Skip to content
2000
Volume 22, Issue 6
  • ISSN: 1567-2018
  • E-ISSN: 1875-5704

Abstract

Introduction

In the present study, a valnemulin hydrogen fumarate prodrug was characterized, its stability was compared with valnemulin hydrochloride, and the efficacy was evaluated in controlling pneumonia among mice experimentally infected with .

Methods

Optical microscopy, X-ray powder diffraction, infrared spectroscopy, and hydrogen nuclear magnetic resonance spectroscopy were used to study the physical and chemical properties of the prodrug. The thermal stability was investigated in comparison with valnemulin hydrochloride to improve the preparation process of valnemulin hydrogen fumarate soluble powder and maximize its drug effect. Additionally, the efficacy of valnemulin hydrogen fumarate was evaluated in a challenge-treatment trial in mice using an infection test .

Results

Valnemulin hydrogen fumarate had high crystallinity. After light irradiation for 20 days, valnemulin hydrogen fumarate did not degrade, whereas valnemulin hydrochloride did. These results showed that the valnemulin hydrogen fumarate was stable. At the same dose in drinking water, the valnemulin hydrogen fumarate was more effective than the reference drug of tiamulin fumarate in an challenge-treatment trial.

Conclusion

Valnemulin hydrogen fumarate shows excellent potential for application as a veterinary drug.


© 2025 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/cdd/10.2174/0115672018289236240530095059
2024-06-05
2025-09-26

