The results of this study indicate that probiotics can reduce this harmful proteolytic fermentation in the gut and the formation of toxic metabolites.

Am J Physiol Gastrointest Liver Physiol 292: G358-G368, 2007. First published September 21, 2006

The authors conclude

“these results strongly suggest that Lactobacillus fermentum alpha-galactosidase is able to partially alleviate a galactosidase deficiency in rats. This offers interesting perspectives in various applications in which lactic acid bacteria could be used as a vector for delivery of digestive enzymes in man and animals.”

BMC Microbiol. 2008 Jan 29;8:22.

Dietary curcumin, capsaicin, piperine and ginger prominantly enhanced intestinal lipase activity and also the disaccharidases sucrase and maltase. Dietary cumin, fenugreek, mustard and asafoetida brought about decreases in the levels of phosphatases and sucrase. The positive influences of a good number of spices on these terminal enzymes of digestive process could be an additional feature of spices that are generally well recognized to stimulate digestion.

The animals were fed the following diets for 8 weeks: control, curcumin (0.5%), capsaicin (15mg%), piperine (20mg%), ginger (50mg%), cumin (1.25%), fenugreek (2%), mustard (250mg%) and asafoetida (250mg%).

International Journal of Food Sciences and Nutrition, Volume 47, Issue 1 January 1996 , pages 55 – 59
Influence of dietary spices or their active principles on digestive enzymes of small intestinal mucosa in rats
Authors: Kalpana Platel ; K. Srinivasan
Affiliation: Department of Biochemistry & Nutrition, Central Food Technological Research Institute, Mysore, India

Prokinetic therapy for gastroesophageal reflux disease. (includes patient information sheet)

From:
American Family Physician
Date:
September 1, 1995
Author:
Robinson, Malcolm

Prokinetic drugs theoretically have the ability to correct the pathophysiologic abnormalities of gastrointestinal motility that lead to gastroesophageal reflux disease. However, the prokinetic agents bethanechol and metoclopramide have been associated with central nervous system and other side effects, as well as uncertain efficacy. In addition, erythromycin seems unsuitable for use as an oral prokinetic agent. A recently introduced prokinetic agent, cisapride, has a minimum incidence of side effects and is effective in the treatment of reflux symptoms, but trials in the United States have not confirmed the symptomatic improvement or healing of erosive esophagitis that has been demonstrated in studies abroad. An expanded role may unfold for cisapride and additional new prokinetic drugs as primary therapy for reflux in some patients, as adjunctive treatment with an antisecretory agent, or as maintenance treatment for a subset of patients with gastroesophageal reflux. Therapy tailored to individual pathophysiology is appropriate and may offer cost savings and improved clinical outcome.

The recent introduction of cisapride (Propulsid), a gastrointestinal prokinetic drug approved by the U.S. Food and Drug Administration for the relief of nocturnal heartburn, has generated renewed interest in the role of this class of agents in the treatment of gastroesophageal reflux disease. Before the availability of cisapride, prokinetic agents were seldom used as primary therapy for patients with gastrointestinal reflux. This article reviews the reasons for the increase in usage, evaluates the efficacy and safety of prokinetic drugs and reassesses their role in the treatment of gastrointestinal reflux disease.

Excessive exposure of the esophageal mucosa to injurious gastric contents causes the diverse symptoms and complications of gastroesophageal reflux disease. Although acid and pepsin are important direct causes of mucosal damage, many factors may determine the duration and frequency of esophageal acid contact. It is becoming increasingly clear that gastroesophageal reflux, a multifactorial disease, is primarily a motility disorder.(1)(2) The lower esophageal sphincter–the smooth muscle that is the chief barrier against reflux–may relax inappropriately or exhibit low basal pressure. Absent or diminished peristaltic contractions can impair the clearance of esophageal acid, while delayed gastric emptying can increase gastric volume and impair the tone of the lower esophageal sphincter.

The rationale for prokinetic therapy is to correct some or all of the defects in gastrointestinal neuromuscular activity that promote reflux by affecting neurotransmitter release at the level of the central or enteric nervous system. The mechanisms by which prokinetic drugs exert their effects on gastrointestinal smooth muscle are not completely understood, but each agent seems to have a unique pharmacologic impact that accounts for variations in clinical efficacy and safety.

Bethanechol

Bethanechol (Myotonachol, Urecholine), a cholinergic agonist, increases pressure of the lower esophageal sphincter and the amplitude of esophageal peristaltic contractions, but it may not coordinate gastrointestinal motility or gastric emptying.(3) Prolonged pH monitoring in patients taking bethanechol indicates improvement in esophageal acid exposure. Subcutaneous administration of bethanechol increases salivary flow, which would be expected to improve esophageal acid clearance, although oral administration does not appear to have the same effect.

In a few small clinical trials, bethanechol in dosages of 25 mg four times daily for eight weeks variably but significantly improved symptoms of gastrointestinal reflux when compared with placebo.(4)(5) In a six-week study requiring intensive adjunctive use of antacids, bethanechol, 25 mg four times daily, and cimetidine (Tagamet), 300 mg four times daily, produced comparable rates of symptomatic improvement and complete healing of esophagitis with a severity of grade 2 or higher.(6) Nevertheless, clinical experience suggests a 10 to 15 percent incidence of abdominal cramping, blurred vision, fatigue and other bothersome cholinergic symptoms.(7) Despite scattered reports supporting its use, bethanechol has not been widely accepted for the treatment of reflux disease.

