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Life Sciences
Life Sciences 75 (2004) 1887 - 1896
www.elsevier.comllocate/lifescie
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Cardiorespiratory effects of diazepam-ketamine,
xylazine-ketamine and thiopentone anesthesia in male Wi star
rats-A comparative analysis
Miriyala Sumitraa,l, Panchatcharam Manikandana,l,
Kalekar Vittalrao Kuppu Rao b, Mohammed N ayeem c,
Bhakthavatsalam Murali Manohar d , Rengarajulu Puvanakrishnan a,*
a
Department of Biotechnology, Central Leather Research Institute, Adyar, Chennai-600 020, India
b HIV AIDS Division, Tuberculosis Research Centre, Indian Council OJ Medical Research,
Chetput, Chennai-600 031, India
cAlved Phanna and Foods Pvt. Ltd., Chennai-600 078, India
d Department of Pathology, Madras VeterinGlJ! College, Vepery, Chennai-600 007, India
Received 2 Febntary 2004; accepted 28 May 2004
Abstract
Several anesthetics are known to cause respiratory and cardiovascular depression in humans and animals;
but, these diverse effects have not been extensively investigated in laboratory rodents. The objective of this
study is to choose a suitable anesthetic combination for use in surgical models ego coronary artery ligation in
rats. Male Wi star rats were anesthetized with three different drugs viz. diazepam-ketamine (DK) (2.5 mgiKg,
intraperitoneally (i.p); 50 mgiKg, i.p), xylazine-ketamine (XK) (5 mgiKg i.p; 50 mgiKg i.p) and thiopentone
(T) (40 mg/Kg i.p) and the respiratory and cardiovascular functions were assessed after coronary artery
ligation. Heart rate (HR), mean arterial pressure (MAP), partial pressure of carbon dioxide (PaC0 2), partial
pressure of oxygen (Pa02), oxygen saturation percentage (0 2 sat (%)), arterial blood pH and rectal body
temperature were studied in detail. During the anesthetic regime, HR was lower till 60 min in XK and T
ligated group (333 ± 6; 304 ± 8 beats/min) and it was near normalcy in the case of DK ligated group (394
± 6 beats/min). Significant respiratory depression was particularly reflected in the T ligated group with an
increase in PaC0 2 at 30 min (40.32 ± 2.64 mmHg), which decreased to 38.2 ± 2.23 mmHg at 60 min.
Throughout the investigation, DK showed the least overall effects compared to XK and · T on respiratory
>I< Corresponding author. Tel.: +91-44-24430273; fax: +91-44-24911589.
E-mail address:[email protected] (R. Puvanakrishnan).
1 Both the authors have contributed equally towards this paper.
0024-3205/$ - see front matter © 2004 Elsevier Inc. All rights reserved.
doi: 10.1 016/j.1fs.2004.05.009
1888
M. Sumilra et al. I Life Sciences 75 (2004) 1887- 1896
functions . Thus, DK could be considered to be a suitable anesthetic for use in a surgical model such as
coronary artery ligation in albino rats.
© 2004 Elsevier Inc. AIl rights reserved.
Keywords: Coronary artery ligation; Diazepam; Blood gas analysis; Ketamine; Thiopentone; Xylazine
Introduction
Knowledge of anesthetic agents alone, or in combination with preanesthetics is a prerequisite to
. understand the changes taking place in the anesthetized patients. Each drug has its own peculiarities
and it acts differently when combined with another (Gonzalez Gil et aI., 2003).
Ketamine hydrochloride is a dissociative anesthetic of the cyclohexylamine group used for chemical
restraint and for the induction and maintenance of anesthesia in a number of species (Muir et aI., 2000).
Unlike many anesthetics, ketamine usually stimulates cardiovascular function in normal animals,
causing increase in heart rate (HR) and mean arterial pressure (MAP) (Haskins et aI., 1985). The use
of ketamine as a sole anesthetic has been limited by muscle hypertonicity and myoclonus, violent
recovery and occasional occurrence of convulsions (Haskins et aI., 1985). In an attempt to counteract
these undesirable effects, ketamine has been used in combination with various drugs including
benzodiazepines, e.g. diazepam (Heyller et aI., 1991) and alpha-2 agonists (Moens and Fargetton,
1990). Diazepam, a potent sedative and muscle relaxant, metabolizes slowly, prolonging its activity and
it has a minimal effect on the cardiovascular system compared with other tranquilizing agents and
sedatives (Koshy et aI., 2003). Diazepam combined with ketamine decreases the effects of ketamine on
the cardiovascular system and produces centrally mediated muscle relaxation with anticonvulsive and
amnetic effects in anesthetized subjects (Koshy et aI., 2003).
