1. ABSTRACTS
ABSTRACTS 1349
1123022
IRL-1620 prevents beta amyloid (Aβ) induced oxidative stress
and cognitive impairment
Seema Briyal, Cortney Shepard, Anil Gulati
Midwestern University, Downers Grove, IL, USA
Statement of Purpose, Innovation or Hypothesis: Alzheimer’s
disease (AD) is a progressive brain disorder leading to impair­
ment of learning and memory. Incidence of AD is higher in dia­
betic patients. Studies indicate that stimulation of ETB receptors
may provide neuroprotection. The present study was conducted
to investigate the involvement of ETB receptors in Aβ-induced
cognitive impairment in non-diabetic and diabetic rats.
Description of Methods and Materials: The expression of ETB
receptors was studied using Western blotting. Parameters of oxi­
dative stress assessed were malondialdehyde (MDA), glutathione
(GSH) and superoxide dismutase (SOD). Learning and memory
behavior was assessed using the Morris water maze. Rats were
treated with Aβ(1-40) (6.67 µg, icv) was administered on day 1, 7 and
14 and all experiments were performed on day 15. Diabetes was
induced by administering streptozotocin (45 mg/kg, ip) 3 days
prior to Aβ injection. Rats were treated chronically with ETB
receptor agonist (IRL-1620) and antagonist (BQ-788) for 14 days.
Data and Results: Diabetic rats showed sluggish behavior and
decreased locomotion compared to non-diabetic rats, but there
was no difference in cognitive impairment or oxidative stress
parameters following Aβ treatment in non-diabetic and diabetic
rats. Aβ treatment produced no change in ETB receptor expres­
sion in the brain, and ETB receptor expression was not altered by
IRL-1620 or BQ-788 treatment. A significant increase in levels of
MDA and a concurrent decrease in GSH and SOD levels was
observed following Aβ treatment in non-diabetic and diabetic
rats. IRL-1620 produced a significant (P<0.001) decrease
(278.4±8.5 nmol/g wet tissue) in MDA level compared to the
vehicle group (516.1±14 nmol/g wet tissue) and reversed the
decrease in GSH and SOD levels following Aβ treatment in non-
diabetic and diabetic rats. In Morris water maze task, Aβ treated
rats showed a significant (P<0.0001) impairment in spatial mem­
ory. Administration of IRL-1620 to Aβ treated rats produced a
significant improvement in learning and memory compared to the
vehicle group in both diabetic and non-diabetic rats. Changes
induced by IRL-1620 were completely blocked by BQ-788.
Interpretation, Conclusion or Significance: Aβ produced an incre­
ase in oxidative stress parameters and loss of learning and mem­
ory, which was significantly improved by ETB agonist, IRL-1620.
1123058
Role of centhaquin in the resuscitation of hemorrhagic shock
Anil Gulati1
, Manish S. Lavhale2
, Suresh Havalad3
1
Midwestern University, Downers Grove, IL, USA; 2
Pharmazz,
Inc., Naperville, IL, USA; 3
Advocate Lutheran General Hospital,
Park Ridge, IL, USA
Statement of Purpose, Innovation or Hypothesis: Centhaquin
may have a role in resuscitative effect by improving the vascular
responsiveness in the resuscitation of hemorrhagic shock (HS). It is
our hypothesis that adding centhaquin to Lactated Ringer’s (LR) or
3% hypertonic saline (SAL) will enhance their resuscitative effect.
Description of Methods and Materials: Rats were anaesthe­
tized with urethane. The femoral vein was canulated for drug
administration and femoral artery was cannulated for measuing
mean arterial pressure (MAP). A calibrated pressure-volume cath­
eter (SPR-869) was placed into the left ventricle and data were
analyzed using a LabChart-5.00 and PVAN analysis program.
After completion of surgery, induction of HS was initiated by
withdrawing blood from the right femoral artery to maintain the
MAP between 35 and 40 mmHg for 30 minutes.
Data and Results: Hemorrhage produced a decrease in hema­
tocrit from ~49% to ~27%, which was similar in all the groups.
Sixty minutes following resusctiation with LR, blood lactate level
was 10.2±0.6 mmol/L, however addition of centhaquin in LR
improved lactate level to 4.1±0.3 mmol/L. Similarly, following
resusctiation with SAL, lactate level was 3.4±0.5 mmol/L, and
addtion of centhaquin improved it to 2.0±0.3 mmol/L. Cardiovas­
cular parameters signficantly improved following addition of
centhaquin in either LR or SAL. Centhaquin improved the sur­
vival following LR treatment from 78±10 mins to 387±38 mins,
and following SAL treatment from 144±22 mins to 326±55 mins.