Metoclopramide

Metoclopramide (Reglan) stimulates gastrointestinal smooth muscle by a number of mechanisms. In addition to inhibiting dopamine receptors, this para-aminobenzoic acid derivative may enhance the release of acetylcholine from intramural nerve cells.(3)(8) Metoclopramide produces dose-dependent increases in lower esophageal sphincter pressure, accelerates gastric emptying and coordinates gastrointestinal motor activity. It does not appear to affect esophageal contractions.

In two placebo-controlled trials, metoclopramide, 10 mg four times daily, improved reflux symptoms significantly.(9)(10) In another study, an eight-week trial of metoclopramide, 10 mg four times a day, in combination with cimetidine, 1,200 mg per day, was more effective in healing esophagitis than cimetidine alone.(11) However, other reports suggest that endoscopic healing is not improved with metoclopramide, either in combination with cimetidine(12) or in single-agent regimens, compared with placebo or cimetidine.(9)

Metoclopramide inhibits dopamine receptors in the central nervous system and peripherally. Hyperprolactinemia related to metoclopramide therapy leads to galactorrhea in some patients and can disrupt normal menstrual function. Antidopaminergic side effects include neurologic and psychotropic reactions (such as lethargy) and extrapyramidal motor effects similar to those commonly associated with phenothiazines (including akathisia, acute dystonia and potentially irreversible tardive dyskinesia).(13) Such adverse effects, which occur in as many as 20 percent of patients,(8) have tempered physicians’ enthusiasm for long-term use of metoclopramide.

Cisapride

Cisapride stimulates the release of acetylcholine by specific enteric nerves or may directly trigger neuromuscular activity in gastrointestinal smooth muscle. This benzamide compound increases lower esophageal sphincter pressure in patients with hypotensive sphincter tone, strengthens the amplitude of esophageal peristaltic contractions, enhances gastric emptying and improves antroduodenal coordination.(14)(15)(16)

Multicenter randomized studies in the United States and Canada have evaluated cisapride, in a dosage of 10 mg or 20 mg four times daily before meals and at bedtime, in patients with moderate to severe heartburn and endoscopically confirmed esophagitis.(17)(18)(19) In one trial,(17) cisapride consistently relieved symptoms of reflux, with the 10-mg regimen significantly decreasing nighttime heartburn by the fourth week. The 20-mg regimen produced significant symptomatic improvement throughout the 12 weeks of the study. Antacid consumption was significantly reduced in patients receiving the higher dose. At 12 weeks, the 20-mg dose significantly improved esophagitis, but the 10-mg dose did not. In a similar trial,(18) 10 mg of cisapride taken four times daily was highly effective in the treatment of heartburn. However, none of the cisapride trials performed in the United States specifically selected patients likely to benefit from prokinetic therapy, such as those with documented motility defects. The reliance on studies of erosive esophagitis may have been inappropriate with cisapride monotherapy, which appears to perform best in nonerosive disease.

The effectiveness of cisapride was recently confirmed in a study involving 48 symptomatic patients with multigrade esophagitis.(14) Compared with placebo, 10 mg of cisapride taken four times a day for 12 weeks significantly decreased dyspeptic symptoms (heartburn, belching and regurgitation). In patients receiving cisapride, antacid consumption decreased and esophagitis scores improved, but not significantly. These results are less dramatic than results described in earlier European reports that supported the effectiveness of cisapride in the healing of esophagitis.(8)(20)(21)

Comparison with other prokinetic agents has been limited to a report of 30 patients receiving subcutaneous administration of cisapride, 10 mg three times a day, or metoclopramide, 10 mg three times a day.(22) At four weeks, both treatment with metoclopramide and treatment with cisapride significantly improved symptoms. No adverse effects were reported with cisapride, while central nervous system reactions in three patients resulted in discontinuation of metoclopramide.

In a European trial including patients with mild to moderate erosive esophagitis, combination therapy with cimetidine, 1 g per day, and cisapride, 10 mg four times per day, produced greater symptomatic and endoscopic improvements than the histamine [H.sub.2] antagonist administered alone.(23) Another trial showed high symptomatic responses to both ranitidine (Zantac), 150 mg twice a day, and a combined regimen of ranitidine, 150 mg twice a day, and cisapride, 10 mg twice a day. Compared with ranitidine alone, the combination therapy resulted in greater endoscopic improvement at 12 weeks in patients with more severe esophagitis.(24) A European study reported significantly better healing of esophagitis (but not significantly better symptom relief) with the combination of ranitidine, 150 mg twice a day, and cisapride, 10 mg three times a day, than with either agent as monotherapy.(25)

Multicenter European studies of patients with esophagitis that healed acutely with an antisecretory regimen suggest that cisapride can maintain symptomatic and mucosal remission with once- or twice-daily regimens using half the acute therapeutic dose.(26)(27) Twelve-month relapse rates were significantly reduced in patients with mild erosive esophagitis who received cisapride.(26)

Cisapride appears to be safe and well tolerated. The overall incidence of adverse events associated with cisapride therapy does not differ significantly from the incidence with placebo (13.7 percent versus 11.2 percent, respectively).(28) Notably absent are the central nervous system side effects and high prolactin levels associated with metoclopramide therapy.

