Improvement of Lidocaine Local Anesthetic Action Using Lallemantia royleana Seed Mucilage as an Excipient

Abstract

Lallemantia royleana (Balangu) is a well known Iranian medicinal plant that its seed mucilage has many applications in modern pharmacology. Plant mucilage traditionally was used as a gel supplement, and natural matrix for sustained release of drugs. But it seems that these compounds are not a simple additive and also have many undiscovered pharmacological properties.
In this research, the anesthetic action of gel prepared from Balangu mucilage alone and its mixture with lidocaine hydrochloride are compared with the effect of commercial 2% lidocaine gel by rat tail flick test.
Mucilage of Balangu seed alone showed analgesic effect. Duration and potency of anesthesia induced by gel containing mucilage alone (0.01 g/mL) were identical to commercial 2% lidocaine gel. But, local anesthetic potency and duration of gel made from 2% lidocaine-mucilage gel mixture was significantly higher than commercial 2% lidocaine gel.
The gel prepared from mucilage causes a good analgesia with unknown mechanism. Besides, mixture of Balangu mucilage prepared gel with lidocaine improves lidocaine anesthesia. The increase in potency of lidocaine action results from mucilage dermal penetration enhancing effects; and longer anesthetic duration of this mixture are related to the capability of mucilage based gel for sustained drug release.

Full text

Original Article
Improvement of Lidocaine Local Anesthetic Action Using
Lallemantia royleana Seed Mucilage as an Excipient
Rabi Atabaki and Majid Hassanpour-ezatti*
Biology Department, School of Sciences, Shahed University, Tehran, Iran.
Abstract
Lallemantia royleana (Balangu) is a well known Iranian medicinal plant that its seed
mucilage has many applications in modern pharmacology. Plant mucilage traditionally was
used as a gel supplement, and natural matrix for sustained release of drugs. But it seems that
these compounds are not a simple additive and also have many undiscovered pharmacological
properties.
In this research, the anesthetic action of gel prepared from Balangu mucilage alone and its
mixture with lidocaine hydrochloride are compared with the effect of commercial 2% lidocaine
gel by rat tail ick test.
Mucilage of Balangu seed alone showed analgesic effect. Duration and potency of
anesthesia induced by gel containing mucilage alone (0.01 g/mL) were identical to commercial
2% lidocaine gel. But, local anesthetic potency and duration of gel made from 2% lidocaine-
mucilage gel mixture was signicantly higher than commercial 2% lidocaine gel.
The gel prepared from mucilage causes a good analgesia with unknown mechanism. Besides,
mixture of Balangu mucilage prepared gel with lidocaine improves lidocaine anesthesia. The
increase in potency of lidocaine action results from mucilage dermal penetration enhancing
effects; and longer anesthetic duration of this mixture are related to the capability of mucilage
based gel for sustained drug release.
Keywords: Lidocaine; Plant mucilage; Anesthesia; Rats; Acute pain; Topical administration.
Copyright © 2014 by School of Pharmacy
Shaheed Beheshti University of Medical Sciences and Health Services
Iranian Journal of Pharmaceutical Research (2014), 13 (4): 1431-1436
Received: September 2013
Accepted: December 2013
* Corresponding author:
E-mail: hassanpour@shahed.ac.ir
Introduction
Compounds generating local anesthesia are
widely used in surgery, treatment of chronic
pains, post-surgery pain relief and have vast
majority of other medical applications (1,2).
Lidocaine commercial gel as a local anesthetic
was generally used for creation of topical
anesthesia and reduction of local pains. Short
duration of action and low anesthetic intensity
are considered as disadvantages of topical
form of lidocaine (3,4). Due to the different
barriers in the epidermis, induction of topical
anesthesia by local prescribe drugs on healthy
and intact skin is not easy (5). Indeed, lidocaine
incomplete diffusion from the skin is proposed
as an explanation for its low potency (6), which
originates from its low skin penetrability (7).
