al.
Plasma aldosterone, vasopressin and atrial natriuretic peptide in hypovolaemia: a preliminary comparative study of neonatal and mature horses.
Equine Vet. J. 40, 64-69 (2008)

S.J. Plunkett and M. McMichael
Cardiopulmonary resuscitation in small animal medicine: an update.
J. Vet. Intern. Med. 22, 9-25 (2008)

F. Zeugswetter et al.
The desmopressin stimulation test in dogs with Cushing’s syndrome.
Domest. Anim. Endocrinol. 34, 254-260 (2008)

R.D. Scroggin Jr. and J. Quandt
The use of vasopressin for treating vasodilatory shock and cardiopulmonary arrest.
J. Vet. Emerg. Crit. Care (San Antonio) 19, 145-157 (2009)

G.A. Hermo et al.
Effect of adjuvant perioperative desmopressinin locally advanced canine mammary carcinoma and its relation to histologic grade.
J. Am. Anim. Hosp. Assoc. 47, 21-27 (2011)

Glucagon, Peptides in Pancreatic Disorders

Glucagon, C-peptide (diabetes)

K. Yasuda et al.
Exocrine pancreatic function in diabetic dogs.
Jpn. J. Vet. Sci. 50, 1271-1273 (1988)

T.M. Montgomery et al.
Basal and glucagon-stimulated plasma C-peptide concentrations in healthy dogs, dogs with diabetes mellitus, and dogs with hyperadrenocorticism.
J. Vet. Intern. Med. 10, 116-122 (1996)

J.R. Fischer et al.
Glucagon constant-rate infusion: a novel strategy for the management of hyperinsulinemic-hypoglycemic crisis in the dog.
J. Am. Anim. Hosp. Assoc. 36, 27-32 (2000)

J.S. Rand et al.
Canine and feline diabetes mellitus: Nature or nurture?
J. Nutr. 134, 2072S-2080S (2004)

T. Fall et al.
Diabetes mellitus in a population of 180,000 insured dogs: incidence, survival, and breed distribution.
J. Vet. Intern. Med. 21, 1209-1216 (2007)

T. Fall et al.
Glucagon stimulation test for estimating endogenous insulin secretion in dogs.
Vet. Rec. 163, 266-270 (2008)

L.M. Fleeman et al.
Pharmacokinetics and pharmacodynamics of porcine insulin zinc suspension in eight diabetic dogs.
Vet. Rec. 164, 232-237 (2009)

R.S. Hess
Insulin resistance in dogs.
Vet. Clin. North Am. Small Anim. Pract. 40, 309-316 (2010)
Glucagon (Hepatic Steatosis)

A.R. Hippen et al.
Alleviation of fatty liver in dairy cows with 14-day intravenous infusions of glucagon.
J. Dairy Sci. 82, 1139-1152 (1999)

A.R. Hippen
Glucagon as a potential therapy for ketosis and fatty liver.
Vet. Clin. North Am. Food Anim. Pract. 16, 267-282 (2000)

R.A. Nafikov et al.
Prevention of fatty liver in transition dairy cows by subcutaneous injections of glucagon.
J. Dairy Sci. 89, 1533-1545 (2006)

G. Bobe et al.
Exogenous glucagon effects on health and reproductive performance of lactating dairy cows with mild fatty liver.
Anim. Reprod. Sci. 102, 194-207 (2007)

M.A. Osman et al.
Acute metabolic responses of postpartal dairy cows to subcutaneous glucagon injections, oral glycerol, or both.
J. Dairy Sci. 91, 3311-3322 (2008)

Octreotide and analogs

K.W. Simpson et al.
Evaluation of the long-acting somatostatin analogue octreotide in the management of insulinoma in three dogs.
J. Small Anim. Pract. 36, 161-165 (1995)

M. Altschul et al.
Evaluation of somatostatin analogues for the detection and treatment of gastrinoma in a dog.
J. Small Anim. Pract. 38, 286-291 (1997)

C. Khanna et al.
A randomized controlled trial of octreotide pamoate long-acting release and carboplatin versus carboplatin alone in dogs with naturally occurring osteosarcoma: evaluation of insulin-like growth factor suppression and chemotherapy.
Clin. Cancer Res. 8, 2406-2412 (2002)