Investigational Prokinetic Agents

DOMPERIDONE

Like metoclopramide, domperidone (Motilium) blocks dopamine receptors. However, this benzimidazole derivative is primarily a peripheral dopamine antagonist and does not easily or completely cross the blood-brain barrier. It is not yet available in the United States, but approval is believed to be pending. Oral domperidone at clinical doses produces variable effects on lower esophageal sphincter pressure and esophageal peristalsis, but does enhance gastric emptying in a dose-dependent manner.(8) Many clinicians believe that domperidone is particularly useful in the control of nausea.

Results of treatment with domperidone in regimens of 20 mg three or four times a day have been equivocal, with a few reports of symptomatic improvement and healing of esophagitis. Some comparative trials have shown similar efficacy between domperidone and [H.sub.2] antagonists (famotidine [Pepcid] or ranitidine). The combination of domperidone plus an antisecretory drug, however, was not more effective than treatment with either agent alone.(29)(30) Domperidone may work synergistically with cisapride.

Domperidone is associated with few significant side effects and is relatively free of extrapyramidal and other central nervous system side effects. Hyperprolactinemia occurs in about 10 to 15 percent of patients, resulting in breast enlargement, galactorrhea and amenorrhea.

ERYTHROMYCIN

The macrolide antimicrobial erythromycin can stimulate gastrointestinal muscle activity. Its mechanism of activity is not known, but it appears either to be a motilin agonist or to act directly on cholinergic nerve cells. Erythromycin, 250 mg three times a day administered orally, increases postprandial esophageal sphincter pressure and strikingly improves gastric emptying, but shows no effect on esophageal peristalsis.(8)

In patients with gastroesophageal reflux, use of oral erythromycin has led to variable results.(31) Limiting factors include a significant incidence of side effects (including nausea, vomiting and abdominal cramping), the potential for drug interactions, concerns regarding undesired effects on bacterial flora and development of drug tolerance.

Reassessing the Role of Prokinetic Agents

Bethanechol and metoclopramide may relieve mild symptoms of gastroesophageal reflux, but these compounds have inconsistently healed esophagitis. The absence of clear-cut efficacy, plus the potential for central nervous system side effects and other serious adverse reactions, has presented obstacles to greater use of these prokinetic agents. The efficacy of cisapride in healing esophagitis also has not been uniformly demonstrated. Nevertheless, this agent may play a role in initial reflux therapy, in adjunctive treatment with an antisecretory agent and potentially in maintenance treatment.

Given their extensive clinical use and record of efficacy and long-term safety,(32) [H.sub.2]-receptor antagonists are often considered the mainstay of antireflux therapy and as initial agents of choice in patients with moderate to severe, persistent reflux symptoms and/or complications (Table 1). Patients should be counseled to adopt conservative treatment measures, such as elevation of the head of the bed and avoidance of foods and medications that adversely affect lower esophageal sphincter pressure (Table 2).

TABLE 1 Pharmacologic Treatment of Gastroesophageal Reflux Disease(*)

Initial empiric prescription drug therapy

[H.sub.2]-receptor antagonist at standard doses

Cimetidine (Tagamet), up to 800 mg 2 times a day or 400 mg 4 times a day

Famotidine (Pepcid), 20 mg 2 times a day

Nizatidine (Axid), 150 mg 2 times a day

Ranitidine (Zantac), 150 mg 2 times a day

Possible use of prokinetic agent (e.g., cisapride [Propulsid], 10 to 20 mg 4 times a day)

Aggressive medical therapy for severe or refractory disease

Famotidine, nizatidine or ranitidine at double the dosing frequency using the standard dose or more

Combination therapy of [H.sub.2] antagonist and prokinetic agent

Cisapride, 10 to 20 mg 4 times a day before meals and at bedtime

Metoclopramide (Reglan), up to 10 mg or 15 mg 4 times a day

Bethanechol (Urecholine), up to 25 mg 4 times a day

Domperidone (Motilium), [dagger] up to 20 mg 4 times a day

Proton pump inhibitor

Omeprazole (Prilosec), 20 mg every morning or 2 times a day

Lansoprazole (Prevacid), 30 mg every day

Potential next step in aggressive medical therapy

Combination therapy of proton pump inhibitor and prokinetic agent

(*)Excluding use of antacids.

([dagger])Not yet available in the United States.