This problem was solved by adding some
pharmacological excipients to lidocaine that
were named penetration enhancers. Terpenes
are a group of herbal active compounds that
exhibit skin penetrating properties and it has
been reported that these compounds can increase
local anesthetic action of lidocaine gel (8). For
instance, adding α-terpineol to lidocaine gel could
increase the local anesthetic effects of lidocaine

Atabaki R et al. / IJPR (2014), 13 (4): 1431-1436
1432
hydrochloride gel is the conventional form of
this gel (24). Some experts tried to increase
anesthetic potency of lidocaine gel by increasing
its dose for using this gel for some especial
conditions (25). In an attempt to solve some of
the problems mentioned above, the gel made
from Lallemantia royleana mucilage was used as
an excipient for preparing topical lidocaine gel.
Then, the analgesic potency and duration of this
gel mixture with %2 lidocaine hydrochloride,
was evaluated after topical application on tail of
adult male rats with tail ick method proposed
by Jin & Shin (26).
Experimental
Microwave assisted mucilage extracting
method
Lallemantia royleana plant seed was
purchased from a medicinal plant store and its
genus and species was conrmed by a plant
biosystematician. For mucilage extraction, dried
and cleaned Balangu seed (2.5 g) was soaked
in 100 mL distilled water for 24 hours. Pure
Balangu seeds mucilage free from seed residues
was extracted, dried, and sterilized by a new
invented method using microwave oven (13,14).
In practice, macerated seeds were spread in the
bottom of a petteri dish (to the thickness of one
seed) and dried slowly in a microwave oven
(Panasonic, IRAN) with 220 watt power for 55
minutes. Then, the dried mucilage was scraped
with a scalpel blade, powdered and kept in a
sterile vial at room temperature until experiment
day. During experiment, dried mucilage powder
(0.01 g) was dissolved in distilled water (1 mL)
and completely mixed until a clear and bright gel
was prepared.
Preparation mixture of mucilage-lidocaine
hydrochloride
Lidocaine hydrochloride powder taken as
a gift from Darou Pakhsh Company (Tehran,
IRAN) and the gel prepared from the extracted
mucilage was completely mixed with 2%
lidocaine hydrochloride powder. The mixture
was kept at 4 °C in the refrigerator for 48 hours
and then used. The utilized mixture should be
clear, without any precipitation and its color
shouldn’t change.
gels (6). Previously, it was shown that the mixture
of lidocaine with a herbal mucilage can increase
duration of its local anesthesia (9). On the other
way, herbal mucilage as a type of polysaccharide
is non-toxic, has high chemical and physical
stability compared to the synthetic forms and
after dissolving in water easily makes a gel (10).
Recently, the gel prepared from plant mucilages
has been used as a compound for sustained drug
release in drug delivery systems (9). Currently,
plant mucilage is used by researchers as a
pharmaceutical excipient (11). Other attractive
abilities of mucilage for pharmaceutical
applications are using them as thickening,
stabilizing agents, additive, release retardants,
binding, emulsifying, gelling, suspending, and
disintegrating in tablets (12, 13). Indeed, the
number of successful usages of herbal mucilage
as supplement for sustained-drug release is
growing now (14,15). The plant Lallemantia
royleana (Labiatae) with the conventional name
“Balangu” is a plant that growth in Iran (16).
Seeds of this plant produce lots of mucilage after
maceration in water. This plant grows in Iran
and nearly all parts of Middle East (17). The dry
mucilage of Balangu after dissolution in water
generates a white and clear gel (18). The use of
this plant seed has long historical background
in human life (19), and the presence of terpenic
compounds in seed of this family is reported
previously (17). Also, gel prepared from Balangu
seed mucilage is prescribed for treatment of
some digestive problems and reduction of
abscess (20). Their anti-inammatory effects
are also reported (21). The muco-adhesive
properties of Balangu mucilage are better than
many other pharmaceutical supplements like
chitosan, Carbopol 934, hydroxypropyl, and
methylcellulose, (22). So, this mucilage may be
a good candidate as an excipient gel for topical
anesthetic drugs. It is reported that the routine
adjuvant added to lidocaine produces side effects
like paleness or redness on skin surface of users.
