in vivo study of synergistic actions of gabapentin and

WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES
Shahid et al.
World Journal of Pharmacy and Pharmaceutical Sciences
Volume 3, Issue 5, 73-83.
Research Article
ISSN 2278 – 4357
IN VIVO STUDY OF SYNERGISTIC ACTIONS OF GABAPENTIN AND
VERAPAMIL ON ACUTE SEIZURE MODELS OF MICE
Itefaq Hussain Qureshi1, Asiya Rehman2, Muhammad Asif Qureshi3, Muhammad
Jawed4, Shabana Usman Simjee1 and Syed M. Shahid5*
1
H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological
Sciences, University of Karachi, Karachi, Pakistan
2
Department of Pharmacology, Liaquat College of Medicine and Dentistry, Karachi, Pakistan
3
Department of Surgery, Liaquat College of Medicine and Dentistry, Karachi, Pakistan
4
Department of Biochemistry, Liaquat College of Medicine and Dentistry, Karachi, Pakistan
5
The Karachi Institute of Biotechnology & Genetic Engineering (KIBGE), University of
Karachi, Karachi, Pakistan
Article Received on
21 February 2014,
Revised on 24 March
2014,
Accepted on 22 April 2014
ABSTRACT
This study aimed to investigate and evaluate in vivo synergistic
anticonvulsant effects of novel regimen of Gabapentin (GBP) and
Verapamil (VP) on acute models of seizures in mice. Chemically
induced seizures model in mice was employed to evaluate in vivo acute
*Correspondence for Author
anticonvulsive activity of the GBP and Verapamil VP as well as their
Dr. Syed M. Shahid
effects were compared with reference drugs i.e. Diazepam (DZ),
The Karachi Institute of
Biotechnology & Genetic
Phenytoin (PHT) and Valproate (VPT). Synergistic anticonvulsive
Engineering (KIBGE),
actions of GBP and VP were evaluated by administrating different
University of Karachi, Karachi,
doses
Pakistan.
Pentylenetetrazole (PTZ) the mice were observed for latency to onset
of
the
GBP
and
VP.
After
administration
of
the
of threshold seizures (LOTS), rearing and falling (R&F) and hind limb
tonic extension (HLTE). Combination regimens of GBP and VP exhibited synergistic antiacute seizure effects. Combination therapy demonstrated synergistic anti-seizure effects at all
tested doses as the percentage of inhibitory effects of combination therapy was more than
sum of the inhibition percentage of individual drugs. The anti-seizure effects of combination
therapy were compared to reference drugs and it completely inhibited the seizures which
were comparable to the DZ and VPT. Combination therapy in higher doses was equivalent in
efficacy to DZ and VPT but it was noted that it was superior to PHT in both LOTS and R&F.
This study provides basic work guidelines for the future clinical use of combination therapy
of GBP and VP in conditions like status epilepticus and non-epilepticus acute seizures. It is
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hoped that the parenteral formulations of GBP would provide better treatment option by
employing instant combination therapy of GBP and VP for the management of various forms
of acute seizures.
Keywords: Synergistic, Antiepileptic drugs (AED), Gabapentine (GBP), Verapamil (VP),
Diazepam (DZ), Phenytoin (PHT), Valproate (VPT), Status epilepticus.
INTRODUCTION
Status epilepticus is a common neurological and life threatening medical emergency. It must
be treated or else it may cause serious damage to the brain and even death in many cases
[1,2]. Lorazepam (LP) and Diazepam (DP) are the first line drugs for the acute short term
management of status epilepticus [3,4]. They are the only benzodiazepines recommended for
the treatment of status epilepticus. If the seizures are uncontrolled then Phenytoin (PHT),
Phenobarbitone (PBT) and Valrpoate (VPT) are given intravenously for long term control of
status epilepticus [5,6]. There is limited choice of first line drugs for treatment of status
epilepticus, status epilepticus in pharmaco-resistance epilepsy is difficult to treat and AEDs
have potential drug-drug interactions and various harmful short terms and long terms side
effects [7,8]. GBP has antiepileptic effects when used as an adjunct or monotherapy. Antiseizure effects of VP have been noted in pharmaco-resistance epilepsy and in patients of
refractory epilepsy suffering from severe myoclonic epilepsy of infancy [9-12]. Verapamil
when used as adjunctive therapy controlled the seizures including status epilepticus [13-18].
