FREE SHIPPING over $40
OVER 9000 FIVE-STAR REVIEWS
5% OFF ALL SUBSCRIPTIONS
100% HAPPINESS GUARANTEE
Analyze Diet
0
Home / Equine Research Bank / J Vet Intern Med / Effect of sirolimus on insulin dynamics in horses.
Journal of veterinary internal medicine2023; 37(2); 703-712; doi: 10.1111/jvim.16650

Effect of sirolimus on insulin dynamics in horses.

Abstract: Sirolimus, a mechanistic target of rapamycin inhibitor, suppresses insulin production in other species and has therapeutic potential for hyperinsulinemia in horses. Objective: Determine the pharmacokinetics (PKs) of sirolimus and evaluate its effect on insulin dynamics in healthy and insulin dysregulation (ID) horses. Methods: Eight Standardbred geldings. Methods: A PK study was performed followed by a placebo-controlled, randomized, crossover study. Blood sirolimus concentrations were measured by liquid chromatography-mass-spectrometry. PK indices were estimated by fitting a 2-compartment model using nonlinear least squares regression. An oral glucose test (OGT) was conducted before and 4, 24, 72, and 144 hours after administration of sirolimus or placebo. Effects of time, treatment and animal on blood glucose and insulin concentrations were analyzed using mixed-effects linear regression. Sirolimus was then administered to 4 horses with dexamethasone-induced ID and an OGT was performed at baseline, after ID induction and after 7 days of treatment. Results: Median (range) maximum sirolimus concentration was 277.0 (247.5-316.06) ng/mL at 5 (5-10) min and half-life was 3552 (3248-4767) min. Mean (range) oral bioavailability was 9.5 (6.8-12.4)%. Sirolimus had a significant effect on insulin concentration 24 hours after a single dose: median (interquartile range) insulin at 60 min (5.0 [3.7-7.0] μIU/mL) was 37 (-5 to 54)% less than placebo (8.7 [5.8-13.7] μIU/mL, P = .03); and at 120 min (10.2 [8.4-12.2] μIU/mL) was 28 (-15 to 53)% less than placebo (14.9 [8.4-24.8] μIU/mL, P = .02). There was minimal effect on glucose concentration. Insulin responses decreased toward baseline in ID horses after 7 days of treatment. Conclusions: Sirolimus decreased the insulinemic response to glucose and warrants further investigation.
© 2023 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals LLC on behalf of American College of Veterinary Internal Medicine.
Get Full Text
Publication Date: 2023-02-25 PubMed ID: 36840433PubMed Central: PMC10061188DOI: 10.1111/jvim.16650Google Scholar: Lookup
The Equine Research Bank provides access to a large database of publicly available scientific literature. Inclusion in the Research Bank does not imply endorsement of study methods or findings by Mad Barn.
LinkedInCopy
  • Randomized Controlled Trial
  • Veterinary
  • Journal Article

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

The research published in this article investigated the effects of the drug sirolimus on insulin levels in horses, particularly in those with insulin disorder. The study aimed to explore sirolimus’s potential as a treatment for hyperinsulinemia (excess insulin) in horses.

Study Methodology

  • The researchers examined the effects of sirolimus, a mechanistic target of rapamycin inhibitor, on insulin dynamics in both healthy and insulin dysregulated (ID) horses. Specifically, they used eight Standardbred geldings for their study.
  • They carried out a pharmacokinetic study (to understand how the body processes the drug) followed by a placebo-controlled, randomized, crossover study to examine specific effects of the drug.
  • After the administration of sirolimus or a placebo, blood samples were taken at specified intervals: before, and 4, 24, 72, and 144 hours after.
  • An oral glucose test (OGT) was also conducted at these times to monitor blood glucose and insulin concentrations. These results were analyzed using mixed-effects linear regression.
  • Part of the study also involved inducing ID in four horses with the steroid hormone dexamethasone, and subsequently administering sirolimus to assess its effects on insulin resistance caused by the hormone.

