title: Acute toxicity study of tilmicosin-loaded hydrogenated castor oil-solid lipid nanoparticles.
abstract: BACKGROUND
  Our previous studies demonstrated that tilmicosin-loaded hydrogenated castor oil solid lipid nanoparticles (Til-HCO-SLN) are a promising formulation for enhanced pharmacological activity and therapeutic efficacy in veterinary use. The purpose of this work was to evaluate the acute toxicity of Til-HCO-SLN.
  
  
  METHODS
  Two nanoparticle doses were used for the study in ICR mice. The low dose (766 mg/kg.bw) with tilmicosin 7.5 times of the clinic dosage and below the median lethal dose (LD(50)) was subcutaneously administered twice on the first and 7th day. The single high dose (5 g/kg.bw) was the practical upper limit in an acute toxicity study and was administered subcutaneously on the first day. Blank HCO-SLN, native tilmicosin, and saline solution were included as controls. After medication, animals were monitored over 14 days, and then necropsied. Signs of toxicity were evaluated via mortality, symptoms of treatment effect, gross and microscopic pathology, and hematologic and biochemical parameters.
  
  
  RESULTS
  After administration of native tilmicosin, all mice died within 2 h in the high dose group, in the low dose group 3 died after the first and 2 died after the second injections. The surviving mice in the tilmicosin low dose group showed hypoactivity, accelerated breath, gloomy spirit and lethargy. In contrast, all mice in Til-HCO-SLN and blank HCO-SLN groups survived at both low and high doses. The high nanoparticle dose induced transient clinical symptoms of treatment effect such as transient reversible action retardation, anorexy and gloomy spirit, increased spleen and liver coefficients and decreased heart coefficients, microscopic pathological changes of liver, spleen and heart, and minor changes in hematologic and biochemical parameters, but no adverse effects were observed in the nanoparticle low dose group.
  
  
  CONCLUSIONS
  The results revealed that the LD50 of Til-HCO-SLN and blank HCO-SLN exceeded 5 g/kg.bw and thus the nanoparticles are considered low toxic according to the toxicity categories of chemicals. Moreover, HCO-SLN significantly decreased the toxicity of tilmicosin. Normal clinic dosage of Til-HCO-SLN is safe as evaluated by acute toxicity.
authors.affiliation: Department of Preventive Veterinary Medicine, College of Veterinary Medicine, China Agricultural University, 2 Yuanmingyuan Road West, Beijing 100193, PR China.
authors.forename: Shuyu
authors.initials: S
authors.lastname: Xie
authors.forename: Fenghua
authors.initials: F
authors.lastname: Wang
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.forename: Luyan
authors.initials: L
authors.lastname: Zhu
authors.forename: Zhao
authors.initials: Z
authors.lastname: Dong
authors.forename: Xiaofang
authors.initials: X
authors.lastname: Wang
authors.forename: Xihe
authors.initials: X
authors.lastname: Li
authors.forename: Wenzhong
authors.initials: W
authors.lastname: Zhou
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000633:toxicity*; D001835:Body Weight / Q000187:drug effects; D002368:Castor Oil / Q000737:chemistry / Q000633:toxicity*; D004326:Drinking / Q000187:drug effects; D004337:Drug Carriers / Q000737:chemistry; D004435:Eating / Q000187:drug effects; D005260:Female; D006321:Heart / Q000187:drug effects; D006865:Hydrogenation; D007928:Lethal Dose 50; D008055:Lipids / Q000737:chemistry; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008136:Longevity / Q000187:drug effects; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009206:Myocardium / Q000473:pathology; D053758:Nanoparticles / Q000737:chemistry / Q000633:toxicity; D010316:Particle Size; D013154:Spleen / Q000187:drug effects / Q000473:pathology; D023382:Toxicity Tests, Acute; D015645:Tylosin / Q000031:analogs & derivatives* / Q000633:toxicity
chemical_list: D000900:Anti-Bacterial Agents; D004337:Drug Carriers; D008055:Lipids; D002368:Castor Oil; C052319:tilmicosin; D015645:Tylosin
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