Pharmacology and toxicology of chronically infused epidural clonidine·HCL in dogs

Tony L. Yaksh, Michael Rathbun, Juergen Jage, Todd Mirzai, Marjorie Grafe, Richard A. Hiles

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

To evaluate the physiological effects and toxicity of epidural clonidine·HCl, male Beagle dogs were prepared with chronic lumbar epidural catheters and administered constant infusions of either saline (N = 10), or 80 μg/hr (N = 6), 200 μg/hr (N = 6), or 320 μg/hr (N = 12) clonidine·HCl at a rate of 4 ml/24 hr for 28 days. Saline infusion had no effect upon any behavioral measure. Epidural clonidine produced a dose-dependent increase in thermal skin-twitch response latency (antinociception), lowering of respiration rate, heart rate, and blood pressure, and increased sedation. The effects were maximum from approximately Day 1 to Day 3 when, with the exception of respiration which remained depressed, a progressive adaptation was observed over the course of the study. There were no negative effects on body weight, body temperature, motor function, bowel or bladder function, or clinical pathology values. After 28 days of continuous infusion, the dogs were deeply anesthetized and terminated. Cistemal cerebrospinal fluid taken at termination displayed no clinically significant differences in protein or glucose concentration. All groups, including control, had dogs which had a chronic inflammatory response in the epidural space, as represented by fibrosis, foreign body giant cells, and lymphocytes, but no spinal cord pathology. Both the steadystate plasma and CSF concentrations of clonidine were proportional to the dose; the ratio of CSF to plasma concentration was approximately 0.5. The failure to see any change in CSF composition, significant spinal cord pathology, or signs of tissue or organ toxicity emphasizes the safety of epidurally administered clonidine at infusion rates up to 320 μg/hr and at infusate concentrations up to 2 mg/ml.

Original languageEnglish (US)
Pages (from-to)319-335
Number of pages17
JournalToxicological Sciences
Volume23
Issue number3
DOIs
StatePublished - Oct 1994
Externally publishedYes

Fingerprint

Clonidine
Pathology
Toxicology
Pharmacology
Dogs
Toxicity
Spinal Cord
Foreign Body Giant Cells
Cerebrospinal fluid
Plasmas
Epidural Space
Clinical Pathology
Lymphocytes
Catheters
Blood pressure
Respiratory Rate
Body Temperature
Reaction Time
Cerebrospinal Fluid
Skin

ASJC Scopus subject areas

  • Molecular Biology
  • Embryology
  • Cell Biology
  • Genetics
  • Developmental Biology
  • Toxicology

Cite this

Pharmacology and toxicology of chronically infused epidural clonidine·HCL in dogs. / Yaksh, Tony L.; Rathbun, Michael; Jage, Juergen; Mirzai, Todd; Grafe, Marjorie; Hiles, Richard A.

In: Toxicological Sciences, Vol. 23, No. 3, 10.1994, p. 319-335.

Research output: Contribution to journalArticle

Yaksh, Tony L. ; Rathbun, Michael ; Jage, Juergen ; Mirzai, Todd ; Grafe, Marjorie ; Hiles, Richard A. / Pharmacology and toxicology of chronically infused epidural clonidine·HCL in dogs. In: Toxicological Sciences. 1994 ; Vol. 23, No. 3. pp. 319-335.
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