TABLE 2 Foods and Drugs That Can Decrease Lower Esophageal Sphincter

Pressure

Foods

Carminatives, such as peppermint and spearmint

Chocolate

Foods with high fat content

Onions

Drugs

Alpha-adrenergic antagonists

[Beta.sub.2]-adrenergic agonists

Calcium channel blockers

Diazepam (Valium)

Meperidine (Demerol)

Progesterone-containing oral contraceptives

Theophylline

Most patients will obtain symptom relief and endoscopic healing with standard-dose [H.sub.2]-antagonist regimens. In those who remain symptomatic, endoscopy is advisable since the presence of extensive erosive esophagitis or Barrett’s esophagus along with refractory symptoms may be an indication for acceleration of therapy. If endoscopic results are normal, possibly including endoscopic biopsies, the diagnosis of gastroesophageal reflux disease should be reconsidered and additional tests (such as pH monitoring and motility studies) should be ordered to assess the basis of existing symptoms. If endoscopic results reveal erosive esophagitis, the clinician might proceed to more frequent dosing of [H.sub.2] antagonists or may consider the addition of a prokinetic drug or possibly the use of a proton pump blocker (Table 1).

For patients who are unresponsive to standard-dose [H.sub.2]-antagonist therapy and who do not improve sufficiently with omeprazole, 20 mg per day, a 20-mg twice-daily regimen might be considered. Unfortunately, once proton-pump blockers are started, it may never be possible to return to less potent therapy.(33) Subsequently, physiologic studies may be undertaken in patients truly refractory even to high-dose omeprazole; results might support the addition of a prokinetic agent to subtherapeutic proton pump inhibitor therapy.

Combination antisecretory and prokinetic therapy may prove synergistic in patients previously determined by esophageal manometry or nuclear imaging of gastric emptying to have motility abnormalities. Studies are needed to test the hypothesis that tailoring therapy to abnormal physiology would improve results, although this approach certainly seems logical.

A sampling of weekly costs of different antireflux regimens is provided in Table 3. Although not a comprehensive comparison, it does suggest that at conventional doses, proton pump inhibitors tend to be more expensive than either [H.sub.2] antagonists or prokinetic agents. It should be emphasized, however, that considerations other than relative cost, in particular proven safety, should be weighed in the selection of appropriate therapy. Additionally, standard [H.sub.2]-antagonist doses are based on ulcerhealing regimens and may not reflect the effective regimen for an individual patient.

TABLE 3 Costs of Standard Dosage Prescription Antireflux Regimens

Daily standard dosage regimen Weekly cost of therapy(*)
Selected [H.sub.2]-receptor antagonists
Cimetidine (Tagamet)[dagger], 400 mg 2 $21 (18-19 for generic)
times a day
Famotidine (Pepcid)[dagger], 20 mg 2 21
times a day
Ranitidine (Zantac), 150 mg 2 times a 23
day
Selected prokinetic agents
Metoclopramide (Reglan), 10 mg 4 times 17 (3-5 for generic)
a day
Cisapride (Propulsid), 10 mg 4 times a 17
day
Proton pump inhibitor
Omeprazole (Prilosec), 20 mg every 25
morning
Lansoprazole (Prevacid), 30 mg every 23
morning

(*)Estimated cost to the pharmacist based on average wholesale prices of 30 tables, rounded to the nearest dollar, in Red book. Montvale, N.J.: Medical Economics Data, 1995. Cost to the patient will be higher, depending on prescription filling fee.

([dagger])Cimetidine and famotidine recently have been approved for over-the-counter use in smaller dosage strengths. These over-the-counter preparations will be less expensive than the prescription forms.

A patient information handout on gastroesophageal reflux disease is provided on page 965.

REFERENCES

(1.)Castell DO. Rationale for high-dose [H.sub.2]-receptor blockade in the treatment of gastro-oesophageal reflux disease. Aliment Pharmacol Ther 1991; 5(Suppl 1):59-67.

(2.)Quigley EM. Gastroesophageal reflux disease: the roles of motility in pathophysiology and therapy [Editorial]. Am J Gastroenterol 1993; 88:1649-51.

(3.)Reynolds JC. Prokinetic agents: a key in the future of gastroenterology. Gastroenterol Clin North Am 1989; 18:437-57.

(4.)Saco LS, Orlando RC, Levinson SL, Bozymski EM, Jones JD, Frakes JT. Double-blind controlled trial of bethanechol and antacid versus placebo and antacid in the treatment of erosive esophagitis. Gastroenterology 1982; 82:1369-73.

(5.)Farrell RL, Roling GT, Castell DO. Cholinergic therapy of chronic heartburn. Ann Intern Med 1974; 8:573-6.

(6.)Thanik K, Chey WY, Shak A, Hamilton D, Nadelson N. Bethanechol or cimetidine in the treatment of symptomatic reflux esophagitis: a double-blind control study. Arch Intern Med 1982; 142:1479-81.

(7.)Thanik K, Chey WY, Shak A, Gutierrez JG. Reflux esophagitis. Ann Intern Med 1980; 93:805-8.

(8.)Ramirez B, Richter JE. Promotility drugs in the treatment of gastro-oesophageal reflux disease. Aliment Pharmacol Ther 1993; 7:5-20.

(9.)Bright-Asare P, El-Bassoussi M. Cimetidine, metoclopramide, or placebo in the treatment of symptomatic gastroesophageal reflux. J Clin Gastroenterol 1980; 2:149-56.