J.H. Robben et al.
Comparison of ultrasonography, computed tomography, and single-photon emission computed tomography for the detection and localization of canine insulinoma.
J. Vet. Intern. Med. 19, 15-22 (2005)

J.H. Robben et al.
Effect of octreotide on plasma concentrations of glucose, insulin, glucagon, growth hormone, and cortisol in healthy dogs and dogs with insulinoma.
Res. Vet. Sci. 80, 25-32 (2006)

L.I. Slingerland et al.
Growth hormone excess and the effect of octreotide in cats with diabetes mellitus.
Domest. Anim. Endocrinol. 35, 352-361 (2008)

U. Oberkirchner et al.
Successful treatment of canine necrolytic migratory erythema (superficial necrolytic dermatitis) due to metastatic glucagonoma with octreotide.
Vet. Dermatol. 21, 510-516 (2010)

Diagnostics

TRH

A. Burkhard and W. Kraft
[The thyrotropin-releasing hormone (TRH) test in the dog: injection or infusion?]
Tierärztl. Prax. 22, 159-164 (1994)

B.P. Meij et al.
Thyroid-stimulating hormone responses after single administration of thyrotropinreleasing hormone and combined administration of four hypothalamic releasing hormones in beagle dogs.
Domest. Anim. Endocrinol. 13, 465-468 (1996)

B.P. Meij et al.
Residual pituitary function after transsphenoidal hypophysectomy in dogs with pituitary-dependent hyperadrenocorticism.
J. Endocrinol. 155, 531-539 (1997)

M.M. Diaz-Espiñeira et al.
Thyrotropin-releasing hormone-induced growth hormone secretion in dogs with primary hypothyroidism.
Domest. Anim. Endocrinol. 34, 176-181 (2008)

TRH (Equine Cushing’s disease)

F.M. Andrews et al.
Diagnosis of pituitary adenoma by using a combined dexamethasone suppression and TRH stimulation test.
AAEP Proc. 43, 349-351 (1997)

M.T. Donaldson et al.
Treatment with pergolide or cyproheptadine of pituitary pars intermedia dysfunction (equine Cushing’s disease).
J. Vet. Intern. Med. 16, 742-746 (2002)

H.C. Schott 2nd
Pituitary pars intermedia dysfunction: equine Cushing’s disease.
Vet. Clin. North Am. Equine Pract. 18, 237-270 (2002)

C.M. McGowan and R. Neiger
Efficacy of trilostane for the treatment of equine Cushing’s syndrome.
Equine Vet. J. 35, 414-418 (2003)

D. McFarlane et al.
Alpha-melanocyte stimulating hormone release in response to thyrotropin releasing hormone in healthy horses, horses with pituitary pars intermedia dysfunction and equine pars intermedia explants.
Domest. Anim. Endocrinol. 30, 276-288 (2006)

J. Beech et al.
Adrenocorticotropin concentration following administration of thyrotropin-releasing hormone in healthy horses and those with pituitary pars intermedia dysfunction and pituitary gland hyperplasia.
J. Am. Vet. Med. Assoc. 231, 417-426 (2007)

ACTH and tetracosactide

H. Eiler et al.
Adrenal gland function in the horse: effects of cosyntropin (synthetic) and corticotropin (natural) stimulation.
Am. J. Vet. Res. 40, 724-726 (1979)

M.E. Peterson and R.J. Kemppainen
Comparison of the immunoreactive plasma corticotropin and cortisol responses to two synthetic corticotropin preparations (tetracosactrin and cosyntropin) in healthy cats.
Am. J. Vet. Res. 53, 1752-1755 (1992)

L.A. Frank and J.W. Oliver
Comparison of serum cortisol concentrations in clinically normal dogs after administration of freshly reconstituted versus reconstituted and stored frozen cosyntropin.
J. Am. Vet. Med. Assoc. 212, 1569-1571 (1998)

L.A. Frank et al.
Cortisol concentrations following stimulation of healthy and adrenopathic dogs with two doses of tetracosactrin.
J. Small Anim. Pract. 41, 308-311 (2000)