The present study was aimed to investigate and evaluate in vivo synergistic anticonvulsant
effects of novel regimen of GBP and VP on acute models of seizures in mice. GBP and VP
are voltage-gated calcium channel blockers; therefore, they can be a potential candidate for
the treatment of status epilepticus.
MATERIALS AND METHODS
The use of study animals was approved by the Institutional Scientific Advisory Committee on
animal care, use, and standards in accordance with the international guidelines for the care
and use of laboratory animals. Male NMRI albino mice weighing 20-25 g were used. The
group size of 12 were used which had 80% power to detect differences in the means.
Parenteral doses were expressed in mg/kg of the body weight of mice.
Pentylenetetrazole (PTZ) was used to induce chemical seizures. GBP and VP were the test
drugs. DZ, PHT and VPT were used as reference dugs. The anticonvulsant effects of GBP
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and VP were compared to PTZ control and then to the reference drugs and lastly combine
regimen of GBP. VP was compared to their individual effects. The chemical convulsant PTZ
was administered subcutaneously in an acute model of seizure. The reference drugs i.e., DZ,
PHT, VPT and the test drugs VP and GBP were administered intraperitoneally. Synergistic
anticonvulsive actions of VP and GBP were evaluated by administrating different doses of
the GBP and VP. The reference drugs or the test drugs were given 40 minutes before the
administration of convulsive dose of PTZ.
After administration of the PTZ, the mice were observed for the presence or absence of three
types of seizure patterns i.e., Latency to onset of Threshold Seizures (LOTS), Rearing and
Falling (R&F) and Hind Limb Tonic Extension (HLTE). The percentage of the seizure score
and seizure protection were recorded in seconds. These seizure parameters were taken as
reference to evaluate the acute anti-seizure effects of combination regimen of GBP and VP.
The statistical analysis was performed using Statistical Package for the Social Sciences
(SPSS) version 17 for Windows and Graph Pad Prism. Results are reported as mean±SEM.
Data of seizure activity was analyzed by nonparametric Student’s t-test and ANOVA with
post hoc Dunnett’s multiple comparison tests. The sequential differences among means were
calculated at the level of p<0.05.
RESULTS
The anti-seizure actions of GBP and VP were studied as a single agent therapy as well as a
combination therapy and were compared in order to evaluate if the synergistic anticonvulsant
activities are better option for the treatment of status epilepticus in short term management.
Latency to Onset of Threshold Seizures (LOTS)
Combined therapy of GBP-VP when compared to PTZ control group the means differences
were more than the sums of the individual GBP and VP means differences. Combined
regimen at highest dose completely inhibited the seizures and the score of LOTS. The data
demonstrated synergistic anti-seizure activity as the net difference in time for LOTS were
more than the sum of GBP and VP individual effects. The combined regimens exhibited
synergistic anti-seizure effects for LOTS whether compared to PTZ control, reference drugs
and to their individual effects (Tables 1-4).
Rearing and Falling (R&F)
Combined regimen exhibited synergistic antiseizure effects for R&F at various doses. This
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study demonstrated synergistic acute anti-seizure effects of combined regimen of GBP-VP as
the percentage of R&F free animals or R&F protection was more than sum of the GBP and
VP when used separately. Also, the combined regimen showed mild to moderate activities for
aborting acute seizures at lower 3 doses; however, the upper three doses exhibited potent
acute anti-seizure activities equal in efficacy to DZ and VPT (Table 6).