Results

  • The maximum sirolimus concentration in the blood was found to be 277.0 (247.5 – 316.06) ng/mL at around 5 to 10 minutes after administration with a half-life of 3552 (3248 – 4767) minutes.
  • The drug’s oral bioavailability (the proportion of the drug that enters circulation when introduced into the body) was recorded to be around 9.5 (6.8 – 12.4)%.
  • Results showed that sirolimus significantly reduced insulin concentrations 24 hours after a single dose. The median insulin level at 60 minutes was 37% less than the placebo.
  • The median insulin level at 120 minutes after administration was 28% less than the placebo’s effect. There was, however, minimal effect on the glucose concentration mainly indicating that the drug specifically targets insulin.
  • In the horses with an induced ID, insulin responses gradually decreased and moved toward baseline after 7 days of treatment with sirolimus.

Conclusion

  • The study concluded that sirolimus could be potentially used to decrease the insulin response to glucose and may be beneficial as a treatment for horses experiencing hyperinsulinemia.

Cite This Article

APA
de Tonnerre DJ, Medina Torres CE, Stefanovski D, Robinson MA, Kemp KL, Bertin FR, van Eps AW. (2023). Effect of sirolimus on insulin dynamics in horses. J Vet Intern Med, 37(2), 703-712. https://doi.org/10.1111/jvim.16650

Publication

Journal of veterinary internal medicine
ISSN: 1939-1676
NlmUniqueID: 8708660
Country: United States
Language: English
Volume: 37
Issue: 2
Pages: 703-712

Researcher Affiliations

de Tonnerre, Demia J
  • School of Veterinary Science, The University of Queensland, Gatton, Queensland, Australia.
Medina Torres, Carlos E
  • Pferdeklinik SaarLorLux GmbH, Altforweiler, Germany.
Stefanovski, Darko
  • Department of Clinical Studies - New Bolton Center, University of Pennsylvania, Kennett Square, Pennsylvania, USA.
Robinson, Mary A
  • Department of Clinical Studies - New Bolton Center, University of Pennsylvania, Kennett Square, Pennsylvania, USA.
Kemp, Kate L
  • School of Veterinary Science, The University of Queensland, Gatton, Queensland, Australia.
Bertin, François-René
  • School of Veterinary Science, The University of Queensland, Gatton, Queensland, Australia.
van Eps, Andrew W
  • Department of Clinical Studies - New Bolton Center, University of Pennsylvania, Kennett Square, Pennsylvania, USA.

MeSH Terms

  • Horses
  • Animals
  • Male
  • Insulin
  • Glucose Tolerance Test / veterinary
  • Cross-Over Studies
  • Blood Glucose / analysis
  • Glucose
  • Horse Diseases

Conflict of Interest Statement

Authors declare no conflict of interest.

