- Email: [email protected]
Multicenter, double-blind, randomized comparison ofwood creosote, the principal active ingredient of seirogan, an herbal antidiarrheal medication, and loperamide in adults with acute nonspecific diarrhea
CLINICALTHERAPEUTICS®/VoL.26, NO. 10, 2004
Multicenter, Double-Blind, Randomized Comparison of Wood Creosote, the Principal Active Ingredient of Seirogan, an Herbal Antidiarrheal Medication, and Loperamide in Adults with Acute Nonspecific Diarrhea Tomoo Kuge, PhD, 1 Takashi Shibata, MD, PhD, 1 and Michael S. Willett, PharmD 2 l gaiko Pharmaceutical Company, Ltd., Osaka, Japan, and 2Advanced Biomedical Research, Inc., Princeton, New Jersey
ABSTRACT
Background: 5eirogan, an herbal medication containing wood creosote, a mixture of simple phenolic (singlering) compounds, has been marketed in Asia for the past century as an antidiarrheal and antispasmodic medication. This was the first randomized, double-blind study of this herbal medication in patients with acute, nonspecific diarrhea. Objective: The aim of this study was to compare the efficacy and tolerability of wood creosote with those of loperamide hydrochloride in patients with acute, nonspecific diarrhea. Methods: This double-blind, randomized, active-controlled study was conducted at 12 centers across the United States and Mexico. Patients aged _>18 years with acute, nonspecific diarrhea, defined as a history of diarrhea for _<72 hours and passage of ->3 unformed stools in the 24 hours before the study, accompanied by ->1 associated symptom (ie, nausea, vomiting, abdominal cramping, and/or fever [<101.0°F or <38.3°C]), were eligible for the study. Patients received wood creosote 135 mg (<5 doses/d) or loperamide 4 mg (loading dose) followed by 2 mg (<8 rag/d) after each loose stool for <3 days. The primary efficacy end point was the time to the last unformed stool (TTLUS). Clinical safety laboratory tests and patient diaries were used to assess tolerability Results: One hundred twenty-three patients (74 women, 49 men; mean [SD] age, 42.6 [14.9] years; age range, 18-90 years) were randomized to receive wood creosote (n = 60) or loperamide (n = 63). Eighty-four o[the 123 enrolled patients (68.3%) were Hispanic, 18 (14.6%) white, 17 (13.8%) black, and 4 (3.3%) Asian or Pacific Islander. The majority of patients (88.3% in the wood creosote group and 95.2% in the loperamide group) had abdominal cramping as the predominant associated symptom. The median (interquartile range [IQR]) TTLUS was similar between groups (24.4 [6.3-36.8] and 22.1 [3.5-32.1] hours in the wood creosote and loperamide groups, respectively), as was the median (IQR) time to total relief (31.0 [15.7-47.8] and 28.5 [13.5-43.5] hours in the wood creosote and loperamide groups, respectively). The mean (SD) numbers of unformed stools on day 1 were 3.31 (2.15) and 2.22 (1.25) in the wood creosote and loperamide groups, respectively (P < 0.002). The percentages of patients with improved or resolved abdominal cramping at the end of day 1 were 92.5% (49/53) and 78.0% (46/59) in the wood creosote and loperamide groups, respectively (P < 0.038). Both medications were well tolerated in the population studied. Conclusions: Wood creosote and loperamide had comparable antidiarrheal effects in these patients with acute, nonspecific diarrhea. Wood creosote appeared somewhat more efficacious in improving or resolving abdominal cramping, whereas loperamide appeared somewhat more efficacious in improving diarrhea. Both treatments were well tolerated. (Clin Ther. 2004;26:1644-1651) Copyright © 2004 Excerpta Medica, Inc. Key words: wood creosote, Seirogan, loperamide, antidiarrheal, antispasmodic, acute nonspecific diarrhea. Accepted.for pc&licationjaly 28, 2004. Printed in the USA. Reproduction in whole or part is not permitted.
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doi:l 0 I016/j.clinthera.2004. I 0.00 I 0149 2918/04/$19 O0
Copyright © 2004 Excerpta Nedica, Inc.
T. Kuge et al.
INTRODUCTION
Seirogan,* an herbal medication containing wood creosote, 1 has been marketed in Asia for the past century as an antispasmodic and antidiarrheal medication for the control of acute diarrhea and relief of associated symptoms (ie, abdominal discomfort and cramping, nausea, vomiting, and/or fever). Wood creosote has been used for medicinal purposes in Europe since the early 1O00s. 2 Seirogan became available in the United States in 2001 as an overthe-counter herbal product and is approved in Canada as an over-the-counter drug. Wood creosote, also referred to as medicinal ctvosote, is a mixture of simple (single-ring) phenolic compounds, including guaiacol, creosol, o-cresol, and ff-ethylguaiacol as major active components.Ls Wood creosote is chemically distinct from, and should not be confused with, coal tar creosote, a known carcinogen) A lack of oncogenicity of wood creosote was observed in a long-term safety study in rats) Wood creosote has been shown to inhibit the peristaltic contraction of intestinal smooth muscle and to promote net fluid absorption or decrease fluid secretion in the intestine in in vivo and ex vivo animal models and in in vitro experiments. ° 10 These studies suggest that the antidiarrheal effects of wood creosote are due, at least in part, to the inhibition of active secretion in the jejunum, ileum, and colon. In double-blind, placebo-controlled, dose-escalation studies 3'11 in 100 healthy volunteers, wood creosote was well tolerated in single doses <225 mg and multiple doses <225 mg 5 times daily. We searched medical and chemical databases (MEDLINE--Medical [1966-200~], Analytical Abstracts--Chemistry [1991-200~], Biological Abstracts [1972-200~], CAB Abstracts--Agriculture [1984-200~-], Chemical Engineering Abstracts [1983-1999], Dissertation Abstracts [1861-2004], US Food and Drug Administration Freedom of Information Disclosures [200~], Federal Research in Progress [200~], International Pharmaceutical Abstracts [1971-200~-], Life Science Collection-Bio [1979-2004], Psychological Abstracts [1998200~-], R&D Insight [2001-2004], and System of *This drug name is generic in some countries in Asia and may or may
not contain the same ingredients as Seirogan ®, a trademark of Taiko Pharmaceutical Company, Ltd. (Osaka, Japan), used in other countries.