•
Xylazine hydrochloride is a typical alpha-2 agonist of the non-opioid group, having analgesic,
sedative and muscle relaxant effects (Wixson et aI., 1987a). Xylazine is commonly used in combination
with ketamine and less often with opioids and guafenesin. Thiopentone, a thiobarbiturate, is also used as
an anesthetic eventhough it induces respiratory depression with certain side effects (Koshy et aI., 2003).
Although anesthetics are known to cause untoward respiratory and cardiovascular effects in humans,
neither their diverse effects nor their optimal combinations and their deleterious cardiovascular functions
in small animals have been extensively investigated. Hence, the aim of this study is to choose a suitable
anesthetic combination viz. diazepam-ketamine (OK), xylazine-ketamine (XK) and thiopentone (T)
suitable for use in a surgical model of coronary artery ligation (CAL). Male Wi star rats have been
anesthetized with the above combinations and the respiratory and cardiovascular functions have been
assessed in detail after CAL.
Materials and methods
This study conforms to the guiding principles of Institutional Animal Ethical Committee (IAEC),
Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA) and the
Guide for the care and use of laboratory animals published by the National Institutes of Health (NIH
publication No. 85-23, revised, 1996).
\
M. Sumitra et al. ! Life Sciences 75 (2004) 1887-1896
1889
Experimental animals
Male Wi star rats weighing 250 ± 10 g obtained from Tamilnadu Veterinary and Animal Sciences
University, Chennai, were housed in a pathogen free facility under strict veterinary supervision and
maintained in controlled rooms with 12 h light/ dark cycle. The animals received commercial rat diet and
water ad libitum.
Different combinations of the anesthetics viz. OK, XK and T were administered intraperitoneally (i.p)
(Wixson et aI., 1987b). Control groups underwent anesthesia without any surgical stress. In the
anesthetized sham operated groups, the third and fourth intercostal ribs were separated avoiding the
coronary artery, while in the ligated groups, the coronary artery was ligated after 10 min of anesthesia
according to Yang et al. (1993) with slight modifications. Briefly, after anesthesia, endotracheal
intubation was performed and a tube was connected to a mechanical respirator. After establishing
positive pressure respiration, left intercostal thoracotomy was performed using aseptic technique and the
third and fourth intercostal ribs were separated with a small retractor to expose the heart. The
pericardium was opened carefully avoiding any injury to the heart. The left coronary artery [LCA]
and its branches could be seen easily without any amplification or use of a surgical microscope. The
pattern of the LCA was carefully examined in order to ligate the left anterior descending coronary artery.
A 6-0 atraumatic proline silk suture was passed through the epicardial layer around the midway of the
left anterior descending coronary artery. Following coronary occlusion, the thorax was closed in layers,
the endotracheal tube was removed and the animals were brought back to normal respiration.
A total of 54 animals were randomly assigned to nine groups (6 rats / group)
Group
Group
Group
Group
Group
Group
Group
Group
Group
1- Diazepam (2.5 mg/Kg, i.p)+ketamine (50 mg/Kg, i.p) - control (DKC)
II-Xylazine (5 mg/Kg, i.p)+ketamine (50 mg/Kg, i.p) - control (XKC)
Ill-Thiopentone (40 mg/Kg, i.p) - control (TC)
IV- Diazepam (2.5 mg/Kg, i.p) + ketamine (50 mg/Kg, i.p) - sham operated (OKS)
V-Xylazine (5 mg/Kg, i.p)+ketamine (50 mg/Kg, i.p) - sham operated (XKS)
VI-Thiopentone (40 mg/Kg, i.p) - sham operated (TS)
VII-Diazepam (2.5 mg/Kg, i.p)+ketamine (50 mg/Kg, i.p) - ligated (DKL)
Vlll-Xylazine (5 mg/Kg, i.p)+ketamine (50 mg/Kg, i.p) - ligated (XKL)
IX-Thiopentone (40 mg/Kg, i.p) - ligated (TL)
Induction and recovery score
The duration of induction was defined as the time of administration of injection till successful tracheal
intubation. An open label study for the quality of induction as well as recovery from anesthesia was
carried out using a scale of 1- 3 according to White et al. (200 I) (Table I).