  • From This Site

    /content/journals/cdd/10.2174/0115672018289236240530095059
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. StipkovitsL. RipleyP.H. VargaJ. PalfiV. Use of valnemulin in the control of Mycoplasma bovis infection under field conditions.Vet. Rec.20011481339940210.1136/vr.148.13.39911327646
     [Google Scholar]
  2. ChenL. YangD. PanZ. LaiL. LiuJ. FangB. ShiS. Synthesis and antimicrobial activity of the hybrid molecules between sulfonamides and active antimicrobial pleuromutilin derivative.Chem. Biol. Drug Des.201586223924510.1111/cbdd.1248625431015
     [Google Scholar]
  3. LobováD. SmolaJ. CizekA. Decreased susceptibility to tiamulin and valnemulin among Czech isolates of Brachyspira hyodysenteriae. J. Med. Microbiol.200453428729110.1099/jmm.0.05407‑015017284
     [Google Scholar]
  4. RipleyP.H. ZeislE. Horkovics-KovatsS. Use of pleuromutilin derivatives for transdermal treatment of bacterial diseases.US6852756B12005
  5. StipkovitsL. RipleyP.H. TenkM. GlávitsR. MolnárT. FodorL. The efficacy of valnemulin (Econor®) in the control of disease caused by experimental infection of calves with Mycoplasma bovis. Res. Vet. Sci.200578320721510.1016/j.rvsc.2004.09.00515766939
     [Google Scholar]
  6. TangY. LuoJ. ChenX. WangB. ShenX. LiuJ. Synthesis and in vitro antibacterial activity of four novel pleuromutilin derivatives.J. Chil. Chem. Soc.20135811537154010.4067/S0717‑97072013000100008
     [Google Scholar]
  7. AitkenI.A. MorganJ.H. DalzielR. BurchD.G.S. RipleyP.H. Comparative in vitro activity of valnemulin against porcine bacterial pathogens.Vet. Rec.1999144512810.1136/vr.144.5.12810070704
     [Google Scholar]
  8. JordanF.T.W. ForresterC.A. RipleyP.H. BurchD.G.S. In vitro and in vivo comparisons of valnemulin, tiamulin, tylosin, enrofloxacin, and lincomycin/spectinomycin against Mycoplasma gallisepticum. Avian Dis.199842473874510.2307/15927099876842
     [Google Scholar]
  9. TzikaE.D. PapatsirosV.G. KyriakisS.C. AlexopoulosC. LymberopoulosA.G. KyriakisC.S. Efficacy of in-feed valnemulin hydrochloride for the treatment and control of ileitis in weaning and growing mice.J. Appl. Anim. Res.200935218118410.1080/09712119.2009.9707013
     [Google Scholar]
  10. LiB.B. ShenJ.Z. CaoX.Y. WangY. DaiL. HuangS.Y. WuC.M. Mutations in 23S rRNA gene associated with decreased susceptibility to tiamulin and valnemulin in Mycoplasma gallisepticum. FEMS Microbiol. Lett.20103082no10.1111/j.1574‑6968.2010.02003.x20487023
     [Google Scholar]
  11. LavenR.A. HuntH. Comparison of valnemulin and lincomycin in the treatment of digital dermatitis by individually applied topical spray.Vet. Rec.20011491030230310.1136/vr.149.10.30211570791
     [Google Scholar]
  12. LongK.S. PoehlsgaardJ. HansenL.H. HobbieS.N. BöttgerE.C. VesterB. Single 23S rRNA mutations at the ribosomal peptidyl transferase centre confer resistance to valnemulin and other antibiotics in Mycobacterium smegmatis by perturbation of the drug binding pocket.Mol. Microbiol.20097151218122710.1111/j.1365‑2958.2009.06596.x19154331
     [Google Scholar]
  13. HosseinkhaniH. Biomedical Engineering: Materials, technology, and applications.WeinheimWiley202210.1002/9783527826674
     [Google Scholar]
  14. HosseinkhaniH. Nanomaterials in advanced medicine.WeinheimWiley-VCH201910.1002/9783527818921
     [Google Scholar]
  15. DombA.J. SharifzadehG. NahumV. HosseinkhaniH. Safety evaluation of nanotechnology products.Pharmaceutics20211310161510.3390/pharmaceutics1310161534683908
     [Google Scholar]
  16. AgrawalN. ChandrasekarM.J. SaraU.V. RohiniA. Synthesis, characterization, and in vitro drug release study of methacrylate diclofenac conjugate as macromolecular prodrug.J. Pharm. Sci. Technol.201064434835521502035
     [Google Scholar]
  17. DongX. ShuX. WangY. NiuZ. XuS. ZhangY. ZhaoS. Synthesis, characterization and in vitro release performance of the pegylated valnemulin prodrug.J. Vet. Med. Sci.201880117318010.1292/jvms.17‑043429187697
     [Google Scholar]
  18. ChenD. XieS. LiangY. HuD. YanY. Preparation and evaluation of valnemulin hydrochloride taste-masking granules.Curr. Drug Deliv.202219333734610.2174/156720181866621090315165834477518
     [Google Scholar]
  19. KollerK. SchwarzF. Formulation of valnemulin.US6284792B12001