Information for Grey Literature in Europe [SIGLE] [1985-2004]) and reviewed citations to support this statement. The search terms Seirogan, wood creosote, beechwood creosote, creosote, and diarrhea were used. Based on this search, this was the first randomized, double-blind study of wood creosote in patients with acute, nonspecific diarrhea. The Seirogan tablet formulation marketed in Asia contains wood creosote plus other herbal ingredients, including gambir, philodendron bark, glycyrrhiza, and citrus unshiu peel, and is available either as a traditional herbal tablet or as a more conventional sugar-coated tablet. The other herbal ingredients in the formulation marketed in Asia are thought to ameliorate any gastrointestinal adverse effects (AEs) attributable to wood creosote, although this assertion is anecdotal and unproved. Potential AEs (which are not all that common) might include dyspepsia, nausea, vomiting, or abdominal bloating. The white, round, odorless Seirogan tablet formulation assessed in this study contains wood creosote, the principal active ingredient, without the other herbal ingredients. The aim of this study was to compare the eflicacy and tolerability of wood creosote with those of loperamide hydrochloride in patients with acute, nonspecific diarrhea. PATIENTS AND
METHODS
This doublelblind, randomized, activelcontrolled study was conducted at 12 centers across the United States and Mexico. A duly constituted local or central human ethics committee approved the study protocol and the informed-consent document before the enrollment of patients at each center. The study was conducted in accordance with the Declaration of Helsinki and its amendments. Inclusion and Exclusion C r i t e r i a
Male and female patients aged _>18 years with acute, nonspecific diarrhea were eligible for the study. Acute, nonspec!fic diarrhea was defined as a history of diarrhea for _<72 hours and the passage of _>3 unformed stools in the 2~- hours before the study, accompanied by z1 associated symptom (nausea, vomiting, abdominal cramping, and/or fever [_IOI.O°F or
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CLINICAL THERAPEUTICS®
>38.3°C), a history of cancer, any clinically unstable medical condition, treatment with investigational drug <30 days before study medication dosing, or known or suspected hypersensitivity to wood creosote or structurally related phenolic compounds or loperamide were excluded. Pregnant, possibly pregnant, or breastfeeding women were excluded from the stud> Women of childbearing age were required to use an effective method of birth control throughout the studT~ Wood creosote has not been found to be teratogenic based on animal reproductive toxicology studiesl2; however, its effects on the developing human fetus are unknown. All patients provided written informed consent before study participation. Treatment
Patients were randomized, in a 1:1 ratio using a computer-generated list of random numbers, to receive wood creosote 135 mg (<5 doses/d) or loperamide 4 mg (loading dose) followed by 2 mg (<8 rag/d) after each loose stool for <3 days. Study medication was packaged in medication blister cards using a doubleblind, double-dummy technique, such that each patient received 3 tablets and 2 capsules per dose (containing active wood creosote 45 rag/tablet or loperamide 2 mg/capsule or matching placebo tablets or capsules). The blister cards contained suflicient study medication for 3 days at 5 dosedd. Patients recorded date, time, and consistency of bowel movements; associated symptoms; medication doses; and AEs in diaries.
Efficacy Assessment The primary efficacy end point was the time to the last unXormed stool (TTLUS), defined as the elapsed time from initiation of study medication to the time of passage of the last unformed stool followed by a firm stool, or (in the absence of a formed stool during the study) the last unformed stool immediately before a 24-hour unformed stool-free period (ie, the last unformed stool followed by no recurrence of diarrhea for a 24-hour period). Each stool was recorded by the patient in the diary and was rated as follows: 1 = loose and watery; 2 = soft and deformable; or 3 = firm or formed. The secondary efficacy end points were (1) time to total relief(TTR), defined as the time from initiation of 1646
medication to the time of resolve of both unformed stools and associated symptoms; (2) improvement in diarrhea, defined as a decrease >50% in the number of unformed stools passed over a 24-hour period compared with the number of unformed stools passed in the corresponding 24-hour pretreatment interval; (3) stool frequenty, defined as the number of total and unformed stools each day; (4) improvement oJfliarrheaassociated symptoms (abdominal cramping, nausea, vomiting, and/or fever) present at baseline and rated and categorized as absent, improved, not improved, or worsened each day; and (5) physician's global assessment of clinical outcome at the exit visit (day 4).
Tolerability Assessment Clinical safety laboratory tests (blood chemistry, hematology, and urinalysis) were performed at the initial screening visit before randomization and at the exit visit. The chemistry laboratory test included a CHEM-20 panel, analyzed using a chemistry autoanalyzer. The hematology test included a complete blood count with differential and platelet count using flow cytometric or cytochemical analytic methods. The urinalysis consisted of a urine dipstick with microscopic examination. Laboratory tests were conducted at accredited local laboratories. AEs were also assessed using patient diaries. Statistical Analysis TTLUS and TTR were analyzed and graphically presented using the Kaplan-Meier survival method; they were also analyzed using a log-rank test for pairwise comparisons. The proportion of patients with improvement in diarrhea and the proportion of patients with a stool frequency of >2 stools/d were analyzed using the Fisher exact test. The number of unformed stools each day was analyzed using a t test. Patient assessment of the predominant diarrheaassociated symptom on each study day and the physician's global assessment of clinical outcome at the end of treatment (day 4) were also analyzed using the Fisher exact test. Statistical analyses were performed using SAS version 8.2 (SAS Institute Inc., Cary, North Carolina). A sample size of 50 patients per group was calculated to have adequate power (80%, o~ level 0.05, 2-tailed test) to detect a difference of 24 hours between treatment groups for TTLUS.