Another experiment showed that centhaquin decreased the
requirement of NE by 10 folds in HS. In hemorrhaged rats, a 50%
decrease in systemic vascular resistance (SVR) was observed in
spite of infusion of a high dose (50 µg/100g/hour) of NE; whereas,
only 36% decrease in SVR was observed following a low dose
(5 µg/100g/hour) infusion of NE in centhaquin treated rats.
Interpretation, Conclusion or Significance: Centhaquin
improves the resuscitative effects of LR and SAL and increases
the vascular responsiveness to NE in hemorrhaged rats.
1123083
Single-dose Plasma PK Parameters of Arbaclofen, R-baclofen
and S-baclofen
Glenn Meyer1
, Gustavo Fischbein2
, David Boyd1
1
Osmotica Pharmaceutical Corp, Wilmington, NC, USA; 2
Osmotica
Pharmaceutical Argentina S.A., Buenos Aires, Argentina
Statement of Purpose, Innovation or Hypothesis: Arbaclofen,
the R-enantiomer of the GABAb agonist baclofen, is in develop­
ment, as the single enantiomer, for the treatment of spasticity due
to multiple sclerosis. We hypothesized that the PK parameters for
the R-enantiomer would be the same when administered alone
versus administration as the racemic mixture.
Description of Methods and Materials: A 4-arm, double blind,
parallel group, dose-ranging PK study of arbaclofen and baclofen
was conducted in healthy subjects to compare the plasma parame­
ters. Twelve subjects in each group received either arbaclofen doses
of 5, 7.5, or 10mg, or baclofen doses of 20mg, initially on Day 1 and
then every six hours thereafter for four days after an up-titration
period of nine days. Here we report the initial, single-dose results.
Data and Results: On Day 1, initial single, equi-molar doses of
the R-enantiomer produced similar PK results for arbaclofen and
the R-enantiomer of baclofen. The p-values for AUC, Cmax,
Tmax, and t1/2 were, 0.97, 0.43, 0.70, and 0.51 respectively. The
same parameters for the S-enantiomer vs. R-enantiomer in the
baclofen group were notably different with p-values less than
0.02 for all above parameters.
Interpretation, Conclusion or Significance: The R and
S-enantiomers of baclofen exhibit different ADME parameters.
Arbaclofen ADME parameters are similar to those of R-baclofen
when administered as the racemic mixture.
PK Parameter*
Arbaclofen 10 mg Baclofen 20 mg
Arbaclofen R-baclofen S-baclofen
AUCt (ng.hr/ml) 784 (147) 782 (126) 704 (135)
Cmax (ng/ml) 165 (39) 178 (44) 116 (33)
Tmax (hr) 1.04 (0.54) 0.96 (0.49) 1.88 (0.88)
T ½ (hr) 6.3 (1.1) 6.7 (1.6) 5.3 (0.9)
CL/F (L/hr) 12.6 (2.4) 12.4 (1.8) 14.1 (3.1)
CLr (L/hr) 11.1 (2.4) 10.8 (2.0) 9.3 (1.8)
fe (%) 84.4 (10.6) 82.8 (11.8) 64.9 (14.5)
*- all values are arithmetic means of single doses (SD)
at ACCP Member on August 24, 2012jcp.sagepub.comDownloaded from

2. ABSTRACTS
ABSTRACTS 1351
1123336
Population Pharmacokinetics-Pharmacodynamics of the
G-Protein Coupled Receptor 40 (GPR40) Agonist TAK-875 in
Subjects with Type 2 Diabetes Mellitus (T2DM)
Majid Vakilynejad, Jing-tao Wu, Prabhakar Viswanathan, Vipin
Arora, Eckhard Leifke
Takeda Global Research & Development Center, Inc., Deerfield, IL,
USA
Statement of Purpose, Innovation or Hypothesis: TAK 875 is
a highly selective and potent GPR40 agonist which causes glu­
cose-dependent insulin secretion and is being developed by
Takeda for the treatment of T2DM. A sequential population
pharmacokinetic-pharmacodynamic (PPKPD) model for TAK-875
was developed to estimate mean population PK and PD parame­
ters using TAK-875 concentrations and fasting plasma glucose
(FPG) levels measured in a short-term 14 day clinical study.