These side effects are consequences of rapid
release of lidocaine and its contracting effect on
skin peripheral vessels (23). So, adding a natural
compound with release retarding property to
lidocaine may control lidocaine fast release
from gel and also reduce its undesirable effects
compared to commercial additives. 2% lidocaine

Lallemantia Mucilage as an Excipient
1433
Tail ick experiments
The male Wistar rats (240 to 300 g) were
obtained and divided into these groups:
1-control group, 2-mucilage treated group,
3-commercial 2% lidocaine gel treated and
4- mixture of mucilage gel with 2% lidocaine
group. The number of rats in each group was
5. The tail ick latency was measured in all
the groups by applying thermal light beam
to the tail of each rat based on Jin & Shin
procedure (26). The tail ick latency of rats
was measured by a domestic automated tail
ick analgesiometer device equipped with a
projector lamp manufactured by Borj Sanat
(http://borjsanat.ir). Beam intensity was
adjusted to level that give a tail-ick latency of
5-8 sec in control animals. A 20 second cut-off
time was used to avoid thermal injury. Before
topical application of each medication, two tail
ick experiments were taken from each rat. Its
average was considered as a baseline latency
of rats. Then, according to the experimental
groups; 250 (mg) of mucilage alone, 2%
lidocaine commercial gel or mucilage-
lidocaine hydrochloride mixture was applied
on 2 ⁄3 distal part of each rat tail and the rat
was tested in response to painful stimulation
every ve minutes for 55 minutes. In control
groups, rat tails were treated topically only
with 250 microliter distilled water.
Statistical analysis of data
The average of tail ick latency of each rat
was calculated during 55 minute with 5 minute
interval and compared between groups by two-
way ANOVA (p<0.05) and Bonferroni post test.
Results
Our prepared gel was white and clear and
lidocaine powder was easily mixed with it
without any change in mucilage quality. The
mixture of gel and lidocaine before use was
kept in refrigerator up to 48 hours for complete
mixing of them and no especial change was
observed in its appearance during this period.
Tail ick latency obtained from control and
experimental groups were shown in Figure
1. Our data indicates topical applying of
mucilage alone on rat tail led to increase in rat
tail ick latency with the same potency of rat
that was treated with commercial 2% lidocaine
gel. Also, the duration of anesthesia in rats
that topically were treated with mucilage
alone was same as rats that were treated with
commercial 2% lidocaine gel (Figure 1).
But tail ick latency of rats treated with 2%
lidocaine-mucilage gel mixture signicantly
increased and stayed for about 35 minutes
in this situation in comparison with other
experimental groups.
Figure 1. Tail ick latency (mean ±SEM) of rats was measured before (base) and after each treatment. Rats groups: Control, topically
treated with distilled water; Commercial lidocaine, treated with 2% commercial lidocaine gel; Mucilage, treated with mucilage alone;
Mixture, treated with mucilage+2%lidocaine (Two-way ANOVA and Bonferroni post test). * p<0.05 Mixture group v.s. Commercial
lidocaine group and # p<0.05 Mucilage or Commercial lidocaine groups v.s. control.”