  20. Wieland-BerghausenS. RakocziF. Cron-EckhardtB.M. Microspherules containing a pleuromutilin derivative.CA2466671C2002
  21. SchwarzF. Valnemulin formulation.WO2001041758A32002
  22. VanackerP. AmiensF.R. Palatability enhancers and methods for enhancing palatability.EP2296481A42011
  23. SerajuddinA.T.M. Salt formation to improve drug solubility.Adv. Drug Deliv. Rev.200759760361610.1016/j.addr.2007.05.01017619064
     [Google Scholar]
  24. BastinR.J. BowkerM.J. SlaterB.J. Salt selection and optimization procedures for pharmaceutical new chemical entities.Org. Process Res. Dev.20004542743510.1021/op000018u
     [Google Scholar]
  25. JamaludinA. MohamadM. NavaratnamV. SelliahK. TanS.C. WernsdorferW.H. YuenK.H. Relative bioavailability of the hydrochloride, sulphate and ethyl carbonate salts of quinine.Br. J. Clin. Pharmacol.198825226126310.1111/j.1365‑2125.1988.tb03299.x3358888
     [Google Scholar]
  26. FangZ.Y. ZhangB.X. XingW.H. JiaH.L. WangX. GongN.B. LuY. DuG.H. A series of stable, metastable and unstable salts of Imatinib with improved solubility.Chin. Chem. Lett.20223342159216410.1016/j.cclet.2021.10.056
     [Google Scholar]
  27. BergeS.M. BighleyL.D. MonkhouseD.C. Pharmaceutical Salts.J. Pharm. Sci.197766111910.1002/jps.2600660104833720
     [Google Scholar]
  28. GouldP.L. Salt selection for basic drugs.Int. J. Pharm.1986331-320121710.1016/0378‑5173(86)90055‑4
     [Google Scholar]
  29. DaviesG. Changing the salt, changing the drug.Pharm. J.2001266322323
     [Google Scholar]
  30. MacherI. GeisslerA. Wieland-BerghausenS.C. Valnemulinsalts with organic acids.WO Patent2006079535A1
     [Google Scholar]
  31. ZhuX. XuS. XuQ. Preparation of valnemulin hydrogen fumarate and its enhanced stability compared with valnemulin hydrochloride.Pharm. Dev. Technol.201621333834510.3109/10837450.2014.100365625597619
     [Google Scholar]
  32. SuH. HeH. TianY. ZhaoN. SunF. ZhangX. JiangQ. ZhuG. Syntheses and characterizations of two curcumin-based cocrystals.Inorg. Chem. Commun.201555929510.1016/j.inoche.2015.03.027
     [Google Scholar]
  33. ZhangX. TianY. JiaJ. ZhangT. ZhuG. Synthesis, characterization and dissolution of three pharmaceutical cocrystals based on deferiprone.J. Mol. Struct.2016110856056610.1016/j.molstruc.2015.12.055
     [Google Scholar]
  34. ZhangX. SunF. ZhangT. JiaJ. SuH. WangC. ZhuG. Three pharmaceuticals cocrystals of adefovir: Syntheses, structures and dissolution study.J. Mol. Struct.2015110039540010.1016/j.molstruc.2015.07.033
     [Google Scholar]
  35. BhandariB.R. HowesT. Implication of glass transition for the drying and stability of dried foods.J. Food Eng.1999401-2717910.1016/S0260‑8774(99)00039‑4
     [Google Scholar]
  36. NagaseH. EndoT. UedaH. NakagakiM. An anhydrous polymorphic form of trehalose.Carbohydr. Res.2002337216717310.1016/S0008‑6215(01)00294‑411814449
     [Google Scholar]
  37. AuerM.E. GriesserU.J. SawatzkiJ. Qualitative and quantitative study of polymorphic forms in drug formulations by near infrared FT-Raman spectroscopy.J. Mol. Struct.2003661-66230731710.1016/j.molstruc.2003.09.002
     [Google Scholar]
  38. HigashiK. UedaK. MoribeK. Recent progress of structural study of polymorphic pharmaceutical drugs.Adv. Drug Deliv. Rev.2017117718510.1016/j.addr.2016.12.00127940141
     [Google Scholar]
  39. NyströmM. RoineJ. MurtomaaM. Mohan SankaranR. SantosH.A. SalonenJ. Solid state transformations in consequence of electrospraying – A novel polymorphic form of piroxicam.Eur. J. Pharm. Biopharm.20158918218910.1016/j.ejpb.2014.11.02725483892
     [Google Scholar]
  40. StahlP.H. WermuthC.G. Monographs on acids and bases. Handbook of Pharmaceutical Salts: Properties, Selection and Use.WeinheimWiley-VCH2002265327
     [Google Scholar]
  41. ByrnS. PfeifferR. GaneyM. HoibergC. PoochikianG. Pharmaceutical solids: A strategic approach to regulatory considerations.Pharm. Res.199512794595410.1023/A:10162419274297494814
     [Google Scholar]
  42. EverettR. DescotesG. RollinM. GreenerY. BradfordJ.C. BenzigerD.P. WardS.J. Nephrotoxicity of pravadoline maleate (WIN 48098-6) in dogs: Evidence of maleic acid-induced acute tubular necrosis.Fundam. Appl. Toxicol.1993211596510.1006/faat.1993.10728365586
     [Google Scholar]