T. Kuge et al.
RESULTS Patient Population One hundred twenty-three patients (7~ women, ~9 men; mean [SD] age, ~2.6 [H.9] years; age range, 1{3-90 years) were randomized to receive wood creosote (n = 60) or loperamide (n = 63). In the wood creosote and loperamide groups, respectively, 35 (58.3%) and 39 (61.9%) patients were women. The mean (SD) ages of patients were 42.8 (15.~) years in the wood creosote group and ~r2.~r (M.6) years in the loperamide group. Eighty-four of the 123 enrolled patients (68.3%) were Hispanic, 18 (H.6%) white, 17 (13.8%) black, and 4 (3.3%) Asian or Pacific Islander. Of patients in the wood creosote and loperamide groups, respectively, ~0 (66.7%) and ~ (69.8%) were Hispanic, 10 (16.7%) and {3 (12.7%) were white, 9 (15.0%) and {3 (12.7%) were black, and 1 (1.6%) and 3 (~.8%) were Asian or Pacific Islander. The majority of patients (53 in the wood creosote group [88.3%] and 59 in the loperamide group [93.7%]) had abdominal cramping as the predominant associated symptom (Table). One patient in the loperamide group was lost to follow-up and no patient diary efficacy data were
available; therefore, 62 patients were assessed for efficacy and 63 patients were assessed for tolerability in the loperamide group. Efficacy TTLUS
The median (interquartile range [IQR]) TTLUS was similar between the 2 groups, at 2~.4 (6.3-36.8) hours in the wood creosote group and 22.1 (3.5-32.1) hours in the loperamide group. On visual examination of the Kaplan-Meier survival curve (Figure 1), the efficacy of wood creosote and loperamide in relieving diarrhea during the first day of treatment appeared similar. TTR
The median (IQR) TTR was similar between the 2 groups, at 31.0 (15.7-47.8) hours in the wood creosote group and 28.5 (13.5-43.5) hours in the loperamide group. On visual examination of the KaplanMeier survival curve (Figure 2), the effica-cy of w o o d creosote and loperamide in providing total relief during the first day of treatment appeared similar.
Table. Baseline demographic and clinical characteristics of the study patients.*t
Characteristic
Wood Creosote (n = 60)
Loperamide (n = 63)
All Patients (N = 123)
42.8 (I 5.4)
42.4 (I 4.6)
~2I 6 (I 4 I9 )
18 90
20 84
18 90
Demographic Age, y
Nean (SD) Range Sex, no. (%) Female Hale Race/ethnicity, no, (%)
Hispanic White Black Asian or Pacific Islander
35 (58,3) 25 (41,7)
39 (61,9) 24 (38, I)
74 (60,2) 49 (39,8)
40 10 9 I
(66.7) (16.7) (I 5.0) (I.7)
44 8 8 3
(69.8) (12.7) (I 2.7) (4.8)
84 (68.3) 8 (14.6) 7 (I 3.8) 4 (3.3)
53 16 4 I
(88.3) (26.7) (6.7) (I.7)
59 18 8 5
(93.7) (28.6) (I 2,7) (7.9)
i 2 (91.1)
Clinical: diarrhea associated symptom, no. (%)$
Abdominal cramping Nausea Vomiting Fever§
34 (27.6) 12 (9.8) 6 (4.9)
~'No significant between group differences were found. ?Percentages may not total 100 due to rounding, tSome patients had I diarrhea associated symptom, §Fever body temperature <101.0°F or < 38.3~C.
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CLINICALTHERAPEUTIC®S
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30
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50
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70
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80
TTLUS (h) Figure I. Time to last unformed stool (TTLUS) by treatment group (medians [interquartile range]: 24.4 [6.3-36.8] and 22. I [3.5-32.1] hours in the wood creosote and Ioperamide groups, respectively). Patients in whom unformed stool was resolved by study end: 55 (91.7%) and 59 (95.2%) in the wood creosote and Ioperamide groups, respectively; patients censored: 5 (8.3%) and 3 (4.8%) in the wood creosote and Ioperamide groups, respectively.
Improvement in Diarrhea The percentage of patients with improvement in diarrhea from 0 to 24 hours compared with pretreatmerit (-24 to 0 hours) was similar between the 2 groups (23.3% [ 14/60] and 33.9% [21/62] of patients in the wood creosote and loperamide groups, respectively; Figure 3). Similarly, no significant differences between the wood creosote and loperamide groups were observed in improvement in diarrhea on days 2 and 3. Stool Frequency On day 1, 73.3% (44160) and 54.8% (34/62) of patients had _>2 stools/d in the wood creosote and loperamide groups, respectively (P < 0.040; Figure 3). On day 2, 45.0% (27/60) and 24.2% (15/62) of patients, respectively, still had >2 stools/d (P < 0.022). No significant differences between wood creosote and loperamide were observed in this finding on day 3. 1648
In the wood creosote (n = 55) and loperamide (n = 51) groups, respectively, the mean (SD) numbers of unformed stools were 3.31 (2.15) and 2.22 (1.25) on day 1 and 1.83 (0.97) and 1.33 (0.70) on day 2 (P < 0.002 and P < 0.035, respectively). No significant difference in the mean number of unformed stools was found between the 2 groups on day 3.
Improvement of Baseline Predominant Symptom The percentages of patients with improved or resolved abdominal cramping at the end of day 1 (based on the proportion of patients with this symptom present at baseline as recorded in the diary) were 92.5% (49/53) and 78.0% (46/59) in the wood creosote and loperamide groups, respectively (P < 0.038; 95% CI, 1.74%-27.23%; Figure 3). Physician's Global Assessment On day 4} based on the physician's global assessment, a similar percentage of patients in each g r o u p
T. Kuge et al.
was assessed as improved or resolved (93.3% [56/60] and 100.0% [62/62] in the wood creosote and loperamide groups, respectively).
