Thursday, July 3, 2008

Wood Creosote, the Principal Active Ingredient of Seirogan, an Herbal Antidiarrheal Medicine: A Single-Dose, Dose-Escalation Safety and Pharmacokinetic Study

antispasmodic Tomoo Kuge, Ph.D.; Takashi Shibata, M.D., Ph.D.; Michael S. Willett, Pharm.D.

Abstract and Introduction


Study Objective: To assess the safety, tolerability, and pharmacokinetics of escalating single doses of wood creosote, an herbal antidiarrheal and antispasmodic agent.
Design: Randomized, double-blind, placebo-controlled study.
Setting: Clinical research center.
Subjects: Forty (32 men, 8 women) healthy volunteers aged 19-42 years.
Intervention: By random assignment, 22 men and 8 women received escalating single doses of wood creosote (45, 90, 135, 180, and 225 mg) and 10 men received placebo (for each of the five dose levels, 6 subjects received active substance and 2 subjects received placebo).
Measurements and Main Results: Vital signs, laboratory tests, and electrocardiograms were assessed; no dose-related or clinically significant changes were noted. Serial blood samples were obtained to determine the pharmacokinetics of four major active components of wood creosote: total (conjugated plus free) guaiacol, creosol, o-cresol, and 4-ethylguaiacol. The most common adverse events were mild headache and dizziness, with no dose-related trends being apparent. Area under the concentration-time curve from time zero to infinity increased in a dose-proportional manner for total guaiacol, creosol, and o-cresol and was not assessed for total 4-ethylguaiacol owing to lack of data at the low dose level. No apparent differences by sex were noted for any of the four active components. All four components were rapidly eliminated.
Conclusion: Single oral doses of wood creosote up to 225 mg were safe and well tolerated in healthy men and women. Also, the doses of wood creosote were rapidly absorbed, conjugated, and eliminated. Such a rapid onset and short duration of action would appear desirable in the treatment of acute nonspecific diarrhea.Introduction

Diarrhea is recognized as a major health problem and one of the leading causes of infant mortality in developing countries.[1-3] Diarrheal illness is also common in developed countries but usually is viewed as an inconvenience rather than a medical hazard. In developed countries, most episodes of diarrhea are mild and are either self-limiting or self-treated with over-the-counter drugs or home remedies. Nonetheless, acute diarrhea significantly affects the United States population through restriction in activity and loss in productivity.[4] In addition, there are certain high-risk populations (e.g., infants, elderly patients with concomitant medical conditions, immunocompromised patients) for whom diarrhea can be severely debilitating. Traveler's diarrhea, although often self-limiting, can also be severe. In some developing countries, the frequency of traveler's diarrhea can exceed 50%.[5, 6]

The cause of acute diarrhea in the United States most often is thought to be infectious; however, in clinical practice, a pathogen is identified less than 50% of the time. Diarrhea in infants and children in the United States is usually associated with infections caused by rotavirus. In adults in the United States, the causative agent may be a bacterial or viral pathogen or may be noninfectious. In clinical trials, traveler's diarrhea is caused by bacterial pathogens in more than half of the cases.[7]

Diarrhea, having many different causes and therefore different effects on the gastrointestinal system, can be categorized based on potential mechanisms of altered fluid and electrolyte movement.[8] The pathophysiologic manifestations of acute diarrhea often include increased luminal osmolality, increased intestinal secretion, inflammation of the intestinal lining, and altered intestinal motility. The goal in management is to correct the underlying pathophysiologic problem when feasible and to provide symptomatic relief.

Available treatments, including prescription and over-the-counter drugs, have several disadvantages. Antibiotic treatment is generally not recommended for most cases of mild-to-moderate, acute, nonspecific diarrhea because the risks of overuse may outweigh the benefits. Other drugs used to treat diarrhea, such as those containing diphenoxylate hydrochloride and atropine, can have central nervous system adverse effects and may be contraindicated in some patients.[9] Loperamide, the most commonly administered drug to treat acute diarrhea, is safe and effective, but it can cause other gastrointestinal adverse effects, such as constipation and abdominal cramps.[10]

Wood creosote is an herbal medicine that has been used as an antidiarrheal and antispasmodic agent in Japan and in other countries in the Pacific Rim under the brand name Seirogan (currently marketed by Taiko Pharmaceutical Company, Ltd., Osaka, Japan) for the past century. Wood creosote also has been used for medicinal purposes in Europe since the early 1800s.[11] Approximately 1.16 billion Seirogan tablets (wood creosote 45 mg/tablet) are sold worldwide each year, representing approximately 42.8 million patient treatment courses, estimated based on a 3-day treatment course of three tablets/dose taken 3 times/day (27 tablets/course). Seirogan recently has been marketed in the United States as an over-the-counter herbal product and is approved in Canada as an over-the-counter drug (drug identification number 02243423). Total Seirogan sales in North America account for less than 5% of worldwide sales at the present time. Seirogan typically is taken for up to 3 days as an acute antidiarrheal agent, and patients typically report relief of symptoms after one to two doses. There are no known drug-drug interactions or contraindications with Seirogan.

Wood creosote (CAS-8021-39-4), also referred to as medicinal creosote, is a mixture of simple phenolic compounds, including guaiacol, creosol, o-cresol, and 4-ethylguaiacol as major active components,[12] and is chemically distinct from, and should not be confused with, coal tar creosote, a known carcinogen. A long-term safety study in rats documented a lack of oncogenicity for wood creosote.[13]

Wood creosote has been shown to suppress gastrointestinal motility, with a consequent increase in intestinal transit time and increase in net fluid absorption from the intestine in in vivo and ex vivo animal models.[14-16] Clinical experience in humans indicates that wood creosote relieves acute diarrhea, often within one or two doses; suppresses intestinal hypermotility; and produces an antispasmodic effect in the setting of acute diarrhea. Also, decreased stool volume and frequency have been observed by clinicians in anecdotal reports.

Despite many years of postmarketing experience with Seirogan, in Asia in particular, rigorously controlled clinical studies evaluating the safety and efficacy of wood creosote are lacking. The objective of our study was to assess the safety, tolerability, and pharmacokinetics of escalating single doses of wood creosote in a rigorous manner with a double-blind, placebo-controlled study design. The Seirogan tablet formulation marketed worldwide contains wood creosote plus other herbal ingredients, including gambir, philodendron bark, glycyrrhiza, and citrus unshiu peel. The formulation evaluated in this study is a sugar-coated tablet that contains wood creosote 45 mg as the principal active ingredient without the other herbal components.

Section 1 of 5 Tomoo Kuge, Ph.D., Takashi Shibata, M.D., Ph.D., and Michael S. Willett, Pharm.D.

From Taiko Pharmaceutical Company, Ltd., Osaka, Japan (Drs. Kuge and Shibata); the Department of Physiology, Nagoya University Graduate School of Medicine, Nagoya, Japan (Dr. Kuge); and Advanced Biomedical Research, Inc., Pennington, New Jersey (Dr. Willett).
Pharmacotherapy 23(11):1391-1400, 2003. © 2003 Pharmacotherapy Publications
This is a part of article Wood Creosote, the Principal Active Ingredient of Seirogan, an Herbal Antidiarrheal Medicine: A Single-Dose, Dose-Escalation Safety and Pharmacokinetic Study Taken from "Atropine Sulfate" Information Blog

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