  43. HuangL. TongW.Q. Impact of solid state properties on developability assessment of drug candidates.Adv. Drug Deliv. Rev.200456332133410.1016/j.addr.2003.10.00714962584
     [Google Scholar]
  44. LinS.L. LachmanL. SwartzC.J. HuebnerC.F. Preformulation investigation. I. Relation of salt forms and biological activity of an experimental antihypertensive.J. Pharm. Sci.19726191418142210.1002/jps.26006109155068948
     [Google Scholar]
  45. WalmsleyL.M. TaylorT. WilkinsonP.A. BrodieR.R. ChasseaudL.F. Alun-JonesV. HunterJ.O. Plasma concentrations and relative bioavailability of naftidrofuryl from different salt forms.Biopharm. Drug Dispos.19867432733410.1002/bdd.25100704033768488
     [Google Scholar]
  46. SegaG.A. SluderA.E. McCoyL.S. OwensJ.G. GenerosoE.E. The use of alkaline elution procedures to measure DNA damage in spermiogenic stages of mice exposed to methyl methanesulfonate.Mutat. Res.19861591-2556310.1016/0027‑5107(86)90112‑03753620
     [Google Scholar]
  47. OlovsonS.G. HavuN. RegårdhC.G. SandbergA. Oesophageal ulcerations and plasma levels of different alprenolol salts: Potential implications for the clinic.Acta Pharmacol. Toxicol. (Copenh.)1986581556010.1111/j.1600‑0773.1986.tb00070.x3953295
     [Google Scholar]
  48. MorrisS.M. McGarrityL.J. DomonO.E. ChenJ.J. HinsonW.G. BucciT.J. WarbrittonA.R. CascianoD.A. The role of programmed cell death in the toxicity of the mutagens, ethyl methanesulfonate and N-ethyl-N′-nitrosourea, in AHH-1 human lymphoblastoid cells.Mutat. Res.19943061193410.1016/0027‑5107(94)90164‑37512200
     [Google Scholar]
  49. Valnemulin hydrochloride for veterinary use.European Pharmacopoeia2006440434044
     [Google Scholar]
  50. BaoC. XiaoJ. LiuB. LiuJ. ZhuR. JiangP. LiL. LangfordP.R. LeiL. Establishment and comparison of Actinobacillus pleuropneumoniae experimental infection model in mice and piglets.Microb. Pathog.201912838138910.1016/j.micpath.2019.01.02830664928
     [Google Scholar]
  51. ReinerG. BertschN. HoeltigD. SelkeM. WillemsH. GerlachG.F. TuemmlerB. ProbstI. HerwigR. DrungowskiM. WaldmannK.H. Identification of QTL affecting resistance/susceptibility to acute Actinobacillus pleuropneumoniae infection in swine.Mamm. Genome2014253-418019110.1007/s00335‑013‑9497‑424445419
     [Google Scholar]
  52. NagaiK. UshioT. MiuraH. NakamuraT. MoribeK. YamamotoK. Four new polymorphic forms of suplatast tosilate.Int. J. Pharm.20144601-2839110.1016/j.ijpharm.2013.10.04924211359
     [Google Scholar]
  53. MesleyR.J. ClementsR.L. Infrared identification of barbiturates with particular reference to the occurrence of polymorphism.J. Pharm. Pharmacol.201120534134710.1111/j.2042‑7158.1968.tb09757.x4385436
     [Google Scholar]
  54. LöbmannK. StrachanC. GrohganzH. RadesT. KorhonenO. LaitinenR. Co-amorphous simvastatin and glipizide combinations show improved physical stability without evidence of intermolecular interactions.Eur. J. Pharm. Biopharm.201281115916910.1016/j.ejpb.2012.02.00422353489
     [Google Scholar]
  55. LöbmannK. LaitinenR. GrohganzH. StrachanC. RadesT. GordonK.C. A theoretical and spectroscopic study of co-amorphous naproxen and indomethacin.Int. J. Pharm.20134531808710.1016/j.ijpharm.2012.05.01622613066
     [Google Scholar]
  56. SpackmanM.A. JayatilakaD. Hirshfeld surface analysis.CrystEngComm2009111193210.1039/B818330A
     [Google Scholar]
  57. McKinnonJ.J. JayatilakaD. SpackmanM.A. Towards quantitative analysis of intermolecular interactions with Hirshfeld surfaces.Chem. Commun. (Camb.)200737373814381610.1039/b704980c18217656
     [Google Scholar]
  58. ClausenH.F. ChevallierM.S. SpackmanM.A. IversenB.B. Three new co-crystals of hydroquinone: Crystal structures and Hirshfeld surface analysis of intermolecular interactions.New J. Chem.201034219319910.1039/B9NJ00463G
     [Google Scholar]
  59. BaraldiC. TintiA. OttaniS. GamberiniM.C. Characterization of polymorphic ampicillin forms.J. Pharm. Biomed. Anal.201410032934010.1016/j.jpba.2014.08.02125194347
     [Google Scholar]
  60. HoeltigD. Hennig-PaukaI. ThiesK. RehmT. BeyerbachM. Strutzberg-MinderK. GerlachG.F. WaldmannK.H. A novel Respiratory Health Score (RHS) supports a role of acute lung damage and pig breed in the course of an Actinobacillus pleuropneumoniae infection.BMC Vet. Res.2009511410.1186/1746‑6148‑5‑1419383120
     [Google Scholar]