and salts lost in diarrheal stools, using oral rehydration solutions (eg, the World Health Organization oral rehydration salts solutionl3). In many cases, antimotility agents may not be required. However, antimotility agents (eg, loperamide) are used by some patients in conjunction with oral rehydration and can provide prompt temporary relief of uncomplicated diarrhea. Antimotility agents should not be used in patients with high fever (>101.0°F or >38.3°C) or blood in their stools. The efficacy of an antidiarrheal medication within the first 2~- hours of treatment is particularly relevant for acute, nonspecific diarrhea, which can interfere with daily activities. In the present study, both wood creosote and loperamide were found to have comparable antidiarrheal effects in the population studied. Loperamide appeared more efficacious in relieving diarrhea on day 1 of treatment than wood creosote when used at recommended doses. The loperamide 4-rag loading dose may have con-
Tolerability
Both medications were well tolerated in the population studied. Treatment-emergent AEs were reported in 23.3% (14/60) and 11.1% (7/63) of patients receiving wood creosote and loperamide, respectively. The most common AEs reported in patients receiving wood creosote were headache in 6 patients (10.0%) and dysgeusia (altered taste) in 2 patients (3.3%). No individual AE was reported in >1 patient in the loperamide group. There were no clinically significant overall changes in blood chemistry, hematology, or urinalysis attributed to wood creosote or loperamide during the study. DISCUSSION
Most cases of acute, nonspecific diarrhea are selflimiting and require simple replacement of fluids
Wood creosote (n = 60) Loperamide (n = 62)
- -
'°°.F7 80
~_
__
] |-|_
70
60-
5O
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1
40-
-I 3O
-,
20-
10I
0
0
I
10
I
20
30
I
40
I
50
I
60
I I
I
70
I
80
TTR (h) Figure 2. Time to total relief (TTR) by treatment group (medians [interquartile range]: 31.0 [15.7-47.8] and 28.5 [I 3.5-43.5] hours in the wood creosote and Ioperamide groups, respectively). Patients in whom total relief was achieved by study end: 51 (85.0%) and 53 (85.5%) in the wood creosote and Ioperamide groups, respectively; patients censored: 8 (13.3%) and 9 (14.5%) in the wood creosote and Ioperamide groups, respectively.
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CLINICAL THERAPEUTICS®
[] Wood creosote • Loperamide
100 90807060~'
50-
a_
403020100
Improved Diarrhea*
Overall Stool Frequency*
Improved or Resolved Abdominal Cramping§
Figure 3. Percentages of patients with improved diarrhea (_>50% reduction in unformed stools), overall stool frequency (_>2 stools/d), and improved or resolved abdominal cramping on day I (0 to 24 hours) compared with pretreatment (-24 to 0 hours). *Numbers of patients in this analysis: 60 and 62 in the wood creosote and Ioperamide groups, respectively; tp < 0.040 between groups; *P < 0.038 between groups; §numbers of patients in this analysis: 53 and 59 in the wood creosote and Ioperamide groups, respectively.
tributed to increased efficacy, particularly during the first 6 to 8 hours. Wood creosote 135 mg appeared more efficacious in improving or resolving abdominal cramping on day 1 of treatment than loperamide. Abdominal cramping relief with wood creosote is consistent with previous experience in Japan regarding the efficacy of 5eirogan for relieving abdominal cramping in patients with acute diarrhea or irritable bowel syndrome (unpublished observations, Taiko Pharmaceutical Company, Ltd., 1996). Further clinical trials to explore the antispasmodic effects of wood creosote at doses _>135 mg may be warranted. CONCLUSIONS Wood creosote and loperamide had comparable antidiarrheal effects in these patients with acute, nonspecific diarrhea. Wood creosote appeared
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s o m e w h a t more efficacious in improving or resolving abdominal cramping, whereas loperamide appeared somewhat more efficacious in improving diarrhea. Both treatments were well tolerated. REFERENCES
1. Ogata N, Baba T. Analysis of beechwood creosote by gas chromatography-mass spectrometry and highperformance liquid chromatograph> Res Commun Chem PaLhol PharmacoI. 1989~66:411-423. 2. Haller jS Jr. Creosote: A short history of its medicinal uses. Corm Med. 1990;54:502-507. 3. Kuge T, Shibata T, Willett MS. Wood creosote, the principal active ingredient of seirogan, an herbal antidiarrheal medicine: A single-dose, dose-escalation safety and pharmacokinetic study Pharmacotherapy. 2003:23: 1391-1400.
T. Kuge et al.
4. US Dept of Health and Human SenTices (DHHS), Public Health Service, National Toxicology Program. Report on Carcinogens. 10th ed. Washington, DC: DHHS; 2002. 5. Kuge T. Shibata T, Willdt MS, et ah Lack of oncogenicity of wood creosote, the principal active ingredient o1 seirogan, an herbal antidiarrheal medication, in Sprague-Dawley rats. I~t J Toxicol. 2001;10:297305. 6. Ogata N, Baba T, Shibata T. Demonstration of antidiarrheal and antimotility dfects of wood creosote. Pharmacology. 1993;46:173-180. 7. Ogata N, Shibata T. Antidiarrheal activity o1 wood creosote: Inhibition of muscle contraction and enterotoxininduced fluid secretion in rabbit small intestine. Pharmacology. 2001;62:181-187. 8. Greenwood-Van Meerveld B, Tyler KR, Venkova K, Kuge T. Comparison of the antidiarrheal eflects of wood creosote and loperamide in the rat .iejunum and colon in vitro. Biol Pharm B~dl. 2000;23:952-956.
9. Kuge T, Venkova K, Greenwood-Van Meerveld B. Effects of sdrogan (wood creosote) on propulsive colonic motility and stool characteristics in ambulatory minipigs. Dig Dis 5ci. 2002;47:2651-2656. 10. Ataka K, Kuge T, Venkova K, Greenwood-Van Meerveld B. Seirogan (wood creosote) inhibits stressinduced ion secretion in rat intestinal epithelium. Dig Dis Sci. 2003;48:1303-1309. 11. Kuge T, Shibata T, Willett MS. Multiple-dose escalation, safety, and tolerability study of wood creosote, the principal active ingredient of seirogan, an herbal antidiarrheal medication, in healthy subjects. J Clin Pharmacol. 2003;43:284-290. 12. Data on file, study nos. TA-107, TA-108, TA-109, and TA114. Taiko Pharmaceutical Co., Ltd., Osaka, Japan, 2004. 13. National Center for Infectious Diseases. Travelers' diarrhea. Atlanta, Ga: Centers for Disease Control and Prevention, 2004. Available at: www.cdc.gov/travel/ diarrhea.htm. Accessed .July 6, 2004.