Description of Methods and Materials: Using historical glyce­
mic data (13 clinical trials and ~8000 subjects from various Takeda
diabetes programs), an empirical linear mixed effect model was
developed to predict long-term effects (changes in HbA1c) from
short-term changes (FPG levels at day 14). Data from a phase 1,
double-blind, randomized, placebo-controlled, multiple rising-dose
study of TAK-875 25, 50, 100, 200 or 400 mg (n=45) or placebo
(n=14) given orally for 14 days to T2DM patients were included.
Data and Results: The PK and FPG profiles were best described
using a two compartment model with first-order absorption and
elimination processes and an Emax stimulatory indirect response
model, respectively. The inter-patient variability was included in
the model as exponential errors for CL, V, and baseline FPG. The
model parameters were estimated precisely [CL/F=0.624 (%RSE=10)
L/h, Vc/F=4.11 (%RSE=19), Ka = 0.0750 (%RSE=13) h-1, baseline
FPG=172 (%RSE=3) mg/dL, EC50=1150 (%RSE=38%), ng/mL,
Emax=0.349 (%RSE=13)] and the model was stable and predictive.
Interpretation, Conclusion or Significance: This modeling and
simulation approach characterized the TAK-875 exposure-response
relationship and suggested a dose range for Phase 2. Oral adminis­
tration of TAK 875 25-50 mg once per day is predicted to show an
A1c reduction at week 12 that is comparable to sulfonylureas.
1123347
Efficacy of Pregabalin, Gabapentin and Duloxetine in Treatment
of Diabetic Neuropathic Pain, Postherpetic Neuralgia and
Fibromyalgia: A Model-Based Meta-Analysis
Ahmed A. Othman1
, Sandeep Dutta1
, Walid Awni1
, Jaap Mandema2
1
Department of Clinical Pharmacology and Pharmacometrics,
Abbott Laboratories, Abbott Park, IL, USA; 2
Quantitative
Solutions, Menlo Park, CA, USA
Statement of Purpose, Innovation or Hypothesis: The objec­
tive of this work was to characterize the efficacy dose-response
relationship of drugs approved or evaluated for treatment of sev­
eral neuropathic pain indications: Diabetic Neuropathic Pain
(DPN), Postherpetic Neuralgia (PHN), and Fibromyalgia (FM).
Description of Methods and Materials: A database of all pub­
licly available efficacy information on drugs approved or evaluated
for treatment of DPN, PHN and FM was developed. Subsequently,
27 controlled clinical trials with data from >9500 patients, for drugs
evaluated across at least two indications (pregabalin, gabapentin
and duloxetine) and reporting LOCF imputed 0-10 points Likert or
Brief Pain Inventory average pain scores were selected for analysis.
A non-linear mixed-effects model-based meta-analysis of change
from baseline average pain score was conducted using NONMEM 7.
Data and Results: The final dose response model was an Emax
model with indication-dependent placebo and Emax parameters and
common Emax for all drugs within an indication. For DPN only, Emax
was found to be dependent on placebo effect (i.e. Emax - E0 model
was better than Emax model). There was no statistical evidence that
ED50 for any of the three drugs differs across tested indications and
therefore one ED50 parameter was used for each drug across indica­
tions. The model-estimated placebo effect was -1.5, -0.9 and -1.1
points for DPN, PHN and FM, respectively; inter-trial standard-
deviation was 0.3 points. The model-estimated maximal effect was
-1.6 points (Emax - E0) for DPN and -2.2 and -1.2 points (Emax) for PHN
and FM, respectively. Estimated ED50 values were 324, 1600 and 28
mg for pregabalin, gabapentin and duloxetine, respectively.
Interpretation, Conclusion or Significance: Results from this
analysis demonstrate higher placebo effect for DPN compared to
PHN and FM and greater maximal drug effect in PHN vs. DPN and
FM. There was no evidence that the potency of the drugs differed
across indications.
1123350
CSF and Plasma PK Parameters of R-baclofen: Arbaclofen Versus
the Racemic Mixture
Glenn Meyer1
, Gustavo Fischbein2
, David Boyd1
1
Osmotica Pharmaceutical Corp, Wilmington, NC, USA; 2
Osmotica
Pharmaceutical Argentina S.A., Buenos Aires, Argentina
Statement of Purpose, Innovation or Hypothesis: Arbaclofen,
the R-enantiomer of the GABAb agonist baclofen, is in development
for the treatment of spasticity due to MS. The PK parameters of oral
R-baclofen in the CSF have not been previously reported. Animal
data suggests competitive transport for the R- and S-enantiomers
across the blood-brain barrier. We hypothesized this difference in
transport into the CSF would be present in humans.