References

This article includes 52 references
  1. Karikoski NP, Patterson-Kane JC, Singer ER, McFarlane D, McGowan CM. Lamellar pathology in horses with pituitary pars intermedia dysfunction.. Equine Vet J 2016 Jul;48(4):472-8.
    pubmed: 25869529doi: 10.1111/evj.12450google scholar: lookup
  2. Tadros EM, Fowlie JG, Refsal KR, Marteniuk J, Schott HC 2nd. Association between hyperinsulinaemia and laminitis severity at the time of pituitary pars intermedia dysfunction diagnosis.. Equine Vet J 2019 Jan;51(1):52-56.
    pubmed: 29761574doi: 10.1111/evj.12963google scholar: lookup
  3. Karikoski NP, McGowan CM, Singer ER, Asplin KE, Tulamo RM, Patterson-Kane JC. Pathology of Natural Cases of Equine Endocrinopathic Laminitis Associated With Hyperinsulinemia.. Vet Pathol 2015 Sep;52(5):945-56.
    pubmed: 25232034doi: 10.1177/0300985814549212google scholar: lookup
  4. Asplin KE, Sillence MN, Pollitt CC, McGowan CM. Induction of laminitis by prolonged hyperinsulinaemia in clinically normal ponies.. Vet J 2007 Nov;174(3):530-5.
    pubmed: 17719811doi: 10.1016/j.tvjl.2007.07.003google scholar: lookup
  5. Meier A, McGree J, Klee R, Preuß J, Reiche D, de Laat M, Sillence M. The application of a new laminitis scoring method to model the rate and pattern of improvement from equine endocrinopathic laminitis in a clinical setting.. BMC Vet Res 2021 Jan 7;17(1):16.
    pmc: PMC7791853pubmed: 33413384doi: 10.1186/s12917-020-02715-7google scholar: lookup
  6. de Laat MA, Sillence MN, McGowan CM, Pollitt CC. Continuous intravenous infusion of glucose induces endogenous hyperinsulinaemia and lamellar histopathology in Standardbred horses.. Vet J 2012 Mar;191(3):317-22.
    pubmed: 21873088doi: 10.1016/j.tvjl.2011.07.007google scholar: lookup
  7. de Laat MA, Reiche DB, Sillence MN, McGree JM. Incidence and risk factors for recurrence of endocrinopathic laminitis in horses.. J Vet Intern Med 2019 May;33(3):1473-1482.
    pmc: PMC6524073pubmed: 30972832doi: 10.1111/jvim.15497google scholar: lookup
  8. Bailey SR, Menzies-Gow NJ, Harris PA, Habershon-Butcher JL, Crawford C, Berhane Y, Boston RC, Elliott J. Effect of dietary fructans and dexamethasone administration on the insulin response of ponies predisposed to laminitis.. J Am Vet Med Assoc 2007 Nov 1;231(9):1365-73.
    pubmed: 17975996doi: 10.2460/javma.231.9.1365google scholar: lookup
  9. de Laat MA, McGree JM, Sillence MN. Equine hyperinsulinemia: investigation of the enteroinsular axis during insulin dysregulation.. Am J Physiol Endocrinol Metab 2016 Jan 1;310(1):E61-72.
    pubmed: 26530154doi: 10.1152/ajpendo.00362.2015google scholar: lookup
  10. Hustace JL, Firshman AM, Mata JE. Pharmacokinetics and bioavailability of metformin in horses.. Am J Vet Res 2009 May;70(5):665-8.
    pubmed: 19405907doi: 10.2460/ajvr.70.5.665google scholar: lookup
  11. Tinworth KD, Edwards S, Noble GK, Harris PA, Sillence MN, Hackett LP. Pharmacokinetics of metformin after enteral administration in insulin-resistant ponies.. Am J Vet Res 2010 Oct;71(10):1201-6.
    pubmed: 20919907doi: 10.2460/ajvr.71.10.1201google scholar: lookup
  12. Rendle DI, Rutledge F, Hughes KJ, Heller J, Durham AE. Effects of metformin hydrochloride on blood glucose and insulin responses to oral dextrose in horses.. Equine Vet J 2013 Nov;45(6):751-4.
    pubmed: 23600690doi: 10.1111/evj.12068google scholar: lookup
  13. Durham AE, Rendle DI, Newton JE. The effect of metformin on measurements of insulin sensitivity and beta cell response in 18 horses and ponies with insulin resistance.. Equine Vet J 2008 Jul;40(5):493-500.
    pubmed: 18482898doi: 10.2746/042516408X273648google scholar: lookup