Measurement of electrocardiography, heart rate and blood pressure
Electrocardiogram (ECG), HR and rhythm were displayed continuously using standard lead II at a
chart speed of 10 crn/sec with sensitivity set at I (Student's Physiograph, INCO, India) during anesthesia
for all the groups. The femoral artery was exposed and cannulated using polyethylene tubing filled with
0.9% physiological saline and heparin (20 units/ml) for the measurement of MAP using a pressure
M. Sumitra et al. / Life Sciences 75 (2004) 1887-1896
1890
Table 1
Scoring system used for assessing the quality of induction as well as recovery from anesthesia
Score
2
3
Quality of induction
Quality of recovery
Good: trachea easily intubated, easy
transition to unconsciousness
Fair: several attempts before successful intubation
Poor: trachea difficult to intubate
Good: quiet, no thrashing, padding
or vocalizing
Fair: some padding, vocalizing
Poor: padding, vocalizing, ataxia
transducer connected to the Student Physiograph. The surgical procedure for the cannulation of a
femoral artery was carried out in the rats of all the groups 5 min after anesthesia induction.
Assessment of respiratory function
Arterial blood samples (300 I·tI) were taken and blood gas analysis was peIformed (Eschweiler,
Combisys ll) for pH, Pa02, PaC02, O 2 sat (%), bicarbonate (HC0 3 ) and base excess (BE) measurements. Only rats with basal PaC0 2 ofless than 32 mmHg were considered to have recovered sufficiently
from anesthesia (Vincent et aI., 2003). The baseline values for OK and XK were recorded at 70 min
while in the case of T, it was at 100 min. The recovery score was evaluated IS - 20 min after baseline
measurements. Blood gases were analyzed at 10, 20, 30, 40, 50 and 60 min following the anesthetics
administration. Rectal body temperature was measured using a digital thermometer.
Histological studies
The animals in all the groups were sacrificed at the end of 60 min and the brain, lung, heart,
liver and kidney tissues were removed for histological analysi~. These samples were then
separately fixed in 10% formal-saline, dehydrated through graded alcohol series, cleared in xylene
and embedded in paraffin wax (melting point- 56°C). Serial sections of 4)lm were cut, stained
with hematoxylin and eosin (HE) and used for the assessment of histological changes.
Statistical measurements
Based on blood gas analysis data, the area under the curve (AUC) was calculated as follows:
(AUC={(PaC0 2 tl + PaC0 2 12) / 2} x (t2-tl)) for each time interval of 10 min. Analysis of variance
(ANOVA) for repeated measurements was used with a 95% confidence limit. Comparison of the AUCPaC02 , AUC-Pa02 and AUC-0 2 sat (%) was done with one-way ANOVA. The post-hoc Tukey test was
used for pairwise multiple comparisons and a p-value < 0.05 was considered statistically significant. All
results were reported as mean ± standard deviation (SO). Statistical analysis was peIformed using SPSS
statistical version 11 software package (SPSS® Inc., USA).
Results
In the anesthetized sham operated groups, the third and fourth intercostal ribs were separated
avoiding ligation of the coronary artery. During the 5 min surgical procedure, the animals were
,
M. Sumitra e/ al. / Life Sciences 75 (2004) 1887-1896
1891
Table 2
Effect of diazepam-ketamine (OK), xylazine-ketamine (XK) and thiopentone (T) on time to intubation in rats
OK (sec)
XK (sec)
T (sec)
±
±
±
79 ± 14
77 ± 13
80 ± 13
165
162
167
55
53
51
Control
Sham operated
Ligated
II
10
12
± 13*
± 11*
±
14*
Values are Mean ± SO of six animals.
* p < 0.05 as compared to their respective OK group.
mechanically ventilated and it did not produce any adverse impact on the respiratory function. Thus,
the mean values among the control groups and the sham-operated groups did not show any
statistical significance.
No statistical significance among the mean body weights of all the nine groups was observed (Data
not shown), while the mean time to tracheal intubation was significantly longer in the TL and XKL
group (167 ± 14; 80 ± 13 sec) as compared to the DKL group (51 ± 12 sec) (Table 2).