Hind-Limb Tonic Extension (HLTE)
This study observed that all the tested doses of GBP treatment exhibited complete inhibition
of HLTE. Similarly, the combined treatment regime i.e., GBP: VP also showed complete
inhibition of HLTE at all doses tested in the present study. However, the VP treatment
showed a dose dependent HLTE behavior (Table 5).
Table 1: Seizure patterns recorded in the acute model of PTZ-induced seizures in mice
following the treatment of GBP-VP. Each value represents the Mean±SEM of 12
animals per group.
Dose
(mg/Kg)
LOTS
(sec)
R&F
(sec)
HLTE
(sec)
Mortality
(%)
% of Mice
Suffering
from R &
F
0.9 %
Saline
0.00
0.00
0.00
0.00
0.00
0.00
90
190±49
365±50
700±55
100
100
0.00
100-5-90
360±30
510±108
0.00
0.00
66.66
100
200-10-90
420±45
650±196
0.00
0.00
50
100
300-15-90
570±37
980±374
0.00
0.00
41.66
100
400-20-90
750±70
1230±524
0.00
0.00
25
100
500-25-90
1060±72
0.00
0.00
0.00
0.00
100
600-30-90
0.00
0.00
0.00
0.00
0.00
100
PHT-PTZ
100-90
920±42
1030±788
0.00
0.00
25
100
VPT-PTZ
200-90
0.00
1220±456
0.00
0.00
33.33
100
DZ-PTZ
10-90
0.00
0.00
0.00
0.00
0.00
100
Group
Normal
Control
PTZ
GBP-VPPTZ
GBP-VPPTZ
GBP-VPPTZ
GBP-VPPTZ
GBP-VPPTZ
GBP-VPPTZ
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Mortality
Protection
(%)
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Table 2: Multiple comparison test of LOTS seizure behavior pattern between test drugs
and PTZ using Dunnett’s test.
Dunnett's Multiple Comparison Test Mean Difference
P<0.05
GBP100-PTZ 90 vs PTZ 90
56.00
Yes
GBP200-PTZ 90 vs PTZ 90
76.00
Yes
GBP300-PTZ 90 vs PTZ 90
146.0
Yes
GBP400-PTZ 90 vs PTZ 90
176.0
Yes
GBP500-PTZ 90 vs PTZ 90
406.0
Yes
GBP600-PTZ 90 vs PTZ 90
556.0
Yes
VP5-PTZ 90 vs PTZ 90
16.00
No
VP10-PTZ 90 vs PTZ 90
46.00
Yes
VP15-PTZ 90 vs PTZ 90
106.0
Yes
VP20-PTZ 90 vs PTZ 90
136.0
Yes
VP25-PTZ 90 vs PTZ 90
216.0
Yes
VP30-PTZ 90 vs PTZ 90
296.0
Yes
GBP100-VP5-PTZ 90 vs PTZ 90
176.0
Yes
GBP200-VP10-PTZ 90 vs PTZ 90
236.0
Yes
GBP300-VP15-PTZ 90 vs PTZ 90
386.0
Yes
GBP400-VP20-PTZ 90 vs PTZ 90
566.0
Yes
GBP500-VP25-PTZ 90 vs PTZ 90
876.0
Yes
GBP600-VP30-PTZ 90 vs PTZ 90
0.00
Yes
Table 3: Comparison of effects on the LOTS seizure behavior between single-agent and
combine-therapy of gabapentin and verapamil.
The data is the mean difference
between the test drug and PTZ score for LOTS represented as a mean in seconds (n=12
animals/group).