  61. RiouxS. DubreuilD. BéginC. LaferrièreC. MartinD. JacquesM. Evaluation of protective efficacy of an Actinobacillus pleuropneumoniae serotype 1 lipopolysaccharide-protein conjugate in mice.Comp. Immunol. Microbiol. Infect. Dis.1997201637410.1016/S0147‑9571(96)00022‑79023043
     [Google Scholar]
  62. ShaoM. WangY. WangC. GuoY. PengY. LiuJ. LiG. LiuH. LiuS. Evaluation of multicomponent recombinant vaccines against Actinobacillus pleuropneumoniae in mice.Acta Vet. Scand.20105215210.1186/1751‑0147‑52‑5220831818
     [Google Scholar]
  63. WangL. ZhaoX. ZhuC. ZhaoY. LiuS. XiaX. LiuX. ZhangH. XuY. HangB. SunY. ChenS. JiangJ. BaiY. ZhangG. LeiL. RichardL.P. FotinaH. HuJ. The antimicrobial peptide MPX kills Actinobacillus pleuropneumoniae and reduces its pathogenicity in mice.Vet. Microbiol.202024310863410.1016/j.vetmic.2020.10863432273013
     [Google Scholar]
  64. ParadisM.A. VessieG.H. MerrillJ.K. DickC.P. MooreC. CharbonneauG. GottschalkM. MacInnesJ.I. HigginsR. MittalK.R. GirardC. AraminiJ.J. WilsonJ.B. Efficacy of tilmicosin in the control of experimentally induced Actinobacillus pleuropneumoniae infection in swine.Can. J. Vet. Res.200468171114979429
     [Google Scholar]
  65. HannanP.C.T. BhogalB.S. FishJ.P. Tylosin tartrate and tiamutilin effects on experimental piglet pneumonia induced with pneumonic pig lung homogenate containing mycoplasmas, bacteria and viruses.Res. Vet. Sci.1982331768810.1016/S0034‑5288(18)32364‑67134653
     [Google Scholar]
  66. FodorL. Reeve-JohnsonL. HodgeA. VargaJ. Efficacy evaluations of the use of oral tilmicosin in pneumonic calves.Vet. J.2000159219420010.1053/tvjl.1999.044310712808
     [Google Scholar]
  67. PoulsenS.M. KarlssonM. JohanssonL.B. VesterB. The pleuromutilin drugs tiamulin and valnemulin bind to the RNA at the peptidyl transferase centre on the ribosome.Mol. Microbiol.20014151091109910.1046/j.1365‑2958.2001.02595.x11555289
     [Google Scholar]
  68. StipkovitsL. MillerD.J.S. MolnarT. FabianK. BurchD.G.S. The efficacy of combinations of econor + CTC and tiamulin + CTC in the treatment of piglets experimentally infected with Mycoplasma hyopneumoniae, Pasteurella multocida and Actinobacillus pleuropneumoniae. Proceedings of the 15th International Pig Veterinary Society Congress 5-9 July 1998, Birmingham, England Nottingham, EnglandNottingham University Press19993226
     [Google Scholar]
  69. StipkovitsL. MillerD. GlavitsR. FodorL. BurchD. Treatment of pigs experimentally infected with Mycoplasma hyopneumoniae, Pasteurella multocida, and Actinobacillus pleuropneumoniae with various antibiotics.Can. J. Vet. Res.200165421322211768127
     [Google Scholar]
  70. KitadaiN. MatsumotoS. NakataK. KataeH. In vitro combined effect of valnemulin with chlortetracycline against Pasteurella multocida, Actinobacillus pleuropneumoniae and Bordetella bronchiseptica. Proceedings of the 15th International Pig Veterinary Society Congress 5-9 July 1998, Birmingham, England Nottingham, EnglandNottingham University Press19993270
     [Google Scholar]
  71. JacqusM. RioxR. ArchambaultM. FoiryB. GalrneauC. LukiN.Y. Evaluation of the effects of tiamulin (“Tiamutin”~(R)) and valnemulin (“Econor”~(R)) on the growth and production of virulence factors of Actinobacillus pleuropneumoniae and Pasteurella multocida. Proceedings of the 15th International Pig Veterinary Society Congress 5-9 July 1998, Birmingham, England Nottingham, EnglandNottingham University Press19993180
     [Google Scholar]
  72. RipleyP.H. HogedalP. BantingA. BantingS. PridmoreA. SilleyP. Adverse reactions following the use of Econor~(R) in pigs: 5) the effect of endotoxin in Econor~(R)-medicated susceptible pigs.Int. Pig Veter. Soc.20021370
     [Google Scholar]
/content/journals/cdd/10.2174/0115672018289236240530095059
Loading
Characterization and In vivo Evaluation of Polymorphic Valnemulin Hydrogen Fumarate
Curr. Drug Deliv. 22, 798 (2025); https://doi.org/10.2174/0115672018289236240530095059
/content/journals/cdd/10.2174/0115672018289236240530095059
/content/journals/cdd/10.2174/0115672018289236240530095059
Loading

Data & Media loading...


  • Article Type:     Research Article
Keyword(s): Actinobacillus pleuropneumoniae; Characterization; efficacy; polymorphic form; stability; valnemulin hydrogen fumarate

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test