Description of Methods and Materials: A 4-arm, double-blind,
parallel group, dose-ranging PK study of arbaclofen and baclofen
was conducted in healthy subjects to compare the plasma and CSF
parameters. Twelve subjects in each group received oral arbaclofen
doses of 5, 7.5, or 10mg, or baclofen doses of 20mg every six hours
for four days after an up-titration period of nine days. Steady state
PK parameters were calculated from samples taken on Day 14.
Data and Results: No difference was observed for AUC, Cmax,
and Cmin in the plasma or CSF for equi-molar doses of R-baclofen
when administered as the single enantiomer or the racemic mixture.
Interpretation, Conclusion or Significance: Plasma and CSF param­
eters were not dose proportional in the arbaclofen treated groups.
Plasma and CSF PK parameters of R-baclofen are not different when
administered as the single enantiomer or the racemic mixture. The
competitive blood brain barrier transport of the R- and S-enantiomers
observed in pre-clinical models was not observed in this study.
1123350: Table 1: R-baclofen PK Results
Treatment
Plasma CSF
AUCt ng*h/ml Cmax ng/ml Cmin ng/ml AUCt ng*h/ml Cmax ng/ml Cmin ng/ml
Arbaclofen 5mg 470 134 45 34.7 8.1 4.5
Arbaclofen 7.5mg 580 181 57 45.5 9.6 4.9
Arbaclofen 10mg 817 224 81 68.1 14.2 7.6
Baclofen 20mg 786 237 77 53.8 11.1 6.9
at ACCP Member on August 24, 2012jcp.sagepub.comDownloaded from

3. 1354 • J Clin Pharmacol 2011;51:1326-1369
ABSTRACTS
patient education is required about drug uses and stricter regula­
tory activities will be needful to promote rational drug uses in
this population.
1123835
A Cross-sectional Study to Assess the Patients’ Satisfaction and
Effectiveness of Complementary and Alternative Medicine
(CAM) in four chronic diseases in a tertiary referral centre in
India
Mangesh S. Bhalerao, Pravin M. Bolshete, Balkrishna D. Swar,
Triveni A. Bangera, Vijaykumar R. Kolhe, Swapnil D. Bhowate,
Mukund J. Tambe, Umesh B. Sonje, Meenal P. Wade, Nithya J.
Gogtay, Urmila M. Thatte
Department of clinical pharmacology, Seth GS Medical College &
KEM hospital Parel, Mumbai, Mumbai, India
Statement of Purpose, Innovation or Hypothesis: The use of
Complementary and Alternative Medicine (CAM) is increasing and
becoming an important treatment option for patients with chronic
diseases. The present study was conducted to assess the patients’
satisfaction and extent of CAM use in four chronic diseases; Rheu­
matoid arthritis (RA), Diabetes mellitus (DM), Epilepsy and HIV.
Description of Methods and Materials: The study was
approved by the IRB and conducted over a 16 week period in
these diseases after written informed consent from participants.
Key selection criteria were age more than 18 yrs and taking CAM
along with established therapy. The Treatment Satisfaction Ques­
tionnaire for Medication (TSQM)TM was used to assess the satis­
faction in domains like Effectiveness, no Side Effect, Convenience
and Global Satisfaction. The domain scores ranged from 0 to 100
with higher scores representing greater satisfaction.
Data and Results: A total of 4664 patients were screened. Of
these 1619 (34.71%) were found to be using CAM. Of these,
969/1619 (59.85%) declined to consent and thus only 650 were
studied. The extent of use of CAM in DM was 63%, RA 42.73 %,
HIV 26.19 % and Epilepsy 7.67%. Ayurveda was found to be most
frequently used CAM 57.07 % (95% CI 53.27-60.89). Satisfaction
in terms of effectiveness and global satisfaction was highest in HIV
(69.43% and 69.24 % respectively) and least in RA (56.61 % and
54.13 % respectively). High scores were reported to “no side effect
“domain in all four diseases indicating satisfaction with CAM.
Interpretation, Conclusion or Significance: The extent of use of
CAM in four chronic diseases in a tertiary referral centre was found
to be 34.71% .The users of CAM in DM, HIV and Epilepsy believed
that CAM were safe, effective and convenient with high satisfac­
tion. Given the potential interaction of CAM with conventional
therapies, patients should be screened at least by history taking for
use of CAM. Studies on the actual effectiveness may help physi­
cians and patients in future management of these diseases.