  14. Meier A, Reiche D, de Laat M, Pollitt C, Walsh D, Sillence M. The sodium-glucose co-transporter 2 inhibitor velagliflozin reduces hyperinsulinemia and prevents laminitis in insulin-dysregulated ponies.. PLoS One 2018;13(9):e0203655.
    pmc: PMC6136744pubmed: 30212530doi: 10.1371/journal.pone.0203655google scholar: lookup
  15. Meier A, de Laat M, Reiche D, Fitzgerald D, Sillence M. The efficacy and safety of velagliflozin over 16 weeks as a treatment for insulin dysregulation in ponies.. BMC Vet Res 2019 Feb 26;15(1):65.
    pmc: PMC6390376pubmed: 30808423doi: 10.1186/s12917-019-1811-2google scholar: lookup
  16. Liu GY, Sabatini DM. mTOR at the nexus of nutrition, growth, ageing and disease.. Nat Rev Mol Cell Biol 2020 Apr;21(4):183-203.
    pmc: PMC7102936pubmed: 31937935doi: 10.1038/s41580-019-0199-ygoogle scholar: lookup
  17. Lane HE, Burns TA, Hegedus OC, Watts MR, Weber PS, Woltman KA, Geor RJ, McCutcheon LJ, Eades SC, Mathes LE, Belknap JK. Lamellar events related to insulin-like growth factor-1 receptor signalling in two models relevant to endocrinopathic laminitis.. Equine Vet J 2017 Sep;49(5):643-654.
    pubmed: 28078757doi: 10.1111/evj.12663google scholar: lookup
  18. Pende M, Kozma SC, Jaquet M, Oorschot V, Burcelin R, Le Marchand-Brustel Y, Klumperman J, Thorens B, Thomas G. Hypoinsulinaemia, glucose intolerance and diminished beta-cell size in S6K1-deficient mice.. Nature 2000 Dec 21-28;408(6815):994-7.
    pubmed: 11140689doi: 10.1038/35050135google scholar: lookup
  19. Warnken T, Delarocque J, Schumacher S, Huber K, Feige K. Retrospective analysis of insulin responses to standard dosed oral glucose tests (OGTs) via naso-gastric tubing towards definition of an objective cut-off value.. Acta Vet Scand 2018 Jan 19;60(1):4.
    pmc: PMC5775575pubmed: 29351765doi: 10.1186/s13028-018-0358-8google scholar: lookup
  20. Tiley HA, Geor RJ, McCutcheon LJ. Effects of dexamethasone on glucose dynamics and insulin sensitivity in healthy horses.. Am J Vet Res 2007 Jul;68(7):753-9.
    pubmed: 17605611doi: 10.2460/ajvr.68.7.753google scholar: lookup
  21. Frank N, Geor RJ, Bailey SR, Durham AE, Johnson PJ. Equine metabolic syndrome.. J Vet Intern Med 2010 May-Jun;24(3):467-75.
    pubmed: 20384947doi: 10.1111/j.1939-1676.2010.0503.xgoogle scholar: lookup
  22. Frank N, Elliott SB, Brandt LE, Keisler DH. Physical characteristics, blood hormone concentrations, and plasma lipid concentrations in obese horses with insulin resistance.. J Am Vet Med Assoc 2006 May 1;228(9):1383-90.
    pubmed: 16649943doi: 10.2460/javma.228.9.1383google scholar: lookup
  23. Bertin FR, de Laat MA. The diagnosis of equine insulin dysregulation.. Equine Vet J 2017 Sep;49(5):570-576.
    pubmed: 28543410doi: 10.1111/evj.12703google scholar: lookup
  24. Leschke DH, Muir GS, Hodgson JK, Coyle M, Horn R, Bertin FR. Immunoreactive insulin stability in horses at risk of insulin dysregulation.. J Vet Intern Med 2019 Nov;33(6):2746-2751.
    pmc: PMC6872612pubmed: 31617618doi: 10.1111/jvim.15629google scholar: lookup
  25. Bansal S, DeStefano A. Key elements of bioanalytical method validation for small molecules.. AAPS J 2007 Mar 30;9(1):E109-14.
    pmc: PMC2751299pubmed: 17408234doi: 10.1208/aapsj0901011google scholar: lookup
  26. Soma LR, Robinson MA, You Y, Boston RC, Rudy J. Pharmacokinetics, disposition, and plasma concentrations of dimethyl sulfoxide (DMSO) in the horse following topical, oral, and intravenous administration.. J Vet Pharmacol Ther 2018 Jun;41(3):384-392.
    pubmed: 29333740doi: 10.1111/jvp.12476google scholar: lookup