J.C. Ousey et al.
Effects of maternally administered depot ACTH(1-24) on fetal maturation and the timing of parturition in the mare.
Equine Vet. J. 32, 489-496 (2000)

J.P. Schoeman et al.
Cortisol response to two different doses of intravenous synthetic ACTH (tetracosactrin) in overweight cats.
J. Small Anim. Pract. 41, 552-557 (2000)

S. Paltrinieri et al.
Effect of 1-24 ACTH administration on sheep blood granulocyte functions.
Vet. Res. 33, 71-82 (2002)

L.A. Frank et al.
Steroid hormone concentration profiles in healthy intact and neutered dogs before and after cosyntropin administration.
Domest. Anim. Endocrinol. 24, 43-57 (2003)

L.A. Frank et al.
Serum concentrations of cortisol, sex hormones of adrenal origin, and adrenocortical steroid intermediates in healthy dogs following stimulation with two doses of cosyntropin.
Am. J. Vet. Res. 65, 1631-1633 (2004)

R.J. Kemppainen et al.
Use of compounded adrenocorticotropic hormone (ACTH) for adrenal function testing in dogs.
J. Am. Anim. Hosp. Assoc. 41, 368-372 (2005)

E.N. Behrend et al.
Intramuscular administration of a low dose of ACTH for ACTH stimulation testing in dogs.
J. Am. Vet. Med. Assoc. 229, 528-530 (2006)

K.A. Hart et al.
Synthetic adrenocorticotropic hormone stimulation tests in healthy neonatal foals.
J. Vet. Intern. Med. 21, 314-321 (2007)

Y. Hedberg et al.
Effect of ACTH (tetracosactide) on steroid hormone levels in the mare. Part A: effect in intact normal mares and mares with possible estrous related behavioral abnormalities.
Anim. Reprod. Sci. 100, 73-91 (2007)

Y. Hedberg et al.
Effect of ACTH (tetracosactide) on steroid hormone levels in the mare. Part B: effect inovariectomized mares (including estrous behavior).
Anim. Reprod. Sci. 100, 92-106 (2007)

L.G. Martin et al.
Effect of low doses of cosyntropin on serum cortisol concentrations in clinically normal dogs.
Am. J. Vet. Res. 68, 555-560 (2007)

J.P. Schoeman and M.E. Herrtage
Adrenal response to the low dose ACTH stimulation test and the cortisol-to-adrenocorticotrophic hormone ratio in canine babesiosis.
Vet. Parasitol. 154, 205-213 (2008)

K.A. Hart et al.
Hypothalamic-pituitary-adrenal axis assessment in healthy term neonatal foals utilizing a paired low dose/high dose ACTH stimulation test.
J. Vet. Intern. Med. 23, 344-351 (2009)

D.M. Wong et al.
Adrenocorticotropic hormone stimulation tests in healthy foals from birth to 12 weeks of age.
Can. J. Vet Res. 73, 65-72 (2009)

T.A. Cohen and E.C. Feldman
Comparison of IV and IM formulations of synthetic ACTH for ACTH stimulation tests in healthy dogs.
J. Vet. Intern. Med. 26, 412-414 (2012)

P.J. Ginel et al.
Evaluation of serum concentrations of cortisol and sex hormones of adrenal gland origin after stimulation with two synthetic ACTH preparations in clinically normal dogs.
Am. J. Vet. Res. 73, 237-241 (2012)

ACTH (Cushing’s disease)

B. Meij et al.
Progress in transsphenoidal hypophysectomy for treatment of pituitary-dependent hyperadrenocorticism in dogs and cats.
Mol. Cell. Endocrinol. 197, 89-96 (2002)

C.E. Reusch
Hyperadrencorticism.
In: Textbook of Veterinary Internal Medicine, Vol. II (S.J. Ettinger & E.C. Feldman, eds), W.B.
Saunders Co., Philadelphia (USA), 6th Ed., 1592-1612 (2005)

M.E. Peterson
Diagnosis of hyperadrenocorticism in dogs.
Clin. Tech. Small Anim. Pract. 22, 2-11 (2007)