S. No
1
2
3
4
5
6
Mean Difference
GBP-PTZ (sec)
56
76
146
176
406
556
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Mean Difference
VP-PTZ (sec)
16
46
106
136
216
296
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Mean Difference
GBP-VP-PTZ (sec)
176
236
386
566
876
0.00
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Table 4: Comparison of means significant difference and difference between means of
LOTS values between GBP-VP treatment with VP as a single-agent therapy. The data is
represented as meanSEM (n=12mice/group).
t-tests for analysis of LOTS between
GBP-VP-PTZ and PHT
GB-VP-PTZ vs PHT
Treatment
Group
GBP-VP-PTZ
vs PHT-PTZ
GBP-VP-PTZ
vs PHT-PTZ
GBP-VP-PTZ
vs PHT-PTZ
GBP-VP-PTZ
vs PHT-PTZ
GBP-VP-PTZ
vs PHT-PTZ
GBP-VP-PTZ
vs PHT-PTZ
Dose (mg/kg)
100-5-90
100-90
200-10-90
100-90
300-15-90
100-90
400-20-90
100-90
500-25-90
100-90
600-30-90
100-90
P<0.05
Difference means
YES
-470.0±12.00
YES
-410.0±9.692
YES
-260.0±13.48
NO
-80.00±11.61
YES
230.0±23.06
YES
0.00
Table 5: Comparison between combination therapy of GBP-VP and individual effects of
GBP and VP treatment on the HLTE seizure behavior.
Treatment Group
GBP-PTZ
GBP-PTZ
GBP-PTZ
GBP-PTZ
GBP-PTZ
GBP-PTZ
VP-PTZ
VP-PTZ
VP-PTZ
VP-PTZ
VP-PTZ
VP-PTZ
GBP-VP-PTZ
GBP-VP-PTZ
GBP-VP-PTZ
GBP-VP-PTZ
GBP-VP-PTZ
GBP-VP-PTZ
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Dose (mg/kg)
HLTE (sec)
100-90
200-90
300-90
400-90
500-90
600-90
5-90
10-90
15-90
20:90
25-90
30-90
100-5-90
200-10-90
300-15-90
400-20-90
500-25-90
600-30-90
0.00
0.00
0.00
0.00
0.00
0.00
70
180
210
240
310
400
0.00
0.00
0.00
0.00
0.00
0.00
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Table 6: Comparison between combination therapies of GBP-VP and individual effects
50
41
25
0
0
8
VP-PTZ
5: 90
200-90
75
25
VP-PTZ
300-90
67
26
VP-PTZ
400-90
50
25
VP-PTZ
500-90
25
-25
VP-PTZ
600-90
0
0
VP-PTZ
10:
90
15:
90
20:
90
25:
90
35:
90
100
33
100
50
84
43
84
59
75
-75
75
-75
Difference
(%)
1600
NORMAL
1400
PTZ 90
1200
1000
800
600
400
200
0
Onset of Seizure
Threshold
Rearing and Falling
Seizure Behavior
HLTE
Difference
75
R&F
(%)
100-90
R & F (%)
Dose (mg/kg)
Treatment
Group
GBPPTZ
GBPPTZ
GBPPTZ
GBPPTZ
GBPPTZ
GBPPTZ
Dose (mg/kg)
67
Treatment
Group
100-590
200-1090
300-1590
400-2090
500-2590
600-3090
Latency of Onset of Seizure Behavior
(secs)
GBP-VPPTZ
GBP-VPPTZ
GBP-VPPTZ
GBP-VPPTZ
GBP-VPPTZ
GBP-VPPTZ
R&F (%)
Treatment
Group
Dose (mg/kg)
of GBP and VP treatment on the percentage of mice suffered from R & F.
VP5+
PTZ 90
VP10+
PTZ 90
VP15+
PTZ 90
VP20+
PTZ 90
VP25+
PTZ 90
VP30+
PTZ 90
PHT100
PTZ 90
VPT200+
PTZ 90
DZ 10+
PTZ 90
Figure 1 : Synergistic effects of GBP and VP on seizure behavior in scPTZ-induced
seizure model. The treatment of GBP-VP showed a dose dependent acute anticonvulsant
activity. Each bar in the figure represents the MeanSEM calculated for each group
consisting of 12 animals.