(10.)McCallum RW, Ippoliti AF, Cooney C, Sturdevant RA. A controlled trial of metoclopramide in symptomatic gastroesophageal reflux. N Engl J Med 1977; 296:354-7.

(11.)Lieberman DA, Keeffe EB. Treatment of severe reflux esophagitis with cimetidine and metoclopramide. Ann Intern Med 1986; 104:21-6.

(12.)Temple JG, Bradby GV, O’Connor FO, Panesar KS, Mulligan TO, Robinson TJ, et al. Cimetidine and metoclopramide in oesophageal reflux disease. Br Med J [Clin Res] 1983; 286:1863-4.

(13.)Ganzini L, Casey DE, Hoffman WF, McCall AL. The prevalence of metoclopramide-induced tardive dyskinesia and acute extrapyramidal movement disorders. Arch Intern Med 1993; 153:1469-75.

(14.)Robertson CS, Evans DF, Ledingham SJ, Atkinson M. Cisapride in the treatment of gastro-oesophageal reflux disease. Aliment Pharmacol Ther 1993; 7:181-90.

(15.)Gilbert RJ, Dodds WJ, Kahrilas PJ, Hogan WJ, Lipman S. Effect of cisapride, a new prokinetic agent, on esophageal motor function. Dig Dis Sci 1987; 32:1331-6.

(16.)Maddern GJ, Jamieson GG, Myers JC, Collins PJ. Effect of cisapride on delayed gastric emptying in gastro-oesophageal reflux disease. Gut 1991; 32:470-4.

(17.)Faruqui S, Sigmund C, Smith R, Fitch D, Mellow M, Orr W. Cisapride in the treatment of GERD: a double-blind, placebo-controlled multicenter dose-response trial [Abstract]. Gastroenterology 1992; 102(2 Pt 2):A66.

(18.)DeMicco M, Berenson M, Wu W, Castell D, Lanza F, Robinson M, et al. Cisapride in the treatment of GERD: a double-blind, placebo-controlled multicenter dose-response trial [Abstract]. Gastroenterology 1992; 102(2 Pt 2):A59.

(19.)Dodds W, Champion M, Orr W, Robinson M, Spechler S, Gilmore P, et al. Oral cisapride in GERD. Gastroenterology 1989; 96(5 Pt 2):A126.

(20.)McCallum RW. Cisapride: a new class of prokinetic agent. Am J Gastroenterol 1991; 86:135-49.

(21.)Galmiche JP, Fraitag B, Filoche B, Evreux M, Vitaux J, Zeitoun P, et al. Double-blind comparison of cisapride and cimetidine in treatment of reflux esophagitis. Dig Dis Sci 1990; 35:649-55.

(22.)Manousos ON, Mandidis A. Treatment of reflux symptoms in oesophagitis patients. Curr Ther Res Clin Exp 1987; 42:807-13.

(23.)Galmiche JP, Brandstatter G, Evreux M, Hentschel E, Kerstan E, Kratochvil P, et al. Combined therapy with cisapride and cimetidine in severe reflux oesophagitis. Gut 1988; 29:675-81.

(24.)Wienbeck M. The Ranpride Study Group. Does a motor stimulating agent improve the therapeutic effect of [H.sub.2]-blockers in reflux esophagitis? Gastroenterology 1986; 90(5 Pt 2):A1691.

(25.)Duvas A, Papalagara G, Ioarinou A, et al. Comparison of cisapride with ranitidine in the treatment of reflux esophagitis. II. United European Gastroenterology Week, Barcelona. July 19-24, 1993; Abstract no. 170.

(26.)Blum AL, Adami B, Bouzo MH, Brandstatter G, Fumagalli I, Galmiche JP, et al. Effect of cisapride on relapse of esophagitis. A multinational, placebo-controlled trial in patients healed with an antisecretory drug. Dig Dis Sci 1993; 38:551-60.

(27.)Tytgat GN, Anker Hansen OJ, Carling L, de Groot GH, Geldof H, Glise H, et al. Effect of cisapride on relapse of reflux oesophagitis, healed with an antisecretory drug. Scand J Gastroenterol 1992; 27:175-83.

(28.)Verlinden M, Reyntijens A, Schuermans V. Safety profile of cisapride. In: Johnson AG, Lux G, eds. Progress in the treatment of gastrointestinal motility disorders. The role of cisapride. New York: Excerpta Medica, 1988:30-6.

(29.)Guslandi M, Dell’Oca M, Molteni V, Romano R, Passaretti S, Ballarin E. Famotidine versus domperidone, versus a combination of both in the treatment of reflux esophagitis: interim report [Abstract]. Gastroenterology 1989; 96(5 Pt 2):A191.

(30.)Masci E, Testoni PA, Passretti S, Guslandi M, Tittobello A. Comparison of ranitidine, domperidone maleate and ranitidine + domperidone maleate in the short-term treatment of reflux oesophagitis. Drugs Exp Clin Res 1985; 11:687-92.

(31.)Harrison ME, Ruzkowski CJ, Young MF, Sanowski RA. Erythromycin improves gastric emptying and esophageal motility without affecting gastroesophageal reflux [Abstract]. Gastroenterology 1991; 100(2 Pt 2):A80.