C.L. McLean
Management of Cushing’s syndrome in dogs.
Vet. Rec. 165, 512 (2009)

ACTH (Addison’s disease)

T.R. Famula et al.
Heritability and complex segregation analysis of hypoadrenocorticismin the standard poodle.
J. Small Anim. Pract. 44, 8-12 (2003)

M.E. Herrtage
Hypoadrencorticism.
In: Textbook of Veterinary Internal Medicine, Vol. II (S.J. Ettinger & E.C. Feldman, eds), W.B.
Saunders Co., Philadelphia(USA), 6th Ed., 1612-1622 (2005)

D.S. Greco
Hypoadrenocorticism in small animals.
Clin. Tech. Small Anim. Pract. 22, 32-35 (2007)

P. Lathan et al.
Use of a low-dose ACTH stimulation test for diagnosis of hypoadrenocorticism in dogs.
J. Vet. Intern. Med. 22, 1070-1073 (2008)

Ceruletide

M. Rufer and E.G. Grünbaum
[Bile acid stimulation test with ceruletide.]
Tierärztl. Prax. 25, 80-84 (1997)

N.B. Bauer et al.
Liver disease in dogs with tracheal collapse.
J. Vet. Intern. Med. 20, 845-849 (2006)

N. Bridger et al.
Comparison of postprandial and ceruletide serum bile acid stimulation in dogs.
J. Vet. Intern. Med. 22, 873-878 (2008)

Prospective Peptide Drugs

Peptide drugs

A. Fuerst et al.
Use of a parathyroid hormone peptide (PTH(1-34))-enriched fibrin hydrogel for the treatment of a subchondral cystic lesion in the proximal interphalangeal joint of a warmblood filly.
J. Vet. Med. A Physiol. Pathol. Clin. Med. 54, 107-112 (2007)

M. Paoloni and C. Khanna
Translation of new cancer treatments from pet dogs to humans.
Nat. Rev. Cancer 8, 147-156 (2008)

C.C. Smith and C.K. Cebra
Effects of exenatide on plasma glucose and insulin concentrations in alpacas.
J. Vet. Intern. Med. 23, 919-925 (2009)

V. Castillo et al.
Effect of SOM230 (pasireotide) on corticotropic cells: action in dogs with Cushing’s disease.
Neuroendocrinology 94, 124-136 (2011)

C. Gilor et al.
The GLP-1 mimetic exenatide potentiates insulin secretion in healthy cats.
Domest. Anim. Endocrinol. 41, 42-49 (2011)

S. Niessen et al.
Pasireotide (SOM230) opens doors to medical management of feline hypersomatotropism.
J. Vet. Intern. Med. 27, 685 (2013)

C.K. Cebra et al.
Exenatide dosing in alpacas.
J. Vet. Pharmacol. Ther. 37, 417-420 (2014)

C.J. Scudder et al.
Pasireotide for the medical management of feline hypersomatotropism.
J. Vet. Intern. Med. 29, 1074-1080 (2015)

Peptide vaccines

J.H. Patarroyo et al.
Immunization of cattle with synthetic peptides derived from the Boophilus microplus gut protein (Bm86).
Vet. Immunol. Immunopathol. 88, 163-172 (2002)

A.S. Beignon et al.
A peptide vaccine administered transcutaneously together with cholera toxin elicits potent neutralising anti-FMDV antibody responses.
Vet. Immunol. Immunopathol. 104, 273-280 (2005)

X.N. Dong et al.
Candidate multi-peptide-vaccine against classical swine fever virus induced potent immunity with serological marker.
Vaccine 23, 3630-3633 (2005)

E. Cox et al.
Adjuvants modulating mucosal immune responses or directing systemic responses towards the mucosa.
Vet. Res. 37, 511-539 (2006)

C.M. Hardy and A.L. Braid
Vaccines for immunological control of fertility in animals.
Rev. Sci. Tech. 26, 461-470 (2007)

E.N.T. Meeusen et al.
Current status of veterinary vaccines.
Clin. Microbiol. Rev. 20, 489-510 (2007)