Five inductions of the DKL group and two of XKL group were without complications and they
were given a score of 1, while four inductions of the TL group fell under the score of 3 implying
respiratory obstruction (Fig. la). Fig. 1b shows that four recoveries of XKL group and three of TL
group were awarded a score of 2 while DK group did not exhibit any complications during recovery
(score 1).
6
a
IiDKC :JXKC !:lTC IllnKS I!lXKS ElTS I!DKl I:'iXKl IITl
!l
~
'0 4
lii
..Cl
§
2
z
0
1.0
2.0
3.0
Induction score
6
b
IiDKC :JXKC !:lTC IllDKS IIlXKS ElTS I!DKl I<XKl ilTl
!l
~
'0 4
lii
..Cl
§
2
z
0
1.0
2.0
3.0
Recovery score
Fig. I. (a) Induction of anesthesia using diazepam-ketamine (OK), xylazine-ketamine (XK) and thiopentone (T). Frequency
distribution of scores indicating quality of induction of anesthesia. I = good, 2 = fair, ~ = poor. (b) Recovery pattern from
anesthesia induced using OK, XK and T. Frequency distribution scores indicating quality of recovery from anesthesia. I = good,
2 = fair, 3 = poor.
M. Sumitra et at. / Life Sciences 75 (2004) 1887-1896
1892
Cardiac functions viz. HR, MAP and rectal body temperahlre after anesthetics administration are
depicted in Fig. 2. Higher levels of HR and MAP in DKC and OKS were observed at 20 min. HR
in XKL and TL group was found to be lower (333 ± 6; 304 ± 8 beats/min) as compared to the
baseline value (414 ± 8 beats/min), while in the DKL group, it was almost near normalcy (394 ±
6 beats/min) at 60 min. Similarly, a lower value was observed in MAP of XKL and TL groups
(77 .98 ± 4.41; 71.19 ± 4.37 mmHg) as compared to the baseline during the anesthetic regime. No
significant variation was observed in the rectal body temperahlre measurements in all groups (Data
not shown).
Respiratory depression was particularly reflected with a higher PaC0 2 value, from the baseline of
30 mmHg to approx imately 40 mmHg in the T groups. Pa02 was lowered at 20 min followed by a
higher value in between 30-60 min in OK groups (Fig. 3). No significant difference was observed
in O 2 sat (%) (Data not shown) while T groups exhibited significant difference in pH (Fig. 4). In
terms of AUC (20-60 min), higher PaC0 2 and Pa02 was observed in the T groups as compared to
the AUC of OK or XK groups (Fig. 5). No significant difference was observed in R wave
.. .•. . OKC
520
'2480
'E
]l
440
~ 400
.0
~
360
::c
320
..•... XKC
. ..•. . . TC
. ..•.. . OKC
160
...-f '. "1
.'
. ! .' .
Oi
J'
::c
r::::l::::l~ ::J ~:~ l:;~ ~~i
. . .•.. . OKS
i
I
E 110
i
1::::::i:::::: I:::: :: .· :: :t: ::::1
. . .• . .. XKS
" .•. .. OKS
. ..• . . TS
160
~
.. 1-.
~.. ,..
400
t:.::1:::: t:::::I-:::::t:::: ::t
360
···1·· .. ··I·· ·· .1-.... j
i-
E
E
· · ·····OKL . ..•. . . XKL ·· ·.··TL
480
iii
400
Q)
.0
~
::c
.;
-"
t::·.~·1' "
360
E
EO
Q
~
'. ,T· · 1····· ·1····+·····1
l·· · ··f···· · ·I· ·····~···
320
280
I
:r::
T·· ··-I····-I-·· ··· 1
10
20
30
40
min
50
.;
60
· ·· .···OKL ...•.. . XKL . .. •.. TL
160
Oi
'2
440
t: ....:t ::: ::j
60
520
U;
I: :::: ::j:: ::: : i::::: '
~
320
I
110
Ii'
...•.. TS
f ·· · .. . !> .. . !
:r::
280
'E
.-!:" .,., ! -- .. ..
Oi
440
.. .• . .. XKS
#
#
'2480
::c
"'i!" ""!" " "!
