LUT12001 March 2012 LUTALYSE® and cloprostenol: Clearing up misconceptions Fred Moreira, DVM, MS, Ph.D. Doug Hammon, DVM, Ph.D. Pfizer Animal Health Pfizer Animal Health Summary • LUTALYSE® (dinoprost tromethamine) Sterile Solution contains the natural prostaglandin F2α (dinoprost) as a tromethamine salt, whereas cloprostenol is an analogue of prostaglandin F2α. • Although active ingredients and their properties differ between the two products, both LUTALYSE and cloprostenol induce luteolysis by triggering a cascade of endogenous events that ultimately lead to the regression of the corpus luteum (CL). • Collectively, data in the scientific literature indicates there are no differences in efficacy between LUTALYSE and cloprostenol. The U.S. Food and Drug Administration (FDA) confirmed this conclusion in a 2010 communication to Intervet/Schering-Plough. • The benefits of using LUTALYSE extend beyond the contents of the vial. LUTALYSE is the most researched prostaglandin in the U.S. and is backed by the Pfizer Animal Health Field Force, the largest of its kind in the industry. The unparalleled support that customers of LUTALYSE receive makes it the undisputable market leader and the prostaglandin of choice to cattle producers. UTALYSE® (dinoprost tromethamine) Nonetheless, competitive suppliers have Sterile Solution has been approved for pursued advertising and sales messaging that synchronizationL of estrus in cattle for more suggest LUTALYSE is not as efficacious than 30 years. It has been the most widely used as cloprostenol or does not work under prostaglandin product since its launch and is the modern conditions. Intervet/Schering-Plough trusted foundation of breeding programs across (now known as Merck Animal Health), the country. Pfizer Animal Health, the makers of which markets cloprostenol as Estrumate® LUTALYSE have invested heavily in research (cloprostenol sodium) in the U.S., was the to understand all aspects of the biology and source of this misleading messaging. FDA practical use of LUTALYSE under commercial issued communication Sept. 16, 2010, ordering conditions. This has not only furthered Intervet/Schering-Plough to immediately cease understanding of LUTALYSE but also has and desist claims of biological superiority in helped move reproductive management forward comparison with LUTALYSE, as these claims within the U.S. dairy industry. have not been demonstrated by substantial evidence or substantial clinical experience. OH Prostaglandin F Cloprostenol sodium 2α OH COOH COOH LUTALYSE® (dinoprost tromethamine) Sterile The route of administration is intramuscular, CH3 O Solution, cloprostenol and other prostaglandins whereas the intravenous administration of have been researched in hundreds of published LUTALYSE is contraindicated. The subcutaneous OH OH Cl OH OH studies. From time to time, any one particular route has not been fully examined; it is not an trial may show one prostaglandin product is approved route of administration and, therefore, LUTALYSE® (dinoprost tromethamine) Sterile Solution or cloprostenol. numerically superior to the other by chance. is not recommended. These differences may even be significant in As with all parenteral products, aseptic technique some cases. Most times, the very same data do should be used to reduce the possibility of post- not indicate a statistical difference between the injection bacterial infections. Do not administer two products, just a numerical difference that it in pregnant animals unless cessation of pregnancy is unduly interpreted as relevant. FDA addressed is desired. Not for intravenous administration. these superiority claims and determined them to Women of childbearing age and persons with be unsubstantiated. respiratory problems should exercise extreme The data in the scientific literature caution when handling this product. overwhelmingly indicate there are no In the U.S., cloprostenol is sold as Estrumate® differences in efficacy between LUTALYSE and the generic product called estroPLAN®, and cloprostenol. The objective of this which contains cloprostenol sodium, a salt technical bulletin is to provide a review of the form of the synthetic analogue. The original science and peer-reviewed, published data on chemical structure of PGF2α (Figure 2) was LUTALYSE and the other prostaglandins. modified to result in cloprostenol. Each milliliter of Estrumate contains 250 mcg of cloprostenol Chemical Structures equivalent. The suggested dose of Estrumate is 2 mL, to be used intramuscularly. LUTALYSE contains the naturally occurring Due to these structural modifications, prostaglandin F2α (PGF2α; dinoprost) as a tromethamine salt. Its chemical structure cloprostenol has some different properties when is depicted in Figure 2. Each milliliter of compared