Atabaki R et al. / IJPR (2014), 13 (4): 1431-1436
1434
Discussion and Conclusion
Our ndings showed the lidocaine-balangu
mucilage gel mixture kept in (4 °C) refrigerator
were stable even after long time. The long
duration of Balangu mucilage gel physical
stability was conrmed for other application,
too (27). Previous experiments demonstrated
that mixture of different compounds with this
gel doesn’t change the molecular structure
of gel and does not disrupt its rheological
properties (27). So, the gel prepared from
Balangu mucilage could be considered as a good
drug carrying matrix for many pharmaceutical
compounds. Also, the gel had shown suspension
property in combination with many chemical
substances (22). Our results proved that the
local application of the Balangu gel alone can
increase acute pain threshold and its anesthetic
duration is same potency as commercial 2%
lidocaine gel. Also, the local application of Aloe
Vera plant mucilage gel in animals could reduce
pain threshold (28). The reactive oxygen species
(ROS) compounds acted as pain mediators
in many different tissues and can stimulate
nociceptors (29). The role of ROS in induction
of acute pain was conrmed by different animal
pain models (30). Also, it was reported that
acute analgesia effect of morphine was mediated
through inhibition of ROS production (31). The
antioxidant activity and ROS reducing effect of
some herbal mucilage were demonstrated (32,
33). For example, mucilages extracted from
three different kinds of Yam plants have shown
antioxidant and radical scavenger properties (34).
By paying attention to chemical similarity of
mucilages, the Balangu seed mucilage analgesic
effect probably was mediated through control
of ROS compound production. The upper layer
of skin or stratum corneum is the main barrier
in the way of dermal application of drugs and
rate limiting step in absorption of topical drugs
(35). In addition, mucilage based gel has a good
dermal penetration power by itself and so can
potentiate dermal penetration rate of drugs as a
pharmaceutical supplement. It has been shown
that herbal mucilage has high skin penetrating
quality; for example, adding Aloe Vera mucilage
to some drugs can increase dermal absorption
of them. The mechanism of their action has not
been identied partly (36). As it was mentioned
earlier, lidocaine is incompletely diffused from
skin (6), and improperly passes from healthy
skin (7). Our results showed the anesthetic
potency of mucilage-lidocaine mixture was
higher than commercial available gel of
lidocaine. The polysaccharide constitutes the
main part of Lallemantia royleana mucilage
gel similar to other mucilage such as Aloe Vera
mucilage (37). Thus, the probable presence
of plant polysaccharides can increase dermal
penetration and improve dermal absorption
of lidocaine and enhance its pharmacological
potency. The presence of trepenoid compounds
in the mucilage of Balangu gel can help as
other mechanisms that increase its dermal
penetration (8). Data gathered from in-vivo
and in-vitro research denoted the enhancement
of topical drugs effect after mixing with a gel
matrix prepared from plant mucilage (38). It
was denoted that the commercial preparation of
lidocaine contains excipient which increase the
rate of its absorption from skin (39, 40), and these
excipient compounds have sugar based structures
such as alkyldisiloxane or glucopyranosyl.
These chemical groups also were found in the
chemical structure of mucilages (41). In support
of our observation, it was reported that Aloe
Vera mucilage alone has analgesic action and
can increase dermal penetration of drugs and be
added as supplement to them (42-44). Our results
show that the analgesic duration of 2% lidocaine
hydrochloride-balangu gel mixture was longer
than its commercial form. In explanation of
present research, we proposed that mucilage
prepared gel works as sustain releasing matrix.
Currently, the capability of mucilages as slow
releasing matrices was proven (45). For instance,
this property of mucilage caused scientists use
them in structure of drugs that are prepared for
treatment of wounds, diagnosis or treatment of
cancer, prevention and treatment of bacterial
and viral diseases (46). This character of herbal
mucilage also changes it as ideal matrix for
topical (15). Finally, commercial 2% lidocaine
gel in some practical application has shown low
therapeutic potency. Thus scientists increased
lidocaine dosage for use in these situations
(6,47-49). But, our ndings in this research about
enhancement of lidocaine anesthetic potency in

Lallemantia Mucilage as an Excipient
1435
mixture with Balangu gel can provide a suitable
natural excipient for improvement of lidocaine
anesthesia potency beside its effect on duration
of lidocaine.
Acknowledgement
We thank from Dr. Tayebeh Radjabian. We
also specially thank from Dr. Asghar Kamrani,
PhD of plant biosystematician that help us for the
plant collection and determination of its genus
and species on the base of samples in herbarium
of Basic Sciences School, Shahed University.
Also, we thank Mrs. N. Rahmani for helping us
during mucilage extraction. We especially thank
Dr. N. Naghdi for gift of lidocaine hydrochloride
pure powder.
References
Dahm P, Lundborg C, Janson M, Olegard C and Nitescu
P. Comparison of 0.5% intrathecal bupivacaine with 0.5%
intrathecal ropivacaine in the treatment of refractory
cancer and noncancer pain conditions: Results from a
prospective, crossover, double-blind, randomized study.
Reg. Anesth. Pain Med. (2000) 25: 480-487.
Colombini BL, Modena KCS, Calvo AM, Sakai VT,
Giglio FPM, Dionisio TJ, Trindade ASJ, Lauris JRP
and Santos CF. Articaine and mepivacaine efcacy in
postoperative analgesia for lower third molar removal:
A double-blind, randomized, crossover study. Oral
Surg. Oral Med. Oral Pathol. Oral Radiol. Endod.
(2006) 102: 169-174.
Ben-David B, DeMeo PJ, Lucyk C and Solosko D.
A comparison of minidose lidocaine-fentanyl spinal
anesthesia and local anesthesia/propofol infusion for
outpatient knee arthroscopy. Anesth. Analg. (2001) 93:
319-325.
Strichartz GR and Ritchie JM. The action of local
anesthetics on ion channels of excitable tissues. In:
Strichartz GR. (eds.) Local Anesthetics Handbook of
Experimental Pharmacology. Vol. 81, Springer Verlag,
Berlin (1987) 21-53.
Cho CW, Kim DB and Shin SC. Development of
bioadhesive transdermal bupivacaine gels for enhanced
local anesthetic action. Iran. J. Pharm. Res. (2012) 11:
423-431.
Lener EV, Bucalo BD, Kist DA and Moy RL. Topical
anesthetic agents in dermatologic surgery. A review.
Dermatol. Surg. (1997) 23: 673-683.
Mohammadi-Samani S, Jamshidzadeh A, Montaseri
H, Rangbar-Zahedani M and Kianrad R. The effects
of some permeability enhancers on the percutaneous
absorption of lidocaine. Pak. J. Pharm. Sci. (2010) 23:
83-88.
Song YH, Gwak HS and Chun IK. The effects of
(1)
(2)
(3)
(4)
(5)
(6)
(7)
(8)
terpenes on the permeation of lidocaine and ooxacin
from moisture-activated patches. Drug Deliv. (2009)
16: 75-81.
Avachat AM, Dash RR and Shrotriya SN. Recent
investigations of plant based natural gums, mucilages
and resins in novel drug delivery systems. Ind. J.
Pharm. Edu. Res. (2011) 45: 86-99.
Jeevanandham S, Dhachinamoorthi D and Bannoth
Chandra Sekhar K. Drug release studies from
caesalpinia pulcherrima seed polysaccharide. Iran. J.
Pharm. Res. (2011) 10: 597-603.
Bharadia PD, Patel MM, Patel GC and Patel GN.
A preliminary investigation on Sesbania gum as a
pharmaceutical excipient. Int. J. Pharma. Excip.
(2004) 3: 99-102.
Deore SL and Khadabadi SS. Standardisation
and pharmaceutical evaluation of Chlorophytum
borivilianum mucilage. Rasayan J. Chem. (2008) 1:
887-892.
Sravani B, Deveswaran R, Bharath S, Basavaraj BV
and Madhavan V. Studies on Vigna mungo mucilage
as a pharmaceutical excipients. J. Chem. Pharm. Res.
(2011) 3: 118-125.
Singh K, Kumar A, Langyan N and Ahuja M.
Evaluation of Mimosa pudica seed mucilage as
sustained-release excipient. AAPS Pharm. Sci. Tech.
(2009) 10: 1121-1127.
Malviya R, Srivastava P and Kulkarni G. Applications
of mucilages in drug delivery-a review. Advan. Biol.
Res. (2011) 5: 1-7.
Hooper D, Field H and Dahlgren BE. Useful Plants
and Drugs of Iran and Iraq. Vol. 9, Field Museum of
Natural History, Chicago (1937).
Naghibi F, Mosaddegh M, Mohammadi-Motamed
S and Ghorbani A. Labiatae family in folk medicine
in Iran: From ethnobotany to pharmacology. Iran. J.
Pharm. Res. (2005) 2: 63-79.
Ghannadi A and Zolfaghari B. Compositional analysis
of the essential oil of Lallemantia royleana (Benth. In
wall.) Benth. From Iran. Flav. Fragr. J. (2003) 18:
237-239.
Jones G and Valamoti SM. Lallemantia, an imported
or introduced oil plant in bronze age northern Greece.
Veget. Hist. Archaeobot. (2005) 14: 571-577.
Abbas M, Mehmood T, Bashir A, Zafar M and Afzal
A. Economics of Lallemantia royleana (thukham-e-
Balangoo) production in the low intensity cropping
zone of the Punjab,Pakistan. Pakistan J. Agric. Res.
(2012) 25: 110-119.
Albayaty N. The most medicinal plants used in Iraq:
Traditional knowledge. Adv. Environ. Biol. (2011) 5:
401-406.
Abdulrasool AA, Naseer AA and Rahi FA. Application
of seed mucilage extracted from Lallemantia royleana
as a suspending agent. Iraqi J. Pharm. Sci. (2011) 20:
8-13.
Juhlin L and Evers H. EMLA: A new topical anesthetic.
Adv. Dermatol. (1990) 5: 75-91.
Thompson TJ, Thompson N, O᾽Brien A, Young MRA
(9)
(10)
(11)
(12)
(13)
(14)
(15)
(16)
(17)
(18)
(19)
(20)
(21)
(22)
(23)
(24)

Atabaki R et al. / IJPR (2014), 13 (4): 1431-1436
1436
This article is available online at http://www.ijpr.ir
Pharm. (2007) 333: 10-16.
Hamman JH. Composition and applications of Aloe
vera leaf gel. Molecules (2008) 13: 1599-1616.
Abd El Rasoul S, Auda SH and Nafady AM. In-vitro
and in-vivo studies of tolmetin release from natural
gel base extracted from Okra seed (Abelmoschus
esculentus) that cultivated in Egypt. Asian J. Pharm.
Hea. Sci. (2002) 2: 342-345.
Cho CW, Choi JS and Shin SC. Enhanced local
anesthetic action of mepivacaine from the bioadhesive
gels. Pak. J. Pharm. Sci. (2011) 24: 87-93.
Shin SC and Cho CW. Enhanced transdermal delivery
of pranoprofen from the bioadhesive gels. Arch.
Pharm. Res. (2006) 29: 928-933.
Akimoto T and Nagase Y. Novel transdermal drug
penetration enhancer: Synthesis and enhancing effect of
alkyldisiloxane compounds containing glucopyranosyl
group. J. Control Release (2003) 88: 243-252.
Saeed MA, Ahmad I, Yaqub U, Akbar S, Waheed A,
Saleem M and Din N-u. Aloe vera: A plant of vital
signicance. Sci. Vision. (2003-2004) 9: 171-183.
Mwale M and Masika P. Analgesic and anti-
inammatory activities of Aloe ferox Mill. Aqueous
extract. Afr. J. Pharm. Pharmacol. (2010) 4: 291-297.
Eshghi F, Hosseinimehr SJ, Rahmani N, Khademloo
M, Norozi MS and Hojati O. Effects of Aloe vera cream
on posthemorrhoidectomy pain and wound healing:
Results of a randomized, blind, placebo-control study.
J. Altern. Complement. Med. (2010) 16: 647-650.
Pirigharnaei M, Hydari R, Siami A, Zaree S and Jamei R.
Isolation and determination of mucilage polysaccharides
from the bulb and leaves of the Allium chrysantherum
species. Pharm. Sci. (2009) 15: 105-114.
Franz G. Polysaccharides in pharmacy: Current
applications and future concepts. Planta Med. (1989)
55: 493-497.
Gajraj NM, Pennant JH and Watcha MF. Eutectic
mixture of local anesthetics (EMLA) cream. Anesth.
Analg. (1994) 78: 574-583.
Kang L, Jun HW and Mani N. Preparation and
characterization of two-phase melt systems of
lidocaine. Int. J. Pharm. (2001) 222: 35-44.
Nortier YL, van de Haven JA, Koks CHW and Beijnen
JH. Preparation and stability testing of a hydrogel for
topical analgesia. Pharm. World Sci. (1995) 17: 214-217.
and McCleane G. To determine whether the temperature
of 2% lignocaine gel affects the initial discomfort
which may be associated with its instillation into the
male urethra. BJU Int. (1999) 84: 1035-1037.
Busbee BG, Alam A and Reichel E. Lidocaine
hydrochloride gel for ocular anesthesia: Results of a
prospective, randomized study. Ophthal. Surg. Lasers
Imag. (2008) 39: 386-390.
Jin WG and Shin SC. Preparation and evaluation of
procaine gels for the enhanced local anesthetic action.
Arch. Pharm. Res. (2008) 31: 235-241.
Razavi SMA, Moghaddam TM and Emadzadeh B.
Rheological interactions of Balangu (Lallemantia
royleana) seed extract with selected food hydrocolloids.
Electronic J. Environ. Agric. Food Chem. (2010) 9:
1540-1550.
Ghosh AK, Banerjee M, Mandal TK, Mishra A and
Bhowmik MK. A study on analgesic efcacy and
adverse effects of Aloe vera in wistar rats. Pharmacol.
(2011) 1: 1098-1108.
Kim HK, Park SK, Zhou JL, Taglialatela G, Chung
K, Coggeshall RE and Chung JM. Reactive oxygen
species (ROS) play an important role in a rat model of
neuropathic pain. Pain. (2004) 111: 116-124.
Chung JM. The role of reactive oxygen species (ROS)
in persistent pain. Mol. Interv. (2004) 4: 248-250.
Ibi M, Matsuno K, Matsumoto M, Sasaki M, Nakagawa
T, Katsuyama M, Iwata K, Zhang J, Kaneko S and
Yabe-Nishimura C. Involvement of NOX1/NADPH
oxidase in morphine-induced analgesia and tolerance.
J. Neurosci. (2011) 31: 18094-18103.
Hou WC, Hsu FL and Lee MH. Yam (Dioscorea
batatas) tuber mucilage exhibited antioxidant activities
In vitro. Planta Med. (2002) 68: 1072-1076.
Sindhu G, Ratheesh M, Shyni GL, Nambisan B
and Helen A. Anti-inammatory and antioxidative
effects of mucilage of Trigonella foenum graecum
(Fenugreek) on adjuvant induced arthritic rats. Int.
Immunopharmacol. (2012) 12: 205-211.
Lin SY, Liu HY, Lu YL and Hou WC. Antioxidant
activities of mucilages from different Taiwanese Yam
cultivars. Bot. Bull. Acad. Sin. (2005) 46: 183-188.
Verma DD, Verma S, Blume G and Fahr A. Particle size
of liposomes inuences dermal delivery of substances
into skin. Int. J. Pharm. (2003) 258: 141-151.
Cole L and Heard C. Skin permeation enhancement
potential of Aloe vera and a proposed mechanism of
action based upon size exclusion and pull effect. Int. J.
(25)
(26)
(27)
(28)
(29)
(30)
(31)
(32)
(33)
(34)
(35)
(36)
(37)
(38)
(39)
(40)
(41)
(42)
(43)
(44)
(45)
(46)
(47)
(48)
(49)