1123838
Evaluation of authenticity and rationality of promotional
pharmaceutical drug literatures
Chetan B. Yeola1
, Gaurav Zope1
, Pravita Yadav1
, Sachin Upasani1
,
Sagar Thakkar1
, Manoj Jadhav1
, Ashish Nabar2
1
Department of Infectious Diseases, Maharashtra University of
Health Sciences & Seth G S Medical College and KEM Hospital,
Parel, Mumbai., Parel ( Mumbai), India; 2
Department of Cardiology,
Seth G S Medical College and KEM Hospital, Parel, Mumbai.,
Parel ( Mumbai), India
Statement of Purpose, Innovation or Hypothesis: The promo­
tional activities of pharmaceutical industry are governed by the
World Health Organization, International Federation of Pharma­
ceutical Manufacturers and Associations, Organization of Phar­
maceutical Producers of India, which are self regulatory codes.
Many studies showed that information disseminated through the
advertisement is inconsistent with the code of ethics. Thus this
study aims to evaluate the authenticity and rationality of the
pharmaceutical promotional drug literatures.
Description of Methods and Materials: In this prospective
observational study we collected 171 promotional pharmaceuti­
cal drugs literature from various departments such as Cardiology,
Medicine, Nephrology, Oncology Orthopedics, and pediatrics at
K.E.M. Hospital, Parel, Mumbai. The collected literatures were
analyzed for rationality according to world health organization
criteria (WHO) and authenticity of therapeutic claims made in
promotional literature were verified by accessing standard litera­
ture through internet databases.
Data and Results: In this prospective observational study on
pharmaceutical promotional drug literatures showed that 19.30%
(33) were rational, 80.70% (138) were irrational, 49.12% (84) were
authentic and 50.88% (87) were not authentic. Multinational com­
panies showed 9.36% (16) rationale, 24.56% (42) irrational,
19.88% (34) authentic, 14.62% (25) not authentic and non multi­
national companies showed 9.36% (16) rationale, 56.72% (97)
irrational, 29.83% (51) authentic and 35.67% (61) not authentic.
Out of 171 promotional literatures 26.90% (46) were from diabetes
blood pressure, 15.79% (27) from analgesics, 15.20% (26) from
antibiotics and 31% (53) from other therapeutic area.
Interpretation, Conclusion or Significance: It was concluded
from this study that pharmaceutical companies did not follow the
WHO guidelines while promoting their drugs. They have only the
commercial motive rather than the ethical educational aspect.
Important information about contraindication, precautions, adverse
drug reaction and drug interactions was usually missing. Non mul­
tinational pharmaceutical companies showed the more irrationality
and non authenticity. There will be need of making stringent laws
for ethical promotion of pharmaceutical drugs material.
1123960
Plasma and CSF Levels of Arbaclofen Are Not Associated With
Drowsiness
Glenn Meyer1
, Gustavo Fischbein2
, David Boyd1
1
Osmotica Pharmaceutical Corp, Wilmington, NC, USA; 2
Osmotica
Pharmaceutical Argentina S.A., Buenos Aires, Argentina
Statement of Purpose, Innovation or Hypothesis: Arbaclofen,
the R-enantiomer of baclofen, is in development for spasticity due
to multiple sclerosis. The primary dose limiting adverse event for
racemic baclofen is drowsiness and sedation. We hypothesized
that the S-enantiomer was the primary cause of these events.
Description of Methods and Materials: A 4-arm, parallel
group, double-blind, dose-ranging PK study of arbaclofen and
baclofen was conducted in healthy subjects to compare the
plasma and CSF parameters. Twelve subjects in each group
received arbaclofen doses of 5, 7.5, or 10mg, or baclofen doses of
20mg every six hours for four days after an up-titration period of
nine days. Subjects completed a drowsiness scale every three
hours while awake on Day 12. Scores ranged from zero “No
Drowsiness” to 10 “Worst Possible Drowsiness”. PK samples were
taken on Day 14. AUC and Cmax values were analyzed by regres­
sion with the mean daily drowsiness scores.
Data and Results: No significant correlation was observed
between drowsiness scores and arbaclofen or baclofen plasma PK
parameters. No significant correlation was found for arbaclofen
CSF parameters. However, baclofen CSF AUC and Cmax were
significantly correlated to daily drowsiness scores with R2 values
of 0.78 and 0.88 and p-values of 0.0016 and 0.0001, respectively.
Interpretation, Conclusion or Significance: These results sug­
gest that drowsiness, the most common dosing-limiting adverse
event for baclofen, is associated with CSF exposures of the
S-enantiomer and not the R-enantiomer.
at ACCP Member on August 24, 2012jcp.sagepub.comDownloaded from