Safety and tolerability of cyclosporin a in severe traumatic brain injury patients: results from a prospective randomized trial.
Cyclosporin A (CsA) has recently been proposed for use in the early phase after traumatic brain injury (TBI), for its ability to preserve mitochondrial integrity in experimental brain injury models, and thereby provide improved behavioral outcomes as well as significant histological protection. The aim of this prospective, randomized, double-blind, dual-center, placebo-controlled trial was to evaluate the safety, tolerability, and pharmacokinetics of a single intravenous infusion of CsA in patients with severe TBI. Fifty adult severe TBI patients were enrolled over a 22-month period. Within 12 h of the injury patients received 5 mg/kg of CsA infused over 24 h, or placebo. Blood urea nitrogen (BUN), creatinine, hemoglobin, platelets, white blood cell count (WBC), and a hepatic panel were monitored on admission, and at 12, 24, 36, and 48 h, and on days 4 and 7. Potential adverse events (AEs) were also recorded. Neurological outcome was recorded at 3 and 6 months after injury. This study revealed only transient differences in BUN levels at 24 and 48 h and for WBC counts at 24 h between the CsA and placebo patients. These modest differences were not clinically significant in that they did not negatively impact on patient course. Both BUN and creatinine values, markers of renal function, remained within their normal limits over the entire monitoring period. There were no significant differences in other mean laboratory values, or in the incidence of AEs at any other measured time point. Also, no significant difference was demonstrated for neurological outcome. Based on these results, we report a good safety profile of CsA infusion when given at the chosen dose of 5 mg/kg, infused over 24 h, during the early phase after severe head injury in humans, with the aim of neuroprotection.
Mazzeo
Anna Teresa
AT
Department of Neurosciences, Psychiatric and Anesthesiological Sciences, University of Messina , Messina, Italy.
Brophy
Gretchen M
GM
Gilman
Charlotte B
CB
Alves
Oscar Luís
OL
Robles
Jaime R
JR
Hayes
Ronald L
RL
Povlishock
John T
JT
Bullock
M Ross
MR
D000293:Adolescent; D000328:Adult; D000368:Aged; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D015415:Biomarkers; D001806:Blood Urea Nitrogen; D001930:Brain Injuries / Q000188:drug therapy* / Q000401:mortality / Q000503:physiopathology*; D003404:Creatinine / Q000097:blood; D016572:Cyclosporine / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D004311:Double-Blind Method; D064420:Drug-Related Side Effects and Adverse Reactions; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D007668:Kidney / Q000187:drug effects; D007958:Leukocyte Count; D008297:Male; D008875:Middle Aged; D018696:Neuroprotective Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D010919:Placebos; D011446:Prospective Studies; D016896:Treatment Outcome; D055815:Young Adult
D000893:Anti-Inflammatory Agents; D015415:Biomarkers; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D018696:Neuroprotective Agents; D010919:Placebos; D016572:Cyclosporine; D003404:Creatinine