A d d r e s s c o r r e s p o n d e n c e to: Tomoo Kuge, PhD, Taiko Pharmaceutical Company, Ltd., 3-34-14 Uchihonmachi, Suita-City 564-0032, Osaka, Japan. E-mail: [email protected]
1651
Multicenter, Double-Blind, Randomized Comparison of Wood Creosote, the Principal Active Ingredient of Seirogan, an Herbal Antidiarrheal Medication, and Loperamide in Adults with Acute Nonspecific Diarrhea Tomoo Kuge, PhD, 1 Takashi Shibata, MD, PhD, 1 and Michael S. Willett, PharmD 2 l gaiko Pharmaceutical Company, Ltd., Osaka, Japan, and 2Advanced Biomedical Research, Inc., Princeton, New Jersey
ABSTRACT
Background: 5eirogan, an herbal medication containing wood creosote, a mixture of simple phenolic (singlering) compounds, has been marketed in Asia for the past century as an antidiarrheal and antispasmodic medication. This was the first randomized, double-blind study of this herbal medication in patients with acute, nonspecific diarrhea. Objective: The aim of this study was to compare the efficacy and tolerability of wood creosote with those of loperamide hydrochloride in patients with acute, nonspecific diarrhea. Methods: This double-blind, randomized, active-controlled study was conducted at 12 centers across the United States and Mexico. Patients aged _>18 years with acute, nonspecific diarrhea, defined as a history of diarrhea for _<72 hours and passage of ->3 unformed stools in the 24 hours before the study, accompanied by ->1 associated symptom (ie, nausea, vomiting, abdominal cramping, and/or fever [<101.0°F or <38.3°C]), were eligible for the study. Patients received wood creosote 135 mg (<5 doses/d) or loperamide 4 mg (loading dose) followed by 2 mg (<8 rag/d) after each loose stool for <3 days. The primary efficacy end point was the time to the last unformed stool (TTLUS). Clinical safety laboratory tests and patient diaries were used to assess tolerability Results: One hundred twenty-three patients (74 women, 49 men; mean [SD] age, 42.6 [14.9] years; age range, 18-90 years) were randomized to receive wood creosote (n = 60) or loperamide (n = 63). Eighty-four o[the 123 enrolled patients (68.3%) were Hispanic, 18 (14.6%) white, 17 (13.8%) black, and 4 (3.3%) Asian or Pacific Islander. The majority of patients (88.3% in the wood creosote group and 95.2% in the loperamide group) had abdominal cramping as the predominant associated symptom. The median (interquartile range [IQR]) TTLUS was similar between groups (24.4 [6.3-36.8] and 22.1 [3.5-32.1] hours in the wood creosote and loperamide groups, respectively), as was the median (IQR) time to total relief (31.0 [15.7-47.8] and 28.5 [13.5-43.5] hours in the wood creosote and loperamide groups, respectively). The mean (SD) numbers of unformed stools on day 1 were 3.31 (2.15) and 2.22 (1.25) in the wood creosote and loperamide groups, respectively (P < 0.002). The percentages of patients with improved or resolved abdominal cramping at the end of day 1 were 92.5% (49/53) and 78.0% (46/59) in the wood creosote and loperamide groups, respectively (P < 0.038). Both medications were well tolerated in the population studied. Conclusions: Wood creosote and loperamide had comparable antidiarrheal effects in these patients with acute, nonspecific diarrhea. Wood creosote appeared somewhat more efficacious in improving or resolving abdominal cramping, whereas loperamide appeared somewhat more efficacious in improving diarrhea. Both treatments were well tolerated. (Clin Ther. 2004;26:1644-1651) Copyright © 2004 Excerpta Medica, Inc. Key words: wood creosote, Seirogan, loperamide, antidiarrheal, antispasmodic, acute nonspecific diarrhea. Accepted.for pc&licationjaly 28, 2004. Printed in the USA. Reproduction in whole or part is not permitted.
]64~r
doi:l 0 I016/j.clinthera.2004. I 0.00 I 0149 2918/04/$19 O0
Copyright © 2004 Excerpta Nedica, Inc.
T. Kuge et al.
INTRODUCTION
Seirogan,* an herbal medication containing wood creosote, 1 has been marketed in Asia for the past century as an antispasmodic and antidiarrheal medication for the control of acute diarrhea and relief of associated symptoms (ie, abdominal discomfort and cramping, nausea, vomiting, and/or fever). Wood creosote has been used for medicinal purposes in Europe since the early 1O00s. 2 Seirogan became available in the United States in 2001 as an overthe-counter herbal product and is approved in Canada as an over-the-counter drug. Wood creosote, also referred to as medicinal ctvosote, is a mixture of simple (single-ring) phenolic compounds, including guaiacol, creosol, o-cresol, and ff-ethylguaiacol as major active components.Ls Wood creosote is chemically distinct from, and should not be confused with, coal tar creosote, a known carcinogen) A lack of oncogenicity of wood creosote was observed in a long-term safety study in rats) Wood creosote has been shown to inhibit the peristaltic contraction of intestinal smooth muscle and to promote net fluid absorption or decrease fluid secretion in the intestine in in vivo and ex vivo animal models and in in vitro experiments. ° 10 These studies suggest that the antidiarrheal effects of wood creosote are due, at least in part, to the inhibition of active secretion in the jejunum, ileum, and colon. In double-blind, placebo-controlled, dose-escalation studies 3'11 in 100 healthy volunteers, wood creosote was well tolerated in single doses <225 mg and multiple doses <225 mg 5 times daily. We searched medical and chemical databases (MEDLINE--Medical [1966-200~], Analytical Abstracts--Chemistry [1991-200~], Biological Abstracts [1972-200~], CAB Abstracts--Agriculture [1984-200~-], Chemical Engineering Abstracts [1983-1999], Dissertation Abstracts [1861-2004], US Food and Drug Administration Freedom of Information Disclosures [200~], Federal Research in Progress [200~], International Pharmaceutical Abstracts [1971-200~-], Life Science Collection-Bio [1979-2004], Psychological Abstracts [1998200~-], R&D Insight [2001-2004], and System of *This drug name is generic in some countries in Asia and may or may
not contain the same ingredients as Seirogan ®, a trademark of Taiko Pharmaceutical Company, Ltd. (Osaka, Japan), used in other countries.