(32.)Feldman M, Burton ME. [Histamine.sub.2]-receptor antagonists. Standard therapy for acid-peptic diseases. N Engl J Med 1990; 323:1672-80,1749-55.

(33.)Antonson CW, Robinson MG, Hawkins TM, McIntosh DL, Campbell DR. High doses of histamine antagonists do not prevent relapses of peptic esophagitis following therapy with a proton pump inhibitor [Abstract]. Gastroenterology 1990; 98(5 Pt 2):A16.

RELATED ARTICLE: What You Can Do About Heartburn

What is heartburn?

Heartburn is a burning, painful feeling that occurs behind your breastbone. Despite its name, heartburn involves your esophagus (swallowing tube), not your heart. You may have heartburn if you generally notice the pain one or two hours after you eat, if the pain is worse when you lie down or bend over, or if the burning goes away after you take antacids or drink some liquids.

What causes heartburn?

Heartburn is caused by acid and other irritating substances rising up, or refluxing, from your stomach into your esophagus. This can damage the esophagus.

In healthy people, stomach acid is usually prevented from getting into the esophagus by a tightening of the muscle around the place where the esophagus joins the stomach. This muscle is called the lower esophageal sphincter (LES). Usually, any acid that rises up into the esophagus goes back down into the stomach quickly. With heartburn, the LES muscle is not working at full strength. Sometimes, this can lead to inflammation or swelling of the membranes that line the lower esophagus. This is called reflux esophagitis.

If your doctor suspects that you have reflux esophagitis, he or she may want to do a test called an endoscopy. During an endoscopy, your doctor looks at your esophagus through a tube with a light at the end. Reflux esophagitis can cause permanent narrowing of the esophagus, known as stricture. It can also lead to bleeding.

What can I do to stop having heartburn?

The goal of treatment is to keep stomach acid out of the esophagus, which allows the damaged esophagus to heal and prevents further damage.

The list on the next page gives tips on preventing stomach acid from rising up into your esophagus. You may not get relief of your symptoms right away, but don’t give up. For severe heartburn, changes in lifestyle may need to be permanent. You may need to continue these changes even after your symptoms improve so that your symptoms don’t return.

Tips for Getting Relief from Heartburn

*Use bed blocks

Raise the head of your bed 4 to 6 inches with wood blocks or bricks. Using extra pillows is not as effective. Placing a foam wedge beneath the upper half of your body may also work.

*Take antacids

Antacids can be taken as often as needed for heartburn. Tablet antacids may be more effective than liquid forms.

*Eat smaller meals

Don’t overfill your stomach.

*Avoid foods that can cause your symptoms

Foods to avoid include spicy and fatty foods, tomato and citrus juices (such as grapefruit and orange juices), chocolate, mint, coffee and alcoholic beverages.

*Do not lie down for 4 hours after eating

Eliminate bedtime or evening snacks. Allow gravity to help move food down past the LES to keep acid out of the esophagus.

*Stop smoking

Talk to your doctor about quitting. If you cannot stop, decrease the number of cigarettes you smoke.

*Maintain your ideal weight

Excess weight increases the amount of pressure constantly placed on your stomach, making reflux worse. Even a small amount of weight loss may help.

*Avoid tight clothing

Avoid wearing tight belts and pants or girdles.

What else can I do?

Your doctor may prescribe a medicine for you to take. Some medicines decrease the amount of stomach acid your body makes, while others make it easier for food to go down the esophagus and empty from the stomach. Every medicine does not work for every person. The medicine should be taken just as prescribed by your doctor. You and your doctor can work together to find the treatment that will help you the most.

This information provides a general overview on heartburn and may not apply to everyone. Talk to your family doctor to find out if this information applies to you and to get more information on this subject.

The authors note that peppermint leaf and peppermint oil have both a long history of use and recent evidence supporting its benefits.

From:

American Family Physician

Date:

April 1, 2007

Author:

Chaudhary, Sapna; Kligler, Benjamin

Peppermint leaf and peppermint oil have a long history of use for digestive disorders. Recent evidence suggests that enteric-coated peppermint oil may be effective in relieving some of the symptoms of irritable bowel syndrome. A combination product including peppermint oil and caraway oil seems to be moderately effective in the treatment of non-ulcer dyspepsia. Topical application of peppermint oil may be effective in the treatment of tension headache. Because of its relaxing effects on smooth muscle, peppermint oil given via enema has been modestly effective for relief of colonic spasm in patients undergoing barium enemas. Peppermint oil is well tolerated at the commonly recommended dosage, but it may cause significant adverse effects at higher dosages.

**********

Peppermint (Mentha x piperita) is a perennial flowering member of the mint family, which grows widely in Europe and North America. The medicinal use of peppermint and other mint plants probably dates back to the herbal pharmacopoeia of ancient Greece, where peppermint leaf traditionally was used internally as a digestive aid and for management of gallbladder disease; it also was used in inhaled form for upper respiratory symptoms and cough. Peppermint oil, which is extracted from the stem, leaves, and flowers of the plant, has become popular as a treatment for a variety of conditions, including irritable bowel syndrome (IBS), headache, and non-ulcer dyspepsia (Table 1). Extracts of peppermint are widely used as flavoring (rather than for their medicinal properties) in many products, including toothpastes, mouthwashes, and over-the-counter gastrointestinal (GI) products. Menthol, which is extracted from peppermint, is a common ingredient in over-the-counter topical products used for respiratory congestion, headache, and muscle pain.