  27. Robinson MA, Guan F, McDonnell S, Uboh CE, Soma LR. Pharmacokinetics and pharmacodynamics of dermorphin in the horse.. J Vet Pharmacol Ther 2015 Aug;38(4):321-9.
    pubmed: 25376170doi: 10.1111/jvp.12179google scholar: lookup
  28. Robinson MA, Stefanovski D, You Y, Boston RC, Soma LR. Bayesian-based withdrawal estimates using pharmacokinetic parameters for two capsaicinoid-containing products administered to horses.. J Vet Pharmacol Ther 2021 May;44(3):349-358.
    pubmed: 33305843doi: 10.1111/jvp.12939google scholar: lookup
  29. Dai C, Walker JT, Shostak A, Padgett A, Spears E, Wisniewski S, Poffenberger G, Aramandla R, Dean ED, Prasad N, Levy SE, Greiner DL, Shultz LD, Bottino R, Powers AC. Tacrolimus- and sirolimus-induced human β cell dysfunction is reversible and preventable.. JCI Insight 2020 Jan 16;5(1).
    pmc: PMC7030815pubmed: 31941840doi: 10.1172/jci.insight.130770google scholar: lookup
  30. Marcelli-Tourvieille S, Hubert T, Moerman E, Gmyr V, Kerr-Conte J, Nunes B, Dherbomez M, Vandewalle B, Pattou F, Vantyghem MC. In vivo and in vitro effect of sirolimus on insulin secretion.. Transplantation 2007 Mar 15;83(5):532-8.
    pubmed: 17353769doi: 10.1097/01.tp.0000255679.81792.ddgoogle scholar: lookup
  31. Fang Y, Westbrook R, Hill C, Boparai RK, Arum O, Spong A, Wang F, Javors MA, Chen J, Sun LY, Bartke A. Duration of rapamycin treatment has differential effects on metabolism in mice.. Cell Metab 2013 Mar 5;17(3):456-62.
    pmc: PMC3658445pubmed: 23473038doi: 10.1016/j.cmet.2013.02.008google scholar: lookup
  32. den Hartigh LJ, Goodspeed L, Wang SA, Kenerson HL, Omer M, O'Brien KD, Ladiges W, Yeung R, Subramanian S. Chronic oral rapamycin decreases adiposity, hepatic triglycerides and insulin resistance in male mice fed a diet high in sucrose and saturated fat.. Exp Physiol 2018 Nov;103(11):1469-1480.
    pmc: PMC6446929pubmed: 30117227doi: 10.1113/EP087207google scholar: lookup
  33. Barlow AD, Nicholson ML, Herbert TP. Evidence for rapamycin toxicity in pancreatic β-cells and a review of the underlying molecular mechanisms.. Diabetes 2013 Aug;62(8):2674-82.
    pmc: PMC3717855pubmed: 23881200doi: 10.2337/db13-0106google scholar: lookup
  34. Kotha S, Lawendy B, Asim S, Gomes C, Yu J, Orchanian-Cheff A, Tomlinson G, Bhat M. Impact of immunosuppression on incidence of post-transplant diabetes mellitus in solid organ transplant recipients: Systematic review and meta-analysis.. World J Transplant 2021 Oct 18;11(10):432-442.
    pmc: PMC8529944pubmed: 34722172doi: 10.5500/wjt.v11.i10.432google scholar: lookup
  35. Houde VP, Brûlé S, Festuccia WT, Blanchard PG, Bellmann K, Deshaies Y, Marette A. Chronic rapamycin treatment causes glucose intolerance and hyperlipidemia by upregulating hepatic gluconeogenesis and impairing lipid deposition in adipose tissue.. Diabetes 2010 Jun;59(6):1338-48.
    pmc: PMC2874694pubmed: 20299475doi: 10.2337/db09-1324google scholar: lookup
  36. Sarbassov DD, Ali SM, Sengupta S, Sheen JH, Hsu PP, Bagley AF, Markhard AL, Sabatini DM. Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB.. Mol Cell 2006 Apr 21;22(2):159-68.
    pubmed: 16603397doi: 10.1016/j.molcel.2006.03.029google scholar: lookup
  37. Le Bacquer O, Queniat G, Gmyr V, Kerr-Conte J, Lefebvre B, Pattou F. mTORC1 and mTORC2 regulate insulin secretion through Akt in INS-1 cells.. J Endocrinol 2013 Jan;216(1):21-9.
    pubmed: 23092880doi: 10.1530/JOE-12-0351google scholar: lookup
  38. Lamming DW, Ye L, Katajisto P, Goncalves MD, Saitoh M, Stevens DM, Davis JG, Salmon AB, Richardson A, Ahima RS, Guertin DA, Sabatini DM, Baur JA. Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity.. Science 2012 Mar 30;335(6076):1638-43.