Information for Grey Literature in Europe [SIGLE] [1985-2004]) and reviewed citations to support this statement. The search terms Seirogan, wood creosote, beechwood creosote, creosote, and diarrhea were used. Based on this search, this was the first randomized, double-blind study of wood creosote in patients with acute, nonspecific diarrhea. The Seirogan tablet formulation marketed in Asia contains wood creosote plus other herbal ingredients, including gambir, philodendron bark, glycyrrhiza, and citrus unshiu peel, and is available either as a traditional herbal tablet or as a more conventional sugar-coated tablet. The other herbal ingredients in the formulation marketed in Asia are thought to ameliorate any gastrointestinal adverse effects (AEs) attributable to wood creosote, although this assertion is anecdotal and unproved. Potential AEs (which are not all that common) might include dyspepsia, nausea, vomiting, or abdominal bloating. The white, round, odorless Seirogan tablet formulation assessed in this study contains wood creosote, the principal active ingredient, without the other herbal ingredients. The aim of this study was to compare the eflicacy and tolerability of wood creosote with those of loperamide hydrochloride in patients with acute, nonspecific diarrhea. PATIENTS AND
METHODS
This doublelblind, randomized, activelcontrolled study was conducted at 12 centers across the United States and Mexico. A duly constituted local or central human ethics committee approved the study protocol and the informed-consent document before the enrollment of patients at each center. The study was conducted in accordance with the Declaration of Helsinki and its amendments. Inclusion and Exclusion C r i t e r i a
Male and female patients aged _>18 years with acute, nonspecific diarrhea were eligible for the study. Acute, nonspec!fic diarrhea was defined as a history of diarrhea for _<72 hours and the passage of _>3 unformed stools in the 2~- hours before the study, accompanied by z1 associated symptom (nausea, vomiting, abdominal cramping, and/or fever [_
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CLINICAL THERAPEUTICS®
>38.3°C), a history of cancer, any clinically unstable medical condition, treatment with investigational drug <30 days before study medication dosing, or known or suspected hypersensitivity to wood creosote or structurally related phenolic compounds or loperamide were excluded. Pregnant, possibly pregnant, or breastfeeding women were excluded from the stud> Women of childbearing age were required to use an effective method of birth control throughout the studT~ Wood creosote has not been found to be teratogenic based on animal reproductive toxicology studiesl2; however, its effects on the developing human fetus are unknown. All patients provided written informed consent before study participation. Treatment
Patients were randomized, in a 1:1 ratio using a computer-generated list of random numbers, to receive wood creosote 135 mg (<5 doses/d) or loperamide 4 mg (loading dose) followed by 2 mg (<8 rag/d) after each loose stool for <3 days. Study medication was packaged in medication blister cards using a doubleblind, double-dummy technique, such that each patient received 3 tablets and 2 capsules per dose (containing active wood creosote 45 rag/tablet or loperamide 2 mg/capsule or matching placebo tablets or capsules). The blister cards contained suflicient study medication for 3 days at 5 dosedd. Patients recorded date, time, and consistency of bowel movements; associated symptoms; medication doses; and AEs in diaries.
Efficacy Assessment The primary efficacy end point was the time to the last unXormed stool (TTLUS), defined as the elapsed time from initiation of study medication to the time of passage of the last unformed stool followed by a firm stool, or (in the absence of a formed stool during the study) the last unformed stool immediately before a 24-hour unformed stool-free period (ie, the last unformed stool followed by no recurrence of diarrhea for a 24-hour period). Each stool was recorded by the patient in the diary and was rated as follows: 1 = loose and watery; 2 = soft and deformable; or 3 = firm or formed. The secondary efficacy end points were (1) time to total relief(TTR), defined as the time from initiation of 1646
medication to the time of resolve of both unformed stools and associated symptoms; (2) improvement in diarrhea, defined as a decrease >50% in the number of unformed stools passed over a 24-hour period compared with the number of unformed stools passed in the corresponding 24-hour pretreatment interval; (3) stool frequenty, defined as the number of total and unformed stools each day; (4) improvement oJfliarrheaassociated symptoms (abdominal cramping, nausea, vomiting, and/or fever) present at baseline and rated and categorized as absent, improved, not improved, or worsened each day; and (5) physician's global assessment of clinical outcome at the exit visit (day 4).
Tolerability Assessment Clinical safety laboratory tests (blood chemistry, hematology, and urinalysis) were performed at the initial screening visit before randomization and at the exit visit. The chemistry laboratory test included a CHEM-20 panel, analyzed using a chemistry autoanalyzer. The hematology test included a complete blood count with differential and platelet count using flow cytometric or cytochemical analytic methods. The urinalysis consisted of a urine dipstick with microscopic examination. Laboratory tests were conducted at accredited local laboratories. AEs were also assessed using patient diaries. Statistical Analysis TTLUS and TTR were analyzed and graphically presented using the Kaplan-Meier survival method; they were also analyzed using a log-rank test for pairwise comparisons. The proportion of patients with improvement in diarrhea and the proportion of patients with a stool frequency of >2 stools/d were analyzed using the Fisher exact test. The number of unformed stools each day was analyzed using a t test. Patient assessment of the predominant diarrheaassociated symptom on each study day and the physician's global assessment of clinical outcome at the end of treatment (day 4) were also analyzed using the Fisher exact test. Statistical analyses were performed using SAS version 8.2 (SAS Institute Inc., Cary, North Carolina). A sample size of 50 patients per group was calculated to have adequate power (80%, o~ level 0.05, 2-tailed test) to detect a difference of 24 hours between treatment groups for TTLUS.