Pharmacology

The active constituents in peppermint oil, which is prepared through distillation of the ground parts of the peppermint plant, include menthol, menthone, cineol, and several other volatile oils. (1) In vitro research shows peppermint oil to be effective in relaxing GI smooth muscle, possibly through an antagonistic effect on calcium channels in the gut. (2) Peppermint oil also has been shown to relax the lower esophageal sphincter, which can result in gastroesophageal reflux. (3) This finding has led to the popularity of enteric-coated peppermint formulations, which bypass the upper GI tract unmetabolized, thereby facilitating its effect in the lower GI tract without effects in the upper tract.

Uses and Effectiveness

Peppermint oil has been studied most extensively in the treatment of IBS. Combinations of peppermint oil and other botanical medicines also have been studied as treatments for non-ulcer dyspepsia. Applied topically, the oil also has been used as a treatment for tension headache.

IBS

Because of the potential for peppermint oil to relax the lower esophageal sphincter and result in heartburn symptoms, most trials have tested enteric-coated preparations. Although results of studies on the use of this herb for the treatment of IBS symptoms have been mixed, (4,5) there seems to be a trend indicating mild effectiveness in the reduction of some IBS symptoms, especially flatulence and abdominal pain and distension. A metaanalysis including 175 patients in five trials found a statistically significant benefit of peppermint oil compared with placebo in the symptomatic treatment of IBS. (6) However, the quality of the included studies was variable, and most did not apply uniform criteria for the diagnosis of IBS.

Since the meta-analysis was performed, two additional trials–one in adults (n = 110) (7) and one in a pediatric population (n = 42) (8)–have shown a modest but statistically significant benefit. In the adult trial, 79 percent of treated patients experienced a reduction in the severity of abdominal pain, compared with 43 percent of control patients; 83 percent had less abdominal distension, compared with 29 percent of control patients; 83 percent had reduced stool frequency, compared with 32 percent of control patients; and 79 percent experienced less flatulence, compared with 22 percent of control patients (P < .05). (7) The pediatric study (in children eight to 17 years of age) found a significant reduction in pain but no significant change in other symptoms; these findings are particularly important given the lack of effective treatment options for children with IBS. (8) After two weeks, 76 percent of patients receiving enteric-coated peppermint reported a reduction in the severity of pain, compared with only 19 percent of control patients. (8) No studies have been done in children younger than eight years.

A more recent systematic review, which included 128 patients in four trials, found peppermint oil to be beneficial in reducing symptoms of IBS when compared with placebo (odds ratio = 2.7; 95% confidence interval, 1.56 to 4.76). (9) However, this analysis showed significant heterogeneity, which limits the interpretability of the results.

REDUCTION OF COLONIC SPASM DURING GI PROCEDURES

As a consequence of its relaxing properties on smooth muscle, peppermint oil given via enema has been examined in two trials as a means to reduce symptoms of gastrointestinal spasm during administration of barium enema and possibly during colonoscopy. (10,11) In a randomized controlled trial (RCT) of 383 patients undergoing barium enemas, 37 to 41 percent of those who received peppermint oil experienced a non-spasm examination, compared with 13.4 percent of those who received placebo (P < .001). (10) In an RCT of 141 patients undergoing barium enemas, no residual spasm was evident in 60 percent of the treated group, compared with 35 percent of the control group (P < .001). (11)

NON-ULCER DYSPEPSIA

A combination of enteric-coated peppermint oil and caraway oil has been shown in several clinical trials to reduce symptoms of non-ulcer dyspepsia (e.g., fullness, bloating, gastrointestinal spasm), (12,13) but the specific preparation used in these trials is not available in the U.S. A meta-analysis of several trials of a preparation containing peppermint and caraway oils plus other herbal extracts (Iberogast) found it to be effective in the treatment of functional dyspepsia. (14) This benefit may be the result of the preparation’s relaxing effect on the lower esophageal sphincter, with concomitant equalization of pressure between stomach and esophagus and reduced sensation of bloating and abdominal pressure. However, this effect theoretically could result in reflux symptoms in patients predisposed to gastroesophageal reflux. Because multiple herbs were used in these trials, it is difficult to draw definitive conclusions about the specific effects of peppermint in this condition.

TENSION HEADACHE

Two trials have shown that topical application of peppermint oil is effective in reducing symptoms of tension headache. (15,16) In one RCT, 32 patients were tested using a variety of topical herbal preparations. (15) Compared with persons who received placebo, there was a significant analgesic effect in patients who applied a peppermint and ethanol preparation. A second RCT that compared the effectiveness of topical peppermint oil and acetaminophen on 164 headaches in 41 patients found that a 10% peppermint oil preparation significantly reduced headache intensity after 15 minutes. (16) There was no significant difference in effectiveness between peppermint oil and acetaminophen, and no adverse effects were reported.