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Figure 2: Percentage protection following GBP and VP treatment in scPTZ-induced
seizure test. The GBP and VP combination demonstrated 100 % mortality protection
from the sc-PTZ administration at all six dose combinations. Each bar in the figure
represents the mean±SEM (n= 12 animals/group).
DISCUSSION
The rationale for selecting GBP and VP combination had many reasons including their
reported characteristics of having inhibitory and modulating effects on voltage gated calcium
channels of CNS [19-20]. GBP has inherent potential of antiepileptic properties which may
be augmented or modified if given in combination with other drugs like calcium channel
blockers i.e. VP. GBP has been approved by the FDA as monotherapy for partial and
complex partial seizures with or without generalized tonic-clonic seizures [21-23]. The VP is
a typical calcium channel blocker that it is not an approved AED for the treatment or adds-on
therapy for epileptic disorders however; in various research studies it has demonstrated its
blocking and inhibitory effects on voltage-gated calcium channels of the CNS [24-26]. We
examined and analyzed the combination therapy from multiple dimensions in acute model of
seizures.
The GBP and VP when employed as individual drug have demonstrated potential anti-seizure
effects compared to PTZ control. However, when compared to reference drugs, both failed to
show a comparable latency to onset of tonic seizures at all tested doses.
The anti-seizure effects of the GBP were potent as compared to VP which exhibited weak
anti-acute seizure effects. Though both the drugs in individual capacity no doubt possess
potential for anti-seizure effects but their effects are not efficacious. Adverting to the
combination regime of GBP and VP almost all the dose regimens of combination therapy
exhibited synergistic anti-acute seizure effects.
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Potency between lowest dose of combination therapy and individual dose therapy of GBP for
LOTS have demonstrated potent synergistic anti-acute seizure effects. Potency analysis
between combination therapy lowest dose regimen and VP individual doses for LOTS
demonstrated combination therapy potent synergistic anti-acute seizure effects (Figure 1).
The other doses of combination therapy also exhibited potent synergistic anti-seizure effects.
In R&F seizure behavior, the combination therapy demonstrated synergistic anti-seizure
effects at all tested doses as the percentage of R&F inhibitory effects of combination therapy
was more than sum of the R&F inhibition percentage of individual drugs (Figure 2).
When the anti-seizure effects of combination therapy were compared to reference drugs for
LOTS, it was observed that combination therapy of GBP and VP at higher doses completely
inhibited the seizure which was comparable to the DZ and VPT. However, in case of R&F,
combination therapy of GBP and VP completely inhibited the seizure behavior of R&F,
thereby, demonstrating that combination therapy in higher doses were equivalent in efficacy
to DZ and VPT and superior to PHT in both LOTS and in R&F (Figures 1-2).
None of the doses of GBP and VP as individual drugs completely inhibited the seizure
behavior of LOTS and hence they were found inferior to reference drugs even at highest
dose. The authors are therefore, inclined to hold that combination therapy has wide potential
and scope for the treatment and management of acute seizures and status epilepticus.
The findings from the present study may imply that the major advantages of combination
therapy would be that lower doses of GBP will be employed in combination therapy that
would be at least four times in potency to its individual effects. Thus reducing the dose of the
GBP would offset some of the short term side effects.
CONCLUSION
The present study assessed and evaluated the synergistic capabilities of the combination
regimen of GBP and VP in acute seizure model and authors are inclined to hold that in acute
model of seizures the combination therapy demonstrated potent synergistic anti-acute seizure
activity at the lowest dose tested. The synergistic affects would provide better option for the
clinicians to use low to moderate doses of GBP in combination with VP and to avoid very
heavy doses which are many time troublesome. Not only this but novel regimen of GBP and
VP can be employed with adjustment of their doses. This study actually provides basic work
guidelines for the future clinical use of combination therapy of GBP and VP in conditions
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like status epilepticus and non epilepticus seizures.
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