    pmc: PMC3324089pubmed: 22461615doi: 10.1126/science.1215135google scholar: lookup
  39. Vergès B, Cariou B. mTOR inhibitors and diabetes.. Diabetes Res Clin Pract 2015 Nov;110(2):101-8.
    pubmed: 26421362doi: 10.1016/j.diabres.2015.09.014google scholar: lookup
  40. Maria G, Antonia D, Michael A, Kate M, Sian E, Sarah FE, Mehul D, Pratik S. Sirolimus: Efficacy and Complications in Children With Hyperinsulinemic Hypoglycemia: A 5-Year Follow-Up Study.. J Endocr Soc 2019 Apr 1;3(4):699-713.
    pmc: PMC6411415pubmed: 30882046doi: 10.1210/js.2018-00417google scholar: lookup
  41. Davi MV, Pia A, Guarnotta V, Pizza G, Colao A, Faggiano A. The treatment of hyperinsulinemic hypoglycaemia in adults: an update.. J Endocrinol Invest 2017 Jan;40(1):9-20.
    pubmed: 27624297doi: 10.1007/s40618-016-0536-3google scholar: lookup
  42. Minute M, Patti G, Tornese G, Faleschini E, Zuiani C, Ventura A. Sirolimus Therapy in Congenital Hyperinsulinism: A Successful Experience Beyond Infancy.. Pediatrics 2015 Nov;136(5):e1373-6.
    pubmed: 26504125doi: 10.1542/peds.2015-1132google scholar: lookup
  43. Senniappan S, Brown RE, Hussain K. Sirolimus in severe hyperinsulinemic hypoglycemia.. N Engl J Med 2014 Jun 19;370(25):2448-9.
    pubmed: 24941187doi: 10.1056/NEJMc1404716google scholar: lookup
  44. Knowles EJ, Elliott J, Harris PA, Chang YM, Menzies-Gow NJ. Predictors of laminitis development in a cohort of nonlaminitic ponies.. Equine Vet J 2023 Jan;55(1):12-23.
    pubmed: 35263471doi: 10.1111/evj.13572google scholar: lookup
  45. Trepanier DJ, Gallant H, Legatt DF, Yatscoff RW. Rapamycin: distribution, pharmacokinetics and therapeutic range investigations: an update.. Clin Biochem 1998 Jul;31(5):345-51.
    pubmed: 9721433doi: 10.1016/s0009-9120(98)00048-4google scholar: lookup
  46. Honcharik N, Fryer J, Yatscoff R. Pharmacokinetics of rapamycin: single-dose studies in the rabbit.. Ther Drug Monit 1992 Dec;14(6):475-8.
    pubmed: 1485369
  47. Larson JC, Allstadt SD, Fan TM, Khanna C, Lunghofer PJ, Hansen RJ, Gustafson DL, Legendre AM, Galyon GD, LeBlanc AK, Martin-Jimenez T. Pharmacokinetics of orally administered low-dose rapamycin in healthy dogs.. Am J Vet Res 2016 Jan;77(1):65-71.
    pmc: PMC5642271pubmed: 26709938doi: 10.2460/ajvr.77.1.65google scholar: lookup
  48. Yatscoff RW, Wang P, Chan K, Hicks D, Zimmerman J. Rapamycin: distribution, pharmacokinetics, and therapeutic range investigations.. Ther Drug Monit 1995 Dec;17(6):666-71.
    pubmed: 8588238doi: 10.1097/00007691-199512000-00020google scholar: lookup
  49. Doenicke A, Roizen MF, Hoernecke R, Mayer M, Ostwald P, Foss J. Haemolysis after etomidate: comparison of propylene glycol and lipid formulations.. Br J Anaesth 1997 Sep;79(3):386-8.
    pubmed: 9389862doi: 10.1093/bja/79.3.386google scholar: lookup
  50. Thomson AW, Turnquist HR, Raimondi G. Immunoregulatory functions of mTOR inhibition.. Nat Rev Immunol 2009 May;9(5):324-37.
    pmc: PMC2847476pubmed: 19390566doi: 10.1038/nri2546google scholar: lookup
  51. Stenton SB, Partovi N, Ensom MH. Sirolimus: the evidence for clinical pharmacokinetic monitoring.. Clin Pharmacokinet 2005;44(8):769-86.
    pubmed: 16029064doi: 10.2165/00003088-200544080-00001google scholar: lookup
  52. Saunders RN, Metcalfe MS, Nicholson ML. Rapamycin in transplantation: a review of the evidence.. Kidney Int 2001 Jan;59(1):3-16.
    pubmed: 11135052doi: 10.1046/j.1523-1755.2001.00460.xgoogle scholar: lookup

Citations

This article has been cited 0 times.
Subscribe to our newsletter
Join 99,383 horse owners like you who receive our email updates on horse health and nutrition.