T. Kuge et al.
RESULTS Patient Population One hundred twenty-three patients (7~ women, ~9 men; mean [SD] age, ~2.6 [H.9] years; age range, 1{3-90 years) were randomized to receive wood creosote (n = 60) or loperamide (n = 63). In the wood creosote and loperamide groups, respectively, 35 (58.3%) and 39 (61.9%) patients were women. The mean (SD) ages of patients were 42.8 (15.~) years in the wood creosote group and ~r2.~r (M.6) years in the loperamide group. Eighty-four of the 123 enrolled patients (68.3%) were Hispanic, 18 (H.6%) white, 17 (13.8%) black, and 4 (3.3%) Asian or Pacific Islander. Of patients in the wood creosote and loperamide groups, respectively, ~0 (66.7%) and ~ (69.8%) were Hispanic, 10 (16.7%) and {3 (12.7%) were white, 9 (15.0%) and {3 (12.7%) were black, and 1 (1.6%) and 3 (~.8%) were Asian or Pacific Islander. The majority of patients (53 in the wood creosote group [88.3%] and 59 in the loperamide group [93.7%]) had abdominal cramping as the predominant associated symptom (Table). One patient in the loperamide group was lost to follow-up and no patient diary efficacy data were
available; therefore, 62 patients were assessed for efficacy and 63 patients were assessed for tolerability in the loperamide group. Efficacy TTLUS
The median (interquartile range [IQR]) TTLUS was similar between the 2 groups, at 2~.4 (6.3-36.8) hours in the wood creosote group and 22.1 (3.5-32.1) hours in the loperamide group. On visual examination of the Kaplan-Meier survival curve (Figure 1), the efficacy of wood creosote and loperamide in relieving diarrhea during the first day of treatment appeared similar. TTR
The median (IQR) TTR was similar between the 2 groups, at 31.0 (15.7-47.8) hours in the wood creosote group and 28.5 (13.5-43.5) hours in the loperamide group. On visual examination of the KaplanMeier survival curve (Figure 2), the effica-cy of w o o d creosote and loperamide in providing total relief during the first day of treatment appeared similar.
Table. Baseline demographic and clinical characteristics of the study patients.*t
Characteristic
Wood Creosote (n = 60)
Loperamide (n = 63)
All Patients (N = 123)
42.8 (I 5.4)
42.4 (I 4.6)
~2I 6 (I 4 I9 )
18 90
20 84
18 90
Demographic Age, y
Nean (SD) Range Sex, no. (%) Female Hale Race/ethnicity, no, (%)
Hispanic White Black Asian or Pacific Islander
35 (58,3) 25 (41,7)
39 (61,9) 24 (38, I)
74 (60,2) 49 (39,8)
40 10 9 I
(66.7) (16.7) (I 5.0) (I.7)
44 8 8 3
(69.8) (12.7) (I 2.7) (4.8)
84 (68.3) 8 (14.6) 7 (I 3.8) 4 (3.3)
53 16 4 I
(88.3) (26.7) (6.7) (I.7)
59 18 8 5
(93.7) (28.6) (I 2,7) (7.9)
i 2 (91.1)
Clinical: diarrhea associated symptom, no. (%)$
Abdominal cramping Nausea Vomiting Fever§
34 (27.6) 12 (9.8) 6 (4.9)
~'No significant between group differences were found. ?Percentages may not total 100 due to rounding, tSome patients had I diarrhea associated symptom, §Fever body temperature <101.0°F or < 38.3~C.
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CLINICALTHERAPEUTIC®S
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TTLUS (h) Figure I. Time to last unformed stool (TTLUS) by treatment group (medians [interquartile range]: 24.4 [6.3-36.8] and 22. I [3.5-32.1] hours in the wood creosote and Ioperamide groups, respectively). Patients in whom unformed stool was resolved by study end: 55 (91.7%) and 59 (95.2%) in the wood creosote and Ioperamide groups, respectively; patients censored: 5 (8.3%) and 3 (4.8%) in the wood creosote and Ioperamide groups, respectively.
Improvement in Diarrhea The percentage of patients with improvement in diarrhea from 0 to 24 hours compared with pretreatmerit (-24 to 0 hours) was similar between the 2 groups (23.3% [ 14/60] and 33.9% [21/62] of patients in the wood creosote and loperamide groups, respectively; Figure 3). Similarly, no significant differences between the wood creosote and loperamide groups were observed in improvement in diarrhea on days 2 and 3. Stool Frequency On day 1, 73.3% (44160) and 54.8% (34/62) of patients had _>2 stools/d in the wood creosote and loperamide groups, respectively (P < 0.040; Figure 3). On day 2, 45.0% (27/60) and 24.2% (15/62) of patients, respectively, still had >2 stools/d (P < 0.022). No significant differences between wood creosote and loperamide were observed in this finding on day 3. 1648
In the wood creosote (n = 55) and loperamide (n = 51) groups, respectively, the mean (SD) numbers of unformed stools were 3.31 (2.15) and 2.22 (1.25) on day 1 and 1.83 (0.97) and 1.33 (0.70) on day 2 (P < 0.002 and P < 0.035, respectively). No significant difference in the mean number of unformed stools was found between the 2 groups on day 3.
Improvement of Baseline Predominant Symptom The percentages of patients with improved or resolved abdominal cramping at the end of day 1 (based on the proportion of patients with this symptom present at baseline as recorded in the diary) were 92.5% (49/53) and 78.0% (46/59) in the wood creosote and loperamide groups, respectively (P < 0.038; 95% CI, 1.74%-27.23%; Figure 3). Physician's Global Assessment On day 4} based on the physician's global assessment, a similar percentage of patients in each g r o u p
T. Kuge et al.
was assessed as improved or resolved (93.3% [56/60] and 100.0% [62/62] in the wood creosote and loperamide groups, respectively).
and salts lost in diarrheal stools, using oral rehydration solutions (eg, the World Health Organization oral rehydration salts solutionl3). In many cases, antimotility agents may not be required. However, antimotility agents (eg, loperamide) are used by some patients in conjunction with oral rehydration and can provide prompt temporary relief of uncomplicated diarrhea. Antimotility agents should not be used in patients with high fever (>101.0°F or >38.3°C) or blood in their stools. The efficacy of an antidiarrheal medication within the first 2~- hours of treatment is particularly relevant for acute, nonspecific diarrhea, which can interfere with daily activities. In the present study, both wood creosote and loperamide were found to have comparable antidiarrheal effects in the population studied. Loperamide appeared more efficacious in relieving diarrhea on day 1 of treatment than wood creosote when used at recommended doses. The loperamide 4-rag loading dose may have con-
Tolerability
Both medications were well tolerated in the population studied. Treatment-emergent AEs were reported in 23.3% (14/60) and 11.1% (7/63) of patients receiving wood creosote and loperamide, respectively. The most common AEs reported in patients receiving wood creosote were headache in 6 patients (10.0%) and dysgeusia (altered taste) in 2 patients (3.3%). No individual AE was reported in >1 patient in the loperamide group. There were no clinically significant overall changes in blood chemistry, hematology, or urinalysis attributed to wood creosote or loperamide during the study. DISCUSSION
Most cases of acute, nonspecific diarrhea are selflimiting and require simple replacement of fluids
Wood creosote (n = 60) Loperamide (n = 62)
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TTR (h) Figure 2. Time to total relief (TTR) by treatment group (medians [interquartile range]: 31.0 [15.7-47.8] and 28.5 [I 3.5-43.5] hours in the wood creosote and Ioperamide groups, respectively). Patients in whom total relief was achieved by study end: 51 (85.0%) and 53 (85.5%) in the wood creosote and Ioperamide groups, respectively; patients censored: 8 (13.3%) and 9 (14.5%) in the wood creosote and Ioperamide groups, respectively.
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CLINICAL THERAPEUTICS®
[] Wood creosote • Loperamide
100 90807060~'
50-
a_
403020100
Improved Diarrhea*
Overall Stool Frequency*
Improved or Resolved Abdominal Cramping§
Figure 3. Percentages of patients with improved diarrhea (_>50% reduction in unformed stools), overall stool frequency (_>2 stools/d), and improved or resolved abdominal cramping on day I (0 to 24 hours) compared with pretreatment (-24 to 0 hours). *Numbers of patients in this analysis: 60 and 62 in the wood creosote and Ioperamide groups, respectively; tp < 0.040 between groups; *P < 0.038 between groups; §numbers of patients in this analysis: 53 and 59 in the wood creosote and Ioperamide groups, respectively.
tributed to increased efficacy, particularly during the first 6 to 8 hours. Wood creosote 135 mg appeared more efficacious in improving or resolving abdominal cramping on day 1 of treatment than loperamide. Abdominal cramping relief with wood creosote is consistent with previous experience in Japan regarding the efficacy of 5eirogan for relieving abdominal cramping in patients with acute diarrhea or irritable bowel syndrome (unpublished observations, Taiko Pharmaceutical Company, Ltd., 1996). Further clinical trials to explore the antispasmodic effects of wood creosote at doses _>135 mg may be warranted. CONCLUSIONS Wood creosote and loperamide had comparable antidiarrheal effects in these patients with acute, nonspecific diarrhea. Wood creosote appeared
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s o m e w h a t more efficacious in improving or resolving abdominal cramping, whereas loperamide appeared somewhat more efficacious in improving diarrhea. Both treatments were well tolerated. REFERENCES
1. Ogata N, Baba T. Analysis of beechwood creosote by gas chromatography-mass spectrometry and highperformance liquid chromatograph> Res Commun Chem PaLhol PharmacoI. 1989~66:411-423. 2. Haller jS Jr. Creosote: A short history of its medicinal uses. Corm Med. 1990;54:502-507. 3. Kuge T, Shibata T, Willett MS. Wood creosote, the principal active ingredient of seirogan, an herbal antidiarrheal medicine: A single-dose, dose-escalation safety and pharmacokinetic study Pharmacotherapy. 2003:23: 1391-1400.
T. Kuge et al.
4. US Dept of Health and Human SenTices (DHHS), Public Health Service, National Toxicology Program. Report on Carcinogens. 10th ed. Washington, DC: DHHS; 2002. 5. Kuge T. Shibata T, Willdt MS, et ah Lack of oncogenicity of wood creosote, the principal active ingredient o1 seirogan, an herbal antidiarrheal medication, in Sprague-Dawley rats. I~t J Toxicol. 2001;10:297305. 6. Ogata N, Baba T, Shibata T. Demonstration of antidiarrheal and antimotility dfects of wood creosote. Pharmacology. 1993;46:173-180. 7. Ogata N, Shibata T. Antidiarrheal activity o1 wood creosote: Inhibition of muscle contraction and enterotoxininduced fluid secretion in rabbit small intestine. Pharmacology. 2001;62:181-187. 8. Greenwood-Van Meerveld B, Tyler KR, Venkova K, Kuge T. Comparison of the antidiarrheal eflects of wood creosote and loperamide in the rat .iejunum and colon in vitro. Biol Pharm B~dl. 2000;23:952-956.
9. Kuge T, Venkova K, Greenwood-Van Meerveld B. Effects of sdrogan (wood creosote) on propulsive colonic motility and stool characteristics in ambulatory minipigs. Dig Dis 5ci. 2002;47:2651-2656. 10. Ataka K, Kuge T, Venkova K, Greenwood-Van Meerveld B. Seirogan (wood creosote) inhibits stressinduced ion secretion in rat intestinal epithelium. Dig Dis Sci. 2003;48:1303-1309. 11. Kuge T, Shibata T, Willett MS. Multiple-dose escalation, safety, and tolerability study of wood creosote, the principal active ingredient of seirogan, an herbal antidiarrheal medication, in healthy subjects. J Clin Pharmacol. 2003;43:284-290. 12. Data on file, study nos. TA-107, TA-108, TA-109, and TA114. Taiko Pharmaceutical Co., Ltd., Osaka, Japan, 2004. 13. National Center for Infectious Diseases. Travelers' diarrhea. Atlanta, Ga: Centers for Disease Control and Prevention, 2004. Available at: www.cdc.gov/travel/ diarrhea.htm. Accessed .July 6, 2004.
A d d r e s s c o r r e s p o n d e n c e to: Tomoo Kuge, PhD, Taiko Pharmaceutical Company, Ltd., 3-34-14 Uchihonmachi, Suita-City 564-0032, Osaka, Japan. E-mail: [email protected]
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