60
/
520
.0
"'1
E
280
~
]i
. . . e· . . TC
...•. " XKC
#
#
J .. "'!" ""
110
.
i· ··· . ·ii· .... . !: " 'f
l::.
. ,
. # .. :::
#
1::::: j:::
: ::i: :.: ::1
#
•
•
60+---~--~--~---r--~--~--~
Baseline
10
20
30
40
50
60
Baseline
min
Fig. 2. Effect of DK, XK and Ton HR and MAP at different time points. Values are mean ± SD of six animals.
*p < 0.0 I as compared to its respective baseline.
#
p<0.05 ;
M Sumitra et af. I Lifo Sciences 75 (2004) 1887-1896
.,
...•... OKC
42
36
N
o(.)
8!.
30
. ..•... XKC
(. :.:. .1:·:·:·{·· .... ~......•......
r····!- ·....I:: ::::l:: :::f"''''!
...•... TC
'
0
<1l
42
ro
30
... 1"'
...•... XKS
...•.. TS
r~·:::!·~·······:I:::: ::1:::::: 1:"'" i
I·
a
<1l
.,
•..•... OKS
...•... XKS
...•.. TS
90
18
70
., . ...... OKL., ......... XKL ...... TL
42
(.) 30
ro
··!
·····-l~:····t······l······t
Q
80
36
i
100
"'1[
24
N
t.·· 1 ·.·.! •....•....
110
...l······l...... ~..
[L
o
. .••. .. TC
70
.. ·.ii . OKS
o(.)
t
80
18
N
90
Q
...•... XKC
... ·1······£
100
N
24
36
...•... OKC
110
1[
1893
.... ··!··· .. ·!···· .. {·· .. ··I· .. ···I
110
f'
j::: ::l:::::i::::::i::::: :{"""i
100
i·
[L
24
a8!.
...•... OKL ...•... XKL ...•.. TL
t.: .. ·l··..
*
18+---~--.---.---.---.---,---,
20
30
40
min
50
60
Baseline
t ..... ·1
!
-~"1:::::1:::::1::::····!: · .. ··-!
90
80
10
·l· .. ··l .... ·l .. ·.. ·!
10
20
30
.,
40
50
60
Baseline
min
Fig. 3. Role of OK, XK and Ton PaC0 2 (mmHg) and Pa02 (mmHg) at different time points. Values are mean ± SO of six
animals. # p < 0.05; *p < 0.0 I as compared to its respective baseline. In sham operated and ligated groups, the thoracotomy was
started at the 8th min and the surgical procedure was completed at the 13th min.
amplitude, ST segment elevation, HC0 3 and BE in all groups at any time point (Data not shown).
No adverse histological manifestations were observed in any tissues under the anesthetic regime
(Data not shown).
Discussion
Studies on cardiovascular and respiratory functions showed that DK combination appeared to be a
suitable anesthetic for use in a surgical model such as CAL in albino rats.
Overall tracheal intubation was good in DK and moderate in XK groups while T groups had poor
tracheal intubation. Pharyngeal and laryngeal muscle activity persisted during tracheal intubation, but did
not preclude successful attempts at tracheal intubation in animals of the T groups, suggesting laryngeal
reflexes were obtunded. Licking of the endotracheal tube, chewing, gagging and retching were absent in all
the groups.
Haskins et al. (1985) reported an increase of 87% and 52% in heart rate at 15 and 60 min in dogs given
ketamine only. The results of this study suggested that the increase in HR could be due to ketamine. Kotrly
et al. (1984) observed that diazepam produced a decline in heart rate when administered rapidly by
•
M. Sumitra et al. / Life Sciences 75 (2004) 1887-1896
1894
. ..•. . . OKC
7.440
7.380
...•... XKC
••••• . 'TC
i~ .....! ... '. , .. : ::.-1" ... ·1· ... ~ =
1
y·:::::l.····· I ··
...... ! ... .
! ...... ! .. .... !
J:
a.
#
7.320
7.260
7.440
.. .•.. . OKS
...•. . . XKS
...•.. ' TS
. ..•.. . OKL
. . .•... XKL
...•.. 'TL
7.380
J:
a.
7.320
7.260
7.440
7.380
I~;:~;:·.i::::: 1'::: :I~~ ~ ~~~i~ ~ ~:::I
-f .. ...
J:
a.
~ .. . ..
#
i
·I
7.320
7.260
+--"""T""----,..---,-----.---.----.-----.
10
20
30
40
50
60
Baseline
min
Fig. 4. Role of DK, XK and T on pH at different time points. Values are mean ± SD of six animals. # p < 0.05 as compared to
its respective baseline. In sham operated and ligated groups, the thoracotomy was started at the 8th min and the surgical
procedure was completed at the 13th min .
intravenous route. Diazepam had no influence on arterial blood pressure, but ketamine preceded b)
diazepam administration might increase arterial pressure (Haskins et al., 1986). The results of this study or
MAP in OK administered groups correlated with earlier findings (Haskins et al., 1986).
Excitatory carotid reflex induced by hypotension and decreased sympathetic and increased vagal
activity induced by xylazine (Rand et al., 1996), might have caused decreased HR in the XK groups.
Xylazine overrided the increased sympathetic activity and depressor effect of baroreceptor feedback, and
decreased vagal tone produced by ketamine (Haskins et al., 1985), resulting in decreased HR. Moens and
Fargetton (1990) found a 27% decrease in HR at 45 min on XK administration in dogs. The observation of
prolonged decrease in HR till 40 min after XK administration as shown in this study is in accordance with
the above findings .
Priano (1982) reported a 5 to 10% decrease in MAP and HR in T administered dogs. In this study, the
decrease in MAP and HR after T administration could be due to peripheral venodilation and increased
hemodynamic sensitivity to hypovolemia in rats (Eckstein et al., 1961). In the OK groups, there appeared
to be moderate effect of diazepam on cardiovascular and central nervous system and our observations are in
consonance with that of Wixson et al. (1987b).
1895
M. Sumitra et at. / Life Sciences 75 (2004) /887-/896
.DKC DXKC I1ITC IlIDKS IIIXKS EHS I!IDKL rLlXKL BTL
2500
2000
8' 1500
CIl
a..
U
~
1000
500
7000
6000
5000
N
0
CIl
a..
U
::J
«
4000
3000
2000
1000
0
Total
Baseline-20
Baseline-30
20-30
20-60
min
Fig. 5. Effect of OK, XK and Ton PaCO z (mmHg) and Pa02 (mmHg) as expressed by AUC. # P < 0.05; *p < 0.0 1 as compared
to OK. In sham operated and ligated groups, the thoracotomy was started at the 8th min and the surgical procedure was
completed at the 13th min.
In an earlier report (Haskins et aI., 1985), it was observed that administration of ketamine indlfced a
transient increase in PaC02 in dogs and the finding of this study showing an initial hike in PaC0 2 at
20 min in XK and OK groups is in agreement with the above report. On the other hand, a significant
increase in PaC02 persisted till 30 min in the T groups. Wright (1982) found that ketamine, when
used alone or in combination with xylazine, producedhypercarbia and acidosis, subsequently reducing
Pa02 and arterial pH. Ketarnine was also observed to decrease pulmonary blood flow in humans
(Wixson et aI., 1987a) and increased pulmonary vascular resistance might cause these effects. The
initial decrease followed by an increase in Pa02 in the XK and OK groups was attributed to the short
lasting depressant effect ofketamine (Wright, 1982). Colby et al. (1981) reported a decrease of23% in
Pa02 in cats with XK combination. Diazepam decreased Pa02 insignificantly but when it was
supplemented with ketamine, it produced a short decrease in Pa02 (Haskins et aI., 1986). Diazepam
might have offset the respiratory depressant effect of ketamine attributed to stimulation of cortical,
subcortical and reticular regions by direct excitation of medullar respiratory neurons and indirect
activation of peripheral chemoreceptors (Kelewala and Parsania, 1992).
In conclusion, OK was shown to be a suitable anesthetic combination for use in CAL in albino
rats. Further, any deleterious effects that ketamine might exert after induction of anesthesia could be
largely overcome by that of diapezam.
1896
M. Slimitra et al. / Life Sciences 75 (2004) 1887-1896
Acknowledgements
The authors thank Dr. T. Ramasami, Director, Central Leather Research Institute, Chennai, India
for his kind permission to publish this work. The financial assistance by CSIR, New Delhi to two
of the authors, (MS) and (PM) is gratefully acknowledged.
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..,,
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