Antimicrobial peptides

A. Sarmasik
Antimicrobial peptides: A potential therapeutic alternative for the treatment of fish diseases.
Turk. J. Biol. 26, 201-207 (2002)

R.D. Joerger
Alternatives to antibiotics: bacteriocins, antimicrobial peptides and bacteriophages.
Poult. Sci. 82, 640-647 (2003)

T. Dorrington and M. Gomez-Chiarri
Antimicrobial peptides for use in oyster aquaculture: effect on pathogens, commensals, and eukaryotic expression systems.
J. Shellfish Res. 27, 365-373 (2008)

A. Falco et al.
Antimicrobial peptides as model molecules for the development of novel antiviral agents in aquaculture.
Mini Rev. Med. Chem. 9, 1159-1164 (2009)

C.H. Li et al.
A review of advances in research on marine molluscan antimicrobial peptides and their potential application in aquaculture.
Molluscan Res. 29, 17-26 (2009)

Non-Peptide Generic APIs

Etomidate

L.S. Pablo and J.E. Bailey
Etomidate and telazol.
Vet. Clin. North Am. Small Anim. Pract. 29, 779-792 (1999)

C.J. Broome and V.P. Walsh
Gastric dilatation-volvulus in dogs.
NZ Vet. J. 51, 275-283 (2003)

L. Fresno et al.
The effects on maternal and fetal cardiovascular and acid-base variables after the administration of etomidate in the pregnant ewe.
Vet. J. 177, 94-103 (2008)

J.M. Rodriguez et al.
Comparison of the cardiopulmonary parameters after induction of anaesthesia with alphaxalone or etomidate in dogs.
Vet. Anaesth. Analg. 39, 357-365 (2012)

G.D. Readman et al.
Do fish perceive anaesthetics as aversive?
PLoS ONE 8, e73773 (2013)

S. Sanchis-Mora et al.
Anaesthetic management and complications of pacemaker implantation in dogs.
Vet. Rec. 175, 303 (2014)

B. Qin et al.
Effects of continuous infusion of etomidate at various dose rates on adrenal function in dogs.
BMC Anesthesiol. 16, 2 (2016)

Propofol

C.E. Short and A. Bufalori
Propofol anesthesia.
Vet. Clin. North Am. Small Anim. Pract. 29, 747-778 (1999)

G.L. Covey-Crump and P.J. Murison
Fentanyl or midazolam for co-induction of anaesthesia with propofol in dogs.
Vet. Anaesth. Analg. 35, 463-472 (2008)

V. Andreoni et al.
Propofol and fentanyl infusions in dogs of various breeds undergoing surgery.
Vet. Anaesth. Analg. 36, 523-531 (2009)

R.J. Brosnan and E.P. Steffey
Sedative effects of propofol in horses.
Vet. Anaesth. Analg. 36, 421-425 (2009)

K.E. Joubert
Computer simulations of propofol infusions for total intravenous anaesthesia in dogs.
J. S. Afr. Vet. Assoc. 80, 2-9 (2009)

K.R. Mama et al.
Multicenter clinical evaluation of a multidose formulation of propofol in the dog.
BMC Vet. Res. 9, 261 (2013)

S. Sanchis-Mora et al.
Anaesthetic management and complications of pacemaker implantation in dogs.
Vet. Rec. 175, 303 (2014)

A. Cattai et al.
The incidence of spontaneous movements (myoclonus) in dogs undergoing total intravenous anaesthesia with propofol.
Vet. Anaesth. Analg. 42, 93-8 (2015)

I. Cerasoli et al.
The effects of intravenous lidocaine before propofol induction in premedicated dogs.
J. Small Anim. Pract. 57, 435-40 (2016)

H.X. Diao et al.
Comparison of the effects of propofol and emulsified isoflurane alone or combined with dexmedetomidine on induction of anesthesia in dogs.
Vet. Anaesth. Analg. 43, 145-52 (2016)

E.A. Minghella et al.
Clinical effects of midazolam or lidocaine co-induction with a propofol target-controlled infusion (TCI) in dogs.
Vet. Anaesth. Analg. 43,472-81 (2016)