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B4-05
SYNERGISTIC EFFECTS OF PHENYTOIN AND ETHOSUX-
IMIDE AGAINST POST-TRAUMATIC NONCONVULSIVE
SEIZURES
Xi-Chun May Lu
1
, Ronald Tallarida,
2
, Ying Cao
1
, Zhilin Liao
1
,
Deborah Shear
1
, Frank Tortella
1
1
Walter Reed Army Institute of Research, Brain Trauma Neuropro-
tection & Neurorestoration/Psychiatry and Neuroscience, Silver
Spring, USA
2
Temple University, Dept. Pharmacology, Philadelphia, USA
A key aspect of isobolic analysis of combination therapy is to de-
termine the proper dose ratios of two drug constituents to achieve
expected synergistic effects. Recently we demonstrated that combined
treatment of phenytoin and ethosuximide (PHT
+
EXM) at a fixed
dose ratio (PHT/EXM: 14.4/44.4 mg/kg) achieved
additive
effects on
attenuating nonconvulsive seizures (NCS) induced by penetrating
ballistic-like brain injury (PBBI) in rats, but not
synergism
as defined
by the isobolic analysis method. In this study we tested a set of
variable dose ratios of PHT
+
2EXM combination, such that one part
of PHT was paired with two parts of EXM in reference to the fixed
dose ratios tested previously, i.e. 0.9/5.5, 1.8/11.1, 3.6/22.2, 7.2/44.4,
or 14.4/88.98 mg/kg (PHT/2EXM). All rats received frontal PBBI
followed by 72-h continuous EEG monitoring. The treatments were
delivered intravenously twice/day for three days (first injection initi-
ated 30 min post-injury). Control animals received matching vehicle
treatments. The results showed that PHT
+
2EXM reduced NCS in-
cidence from 75% (vehicle group) to 44–56% (p
>
0.05) and signifi-
cantly delayed NCS onset latency from 22h (vehicle group) to 41–52h
post-injury (p
<
0.05) across all PHT
+
2EXM groups. PHT
+
2EXM
treatments also decreased NCS frequency by 29–76% and shortened
NCS cumulative duration by 3–77% compared to vehicle treatments.
For these latter two measurements, the most significant effects were
afforded by the three low dose ratios of PHT
+
2EXM combination
(p
<
0.05). More importantly, the dose equivalent analysis indicated
that the observed efficacy of these three dose ratios
achieved syner-
gism
when compared to the expected efficacy. The results of this study
not only demonstrated that enhanced anti-seizure efficacy was pro-
vided by the reduced dosages of PHT and EXM as a combination
therapy, but also emphasize the importance of testing proper dose
ratios of any two drugs in achieving objectively defined synergism.
This research was funded by the Army Combat Casualty Care
Research Program.
Keywords: Combination Therapy, Penetrating Brain Injury, Phe-
nytoin, Ethoxusimide, Isobolographic Analysis
B5 Poster Session IV - Group B: Function
B5-01
SUICIDAL IDEATION IN THE FIRST 6 MONTHS POST-
MILD TRAUMATIC BRAIN INJURY
Mercy Joyce
2
, Hope Clark-Bell
1,2
, Christopher Panks
1,2
, Adrienne
James
1,2
,
Hilaire Thompson
1,2
1
The Univ. of Washington, Biobehavioral Nursing & Health Systems,
Seattle, USA
2
The Univ. of Washington, Harborview Injury Prevention and Re-
search Center, Seattle, USA
Purpose:
The aims of this study were to 1) assess the prevalence of
suicidal ideation (SI) in persons post-mild traumatic brain injury
(TBI) compared to control non-injured subjects and 2) to examine if
demographic or social factors increase risk of SI endorsement to 6
months post-mild TBI.
Protocol/Methods:
This was secondary data analysis of an ongoing
cohort study. Cohorts under study include those with mild TBI (via
CDC definition) and non-injured age/gender matched controls. De-
mographic characteristics and social support (MOS Social Support
Scale-MOS-SSS) were assessed at baseline. Suicidal ideation was
endorsed if subjects scored 1 or higher on question 17 of the Brief
Symptom Inventory-18 (BSI-18). The BSI-18 was administered at day
7, 1, 3 and 6 months post-injury/enrollment. Chi-squared and logistic
regression analyses were used, with a significance level set a p
<
0.05.
Results:
Data were available on 256 subjects (n
=
135 mild TBI;
n
=
121 non-injured controls). The prevalence of persons endorsing
any SI was higher in those with mild TBI (16.3%) compared to
non-injured controls (11.6%), but this difference was not statisti-
cally significant (p
=
.18). Similar differences were seen between
those expressing being bothered moderately or more by thoughts of
ending their life in the past 7 days (7.4% TBI vs. 4.9% of control).
The prevalence of SI was slightly lower in persons 55 and older
following TBI (15%) compared to younger individuals (17.3%). Of
the demographic and social variables only social support was a
significant predictor of SI. For every one point increase in the
MOS-SSS, the risk of endorsing SI decreased by 4% (95% CI 1.5–
7%).
Conclusion:
While there is prevalent SI in community-dwelling
persons following mild TBI, the rate was no higher than that of a
matched cohort of non-injured persons. Interventions that increase
levels of social support are needed to improve mental health post-
injury.
Supported by NIH/NINDS R01NS077913
Keywords: mental health, aging, social support
B5-02
MONITORING SENSORY FUNCTION AFTER CERVICAL
SPINAL CORD INJURY IN NON-HUMAN PRIMATES
Jenny Haefeli
1
, Ernesto A Salegio
1
, Jessica L Nielson
1
, Rod
Moseanko
2
, Sarah Strand
2
, Stephanie Hawbecker
2
, Ephron S
Rosenzweig
3
, Mark H Tuszynski
3
, Michael S Beattie
1
, Adam R
Ferguson
1
, Jacqueline C Bresnahan
1
1
University of California, San Francisco, Neurological Surgery, San
Francisco, USA
2
University of California, Davis, California National Primate Re-
search Center, Davis, USA
3
University of California, San Diego, Neurosciences, San Diego, USA
A recent query of a large multicenter, multispecies spinal cord injury
(SCI) database (i.e., VISION–SCI) revealed that sensory outcomes are
rarely assessed in preclinical SCI models (10.2%) compared to motor
outcomes (59.1%). Sensory measures are important to further trans-
lational research to screen for (mal-)adaptive changes in sensation.
Efforts linking outcomes across species are crucial to relate knowl-
edge of mechanism gained in preclinical research to clinical symp-
toms. Towards this goal von Frey hair (VFH) assessments were
performed in a non-human primate cervical (C6-C7) hemi-contusion
model of SCI. Four animals were assessed during early, mid- and late
recovery periods at 5 sites (i.e., shoulder, hand, thorax, knee and foot).
The response to the electronic VFH stimulus was classified into 4
categories: no response, segmental responses (withdrawal, skin con-
traction or flinch), supraspinal responses (orientation, activity arrest)
and facial supraspinal responses (wince and vocalization). Data were
A-57