with dinoprost. Cloprostenol does LUTALYSE contains dinoprost tromethamine have a higher affinity for the PGF2α receptor, and equivalent to 5 mg of dinoprost. Dose titration there are indications it may have a slightly longer studies have indicated 25 mg of dinoprost half-life. However, as indicated below, these (i.e., 5 mL of LUTALYSE) is the most attributes do not correlate with a higher efficacy appropriate dose. to synchronize estrus in cattle. Also noteworthy is the fact that cloprostenol, as it relates to its optical orientation, is a racemic solution. That means it can be either dextrorotatory (D-) or levorotatory (L-). It was observed that only D-cloprostenol binds to the prostaglandin receptors. In some countries, companies started producing the D- form and selling the concept that this is the reason why “now” cloprostenol works better than dinoprost. Unless recent modifications were introduced, Estrumate remains a racemic solution. Figure 1 – Number of original research articles since 1994 published in the Journal of Animal Science, Journal of Dairy Science and Theriogenology that reported use of prostaglandins. LUTALYSE was the prostaglandin product cited in 87% (186/214) of the references. OH Prostaglandin F Cloprostenol sodium 2α OH COOH COOH CH3 O OH Cl OH OH OH LUTALYSE® (dinoprost tromethamine) Sterile Solution or cloprostenol. Figure 2 – Chemical structures of PGF 2a (dinoprost) and cloprostenol sodium. 2 OH Prostaglandin F Cloprostenol sodium 2α OH COOH COOH CH3 O OH Cl OH OH OH LUTALYSE® (dinoprost tromethamine) Sterile Solution or cloprostenol. The Luteolytic Process Figure 3A – This depicts the reproductive tract with the uterine The complete regression of the CL is the main body, uterine horns, oviducts, and objective to be achieved after an injection of right and left ovaries are in blue. A corpus luteum (CL; in orange) is PGF2α or its analogues. The regression of the depicted on the right ovary, and a CL and the consequent decrease in progesterone dominant follicle is shown (in red) concentration allow for the final maturation of on the left ovary. The CL in the right ovary is actively producing the pre-ovulatory follicle and for an increase in progesterone. Secretion of the circulating levels of estradiol. estradiol by the dominant follicle is low, due to the high The rise in estradiol concentrations stimulate concentrations of progesterone the immune system in the uterus and leads to a secreted by the CL. surge of luteinizing hormone (LH) release that Figure 3B – The events that will induce ovulation. These events ultimately follow an injection of PGF2a: the are responsible for the main indications of injected PGF2a reaches the CL (1) and functions as a “trigger” prostaglandins: that induces the secretion of • Synchronization of estrus in cattle oxytocin from the CL (2). Oxytocin secreted by the CL reaches the • Treatment of uterine infections such uterus and stimulates the release as pyometra of endogenous PGF2a (3). The • Induction of abortion in pregnant cattle endogenous PGF2a goes back to the CL and induces the release of The series of illustrations to the right demonstrate more oxytocin. the events that occur in the reproductive tract Figure 3C – The continuous following an injection of PGF2α or its analogues. PGF2a- oxytocin cycle is triggered by the initial injection of PGF2a. As described in Figures 3A-3D, the initial The oxytocin produced by the injection of PGF2α simply triggers the events CL continues to stimulate the that ultimately will lead to the regression of secretion of endogenous PGF2a by the uterus, which further the CL and to the decrease of progesterone stimulates the secretion of concentrations. oxytocin by the CL in a classic feedback mechanism. As the CL regresses, concentrations Effects on Progesterone of progesterone decrease. This Concentration cycle continues until the CL is completely regressed. The decrease in progesterone concentration is Figure 3D – In Figure 2D, at the signal for the increase in estradiol, which will the end of the feedback cycle, induce estrous behavior. Thus, when comparing the the CL is completely regressed ® and, in its place, there only efficacy of LUTALYSE (dinoprost tromethamine) remains a scar (corpus albicans). Sterile Solution and cloprostenol, researchers Since progesterone is not being measured the ability of each prostaglandin to produced, secretion of estradiol decrease progesterone concentrations. from the dominant follicle is increased. Estradiol will reach Seguin, et al. (1985), injected nonlactating behavioral centers in the brain dairy cows with either LUTALYSE (n=62) and stimulate estrous behavior. Estradiol will also induce a surge or cloprostenol (n=62) and measured plasma of luteinizing hormone (LH) that progesterone