Contraindications, Adverse Effects, and Interactions

Like many essential oils, peppermint oil can be toxic and even lethal at excessive dosages; it has been associated with interstitial nephritis and acute renal failure. (17) It may have a choleretic effect and is contraindicated in patients with cholelithiasis or cholecystitis. Peppermint oil is relatively contraindicated in patients with hiatal hernia or significant gastroesophageal reflux disease, because its effect on the lower esophageal sphincter can lead to exacerbation of symptoms.

Peppermint oil has been used to trigger menstruation and should be avoided during pregnancy. There are insufficient data to assess its safety during lactation. Peppermint oil should not be used internally or on or near the face in infants and young children because of its potential to cause bronchospasm, tongue spasms, and, possibly, respiratory arrest. (1) However, the amount of peppermint in over-the-counter medications, topical preparations, and herbal teas is likely safe in pregnant and lactating women and in young children.

Common adverse effects reported in clinical trials include allergic reactions, heartburn, perianal burning, blurred vision, nausea, and vomiting. (6) Preliminary evidence from laboratory studies suggests that peppermint leaf and peppermint oil may inhibit the cytochrome P450 1A2 system, (18) which theoretically could lead to increased serum levels of drugs such as amitriptyline, cyclosporine (Sandimmune), and haloperidol (Haldol) in patients who regularly consume large amounts of peppermint leaf or peppermint oil. However, this interaction has not been proven to occur in humans. Peppermint oil has been reported to raise serum levels of simvastatin (Zocor) and felodipine (Plendil) in at least one case report. (19)

Dosage

The therapeutic dosage range studied in most IBS trials was 0.2 to 0.4 mL of peppermint oil taken three times daily in enteric-coated capsules. The dosage used in the single clinical trial in children was 0.1 mL three times daily for children weighing less than 45 kg (99 lb, 3 oz). (8) The trials for dyspepsia used a dose of 90 mg of peppermint oil in combination with 50 mg of caraway oil in a specific standardized preparation that is not currently available in the United States.

Bottom Line

Although results from clinical trials are mixed, the majority of evidence indicates that enteric-coated peppermint oil may be modestly effective in reducing some of the common symptoms of IBS. In combination with caraway oil, it also may be effective in treating non-ulcer dyspepsia. Limited data show a modest effect at reducing colonic spasm during barium enema. Topical peppermint oil also may be helpful for treatment of tension headache. Peppermint oil should only be used at the recommended doses because significant toxicity can occur at higher doses. Even the recommended medicinal doses of peppermint oil should not be used in infants or very young children, or in women who are pregnant or lactating.

Members of various family medicine departments develop articles for “Complementary and Alternative Medicine.” This is one in a series coordinated by Sumi Sexton, M.D.

REFERENCES

(1.) Blumenthal M. Herbal Medicine: Expanded Commission E Monographs. 1st ed. Newton, Mass.: Integrative Medicine Communications, 2000.

(2.) Hills JM, Aaronson PI. The mechanism of action of peppermint oil on gastrointestinal smooth muscle. An analysis using patch clamp electrophysiology and isolated tissue pharmacology in rabbit and guinea pig. Gastroenterology 1991;101:55-65.

(3.) Brinker FJ. Herb Contraindications and Drug Interactions: With Appendices Addressing Specific Conditions and Medicines. 2nd ed. Sandy, Ore.: Eclectic Medical Publications, 1998.

(4.) Lawson MJ, Knight RE, Tran K, Walker G, Roberts-Thompson A. Failure of enteric-coated peppermint oil in the irritable bowel syndrome: a randomized, double-blind crossover study. J Gastroenterol Hepatol 1988; 3:235-8.

(5.) Nash P, Gould SR, Bernardo DE. Peppermint oil does not relieve the pain of irritable bowel syndrome. Br J Clin Pract 1986;40:292-3.

(6.) Pittler MH, Ernst E. Peppermint oil for irritable bowel syndrome: a critical review and metaanalysis. Am J Gastroenterol 1998;93:1131-5.

(7.) Kline RM, Kline JJ, Di Palma J, Barbero GJ. Enteric-coated, pH-dependent peppermint oil capsules for the treatment of irritable bowel syndrome in children. J Pediatr 2001;138:125-8.

(8.) Liu JH, Chen GH, Yeh HZ, Huang CK, Poon SK. Enteric-coated peppermint-oil capsules in the treatment of irritable bowel syndrome: a prospective, randomized trial. J Gastroenterol 1997;32:765-8.

(9.) Spanier JA, Howden CW, Jones MP. A systematic review of alternative therapies in the irritable bowel syndrome. Arch Intern Med 2003;163:265-74.

(10.) Asao T, Kuwano H, Ide M, Hirayama I, Nakamura JI, Fujita KI, et al. Spasmolytic effect of peppermint oil in barium during double-contrast barium enema compared with Buscopan. Clin Radiol 2003;58:301-5.

(11.) Sparks MJ, O’Sullivan P, Herrington AA, