Cancer
Therapy Vol 7, 277-281, 2009
Stability of hospital preparations of
Azunol Water Gargles for pain relief in oral cancer patients with oral
mucositis
Research Article
Mina Ushiyama1,7, Ryuji Ikeda1,7,
Tetsuya Nitta2,7, Yusuke
Tazitsu3, Akihiko
Miyawaki4, Yukihiko
Nishizawa3, Tatsuya
Yamaguchi1, Hiroko
Yamaguchi1,
Chifumi Akatsuka5, Yoshihiro
Shimodouzono1, Kazami
Ushinohama1, Hideki Sugawara1, Kazumasa Sugihara6, Norifumi Nakamura4, Yasuo Takeda1,3, Katsushi Yamada1,3*
1Department of Clinical
Pharmacy and Pharmacology, Kagoshima University Hospital
2Department of Oral and Maxillofacial Surgery, Fukui
Prefectural Hospital
3Department of Clinical
Pharmacy and Pharmacology, Graduate School of Medical and Dental Sciences,
Kagoshima University
4Department of Oral and
Maxillofacial Surgery, Graduate School of Medical and Dental Sciences,
Kagoshima University
5Department of
Pharmacy, Kagoshima Prefectural Oshima Hospital
6Department of
Maxillofacial Diagnostic and Surgical Sciences, Graduate School of Medical and
Dental Sciences, Kagoshima University
7These authors
contributed equally to this work.
*Correspondence:
Department of Clinical Pharmacy and Pharmacology, Graduate School of Medical
and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima,
890-8520, Japan, Tel: +81-99-275-5543, Fax: +81-99-265-5293, E-mail: yamada@m3.kufm.kagoshima-u.ac.jp
Keywords: sodium gualenate hydrate
(GAS-Na), oral mucositis, oral cancer, hospital preparation, pain relief
Abbreviations: sodium gualenate hydrate,
(GAS-Na); Azunol Saline Gargle, (AS); Azunol Lidocaine Saline Gargle, (ALS);
Azunol Water Gargle, (AW); Azunol Lidocaine Water Gargle, (ALW);
Received:
13 March 2009; Revised 6 April 2009;
Accepted:
13 April 2009; electronically published: 23 April 2009
Summary
An
important factor in caring for oral cancer patients receiving chemotherapy
and/or radiation therapy is palliation of oral mucositis and acute oral pain
due to oral mucositis. One effective treatment is the Azunol Gargle, which contains sodium gualenate
hydrate (GAS-Na) with or without lidocaine hydrochloride, and is prepared in
four forms: Azunol Saline Gargle (AS, saline solution containing 0.006%
GAS-Na), Azunol Lidocaine Saline Gargle (ALS, AS with lidocaine), Azunol Water
Gargle (AW, aqueous solution
containing 0.006% GAS-Na) and Azunol Lidocaine Water Gargle (ALW, AW with
lidocaine). However, the four Azunol Gargles are expected to improve the
quality of life of patients with oral mucositis, little is known about the stability of AW and ALW. Therefore, we
examined stability of those solutions to the light and the temperature as an
index of residual ratio of GAS-Na. As a result, AW and ALW were stable for seven days at room temperature if shielded
from light, and at 4¡C under lighting conditions similar to those at
nursing stations. These results provide useful information regarding the
management of oral mucositis in oral cancer patients.
I. Introduction
Oral mucositis is a common
complication in oral cancer patients receiving chemotherapy, radiation therapy,
or both (Rubenstein et al, 2004; Ikemura et al, 2007; Keefe et al, 2007; Hata et
al, 2007). Nearly all (85%-100%) patients receiving radiotherapy with or without
chemotherapy in head and neck develop some degree of oral mucositis (Wilkes et al, 1998; Barasch
et al, 2003; Trotti et al, 2003; Naidu et al, 2004).
Although patients report
oral mucositis as one of the most difficult and debilitating complications of
their cancer treatment, it has been underestimated and overlooked by medical
staffs. Symptoms of oral mucositis vary from pain and discomfort to an
inability to tolerate food or fluids (Larsson et al, 2005; Murphy et al, 2009; Rosenthal
et al, 2009). Oral mucositis may also limit the
ability of patients to tolerate chemotherapy or radiation therapy, hence
drastically affecting cancer treatment and outcome.
The biological basis and pathogenesis of oral mucositis has been studied
in detail (Sonis, 2004; Lionel et al, 2006; Sonis, 2007). And a few approaches
also have been shown to be effective in its prevention or treatment (Kim et al, 1985; Potting et
al, 2006; Madan et al, 2008; Rosenthal et al, 2009). In particular, it has
been reported that benzydamine oral rinse is effective, safe, and well
tolerated for prophylactic treatment of radiation induced oral mucositis in
head and neck cancer (Epstein et al, 2001).
Sodium gualenate hydrate (GAS-Na) is a
hydrophilic derivative of guaiazulene, an active component of the plant Matricaria
chamomilla L., which has excellent anti-inflammatory properties (Shibata
et al, 1986) and has been clinically used for the treatment
of pharyngitis as well as gastric ulcer, gastritis, conjunctivitis,
adenoiditis, and stomatitis (Sakai et al, 2005; Ogata et al, 2005). In our
hospital, four kinds of Azunol Gargles containing GAS-Na with or without
lidocaine are used for the treatment of oral mucositis. Although Azunol Saline
Gargle (AS) and Azunol Lidocaine Saline Gargle (ALS) are prescribed with a high
frequency, some patients refuse to use AS and ALS because of their salty taste.
In such cases, Azunol Water Gargle (AW) or Azunol Lidocaine Water Gargle (ALW) is prepared in our hospital.
The total number of prescriptions of the four Aznol Gargles and the
patients prescribed them has tended to increase with an increment of
the number of patients receiving concomitant chemotherapy and localized
radiation therapy after 2003 as shown in Table 1 and Table 2. Additionally, the
increment in the number of outpatients prescribed Azunol Gargles in recent years was due to usage as a treatment of herpes labialis
and intractable stomatitis.
It
has been reported that GAS-Na is a relatively unstable compound that gradually
decomposes when exposed to light, elevated temperatures and acidic solutions (Yuki
et al, 1990; Nakamichi et al, 2003), little is known about the stability of AW
and ALW.
In this study we assess the stability
of AW and ALW by measuring their pH and the percentage of GAS-Na remaining in
them after exposure to various light and temperature conditions.
II.
Materials and methods
A. Preparation of the four Azunol
Gargles
All gargles were
prepared under non-sterile conditions.
1. Aqueous solution containing 0.006% GAS-Na (Azunol
Water Gargle, AW): Thirty Azunol¨
Tablets 2mg (Nippon Shinyaku Co., Ltd., Kyoto, Japan) were dissolved in 1000 mL
of Water for Injection (Hikari
Pharmaceutical Co., Ltd., Tokyo, Japan).
2. Aqueous
solution containing 0.006% GAS-Na and 0.08% lidocaine hydrochloride (Azunol
Lidocaine Water Gargle, ALW): Thirty Azunol¨ Tablets 2mg were dissolved in 1000 mL of Water for Injection, and 20 mL of Xylocaine¨ Solution4% (AstraZeneca
K.K., Osaka, Japan) was then added.
3. Saline
solution containing 0.006% GAS-Na (Azunol Saline Gargle, AS): Thirty Azunol¨ Tablets 2mg were dissolved in
1000 mL of Saline (Hikari
Pharmaceutical Co., Ltd., Tokyo, Japan).
4. Saline
solution containing 0.006% GAS-Na and 0.08% lidocaine hydrochloride (Azunol
Lidocaine Saline Gargle, ALS): Thirty Azunol¨ Tablets 2mg were dissolved in 1000 mL of Saline and 20 mL of Xylocaine¨ Solution4% was then
added.
B. Preservation conditions
Illuminance at
the receiving surface:
light shielding (0 lux), 500 lux, or 1000 lux.
Temperature: 4¡C, 25¡C or 37¡C.
Table 1: Numbers of
prescriptions of the four Azunol Gargles.
Table 2: Total number of patients prescribed the four Azunol
Gargles and the numbers and proportions of patients with oral cancer and
outpatients.
C. Measurements of absorbance and pH
On days 0, 3, and 7, two hundred
microliter of AW or ALW was plated in 96-well flat-bottomed tissue culture
plates. The maximal absorption wavelength of GAS-Na, proportional to the amount
of GAS-Na remaining, was read at 570nm using a model 550 Microplate reader
(Bio-Rad, CA, USA). The amount of GAS-Na remaining on days 3 and 7 was
calculated by comparing absorbance to that on day 0. The pH of AW and ALW
preserved under each condition was measured with a pH meter (Thermo Fisher Scientific Inc., MA, USA) on days 0, 3 and 7. Within each study, one-way analysis of
variance (ANOVA) test was performed to analyze statistical significance. P < 0.05 was considered statistically
significant. Values are presented as the means ± SD.
III.
Results
A.
The effects of illuminance and temperature on
the stability of AW and ALW
The
degree to which light and temperature affected the stability of AW and ALW was
evaluated by measuring the content of GAS-Na in each solution after preparation
and again after storage for three and seven days (Figure 1). When AW and ALW were
preserved with light shielding or exposed to 500 lux at 4¡C for seven days, the
amount of remaining GAS-Na did not decrease significantly (P < 0.05). However,
exposing to 1000 lux led to a reduction in the amount of GAS-Na remaining, to
25% in AW and to 35% in ALW. When AW and ALW were stored for seven days with
light shielding at 25¡C, the amount of GAS-Na did not decrease. However,
exposing the solutions to 500 lux led to a reduction in the amount of GAS-Na
remaining, to 77% in AW and to 85% in ALW and exposing to 1000 lux caused the
percentage of GAS-Na remaining to fall to 18% in AW and to 28% in ALW.
Furthermore, when the AW and ALW were stored with light shielding at 37¡C for
seven days, the amount of GAS-Na did not entirely decrease.
At the same temperature, exposing AW to 500 lux and 1000 lux caused a decrease
in remaining GAS-Na to 73% and to 15%, respectively. Similarly, exposing ALW to
500 lux and 1000 lux caused a decrease in remaining GAS-Na to 88% and to 29%,
respectively.
B. The effects of
illuminance and temperature on the pH of AW and ALW
The
effects of light and temperature on the pH of AW and ALW were evaluated by
measuring the pH after three and seven days of storage (Figure 2). Although the pH of AW and ALW stored for seven days
increased in proportion to the preservation temperature, it did not exceed the
reference pH (6.0-9.0) of a 200:1 aqueous dilution of 2 mg Azunol¨ Tablets.
The
pH of AW and ALW after seven days of storage increased significantly in comparison with the pH on day 0 in every storage condition,
the one exception being ALW exposed to 500 lux AW and ALW exposed or 1000 lux
at 4¡C. The pH of both solutions was similar after storage for seven
days at 25¡C and 37¡C, but was significantly lower when preserved at 4¡C (P < 0.05).
IV. Discussion
Although
oral mucositis is rarely life-threatening, it can lead to reductions in
chemotherapy or radiotherapy
doses or modifications of treatment schedules and thus prevent optimal cancer
therapy and directly affect patient survival. Treatment approaches have
included systemic analgesics and other individual agents, mixtures of
palliative agents, topical anesthetics and analgesics, and anti-inflammatory
agents.
In
this study, we examined the effect of light and temperature on the stability of
AW and ALW used as a treatment of oral mucositis in our hospital. When the solutions
were preserved for seven days and shielded from light, GAS-Na did not decompose
regardless of the preservation temperature. AW and ALW exposed to 1000 lux and
varying temperatures for seven days resulted in the preservation of 15% to 35% of GAS-Na in each solution,
respectively. These results indicate that the stability of AW and ALW is
affected far more by light than by temperature. However, Japanese Industrial
Standards recommend an illuminance of 500 lux at nursing stations. At that
illuminance, the stability of GAS-Na in AW and ALW was determined both by light
and temperature. Our results indicated that at 500 lux, AW and ALW are stable for seven days at 4¡C, while light shielding
assured stability for seven days at room temperature. Based on the results
of a Japanese Pharmacopoeia (15th Edition) Microbial Limit Test, we
previously reported that AS and ALS could be adequately preserved at 4¡C (Ushiyama et al,
2008), and hypothesized that the same would hold true for AW and
ALW. Moreover, lidocaine has been shown to be stable for three months at room
temperature in the package insert of Xylocaine¨
Solution4%. Detailed examinations of the stability of AW and ALW in this
study revealed that both are stable for
seven days at 4¡C under lighting conditions similar to those at nursing
stations, and might be safe
and effective for seven days when preserved in this way.
In conclusion, we have demonstrated
the stability and the appropriate preservation method of AW and ALW used as
treatment of oral mucositis in our hospital. Management of oral mucositis
facilitates the delivery of optimal cancer therapy without dose reduction or
treatment schedule modifications. This study provides useful information
regarding the management of oral mucositis in oral cancer patients.
Acknowledgements
This research was supported by a Grant-in-Aid for the
Encouragement of Scientists,
19923012, 2007 from the Japan Society for the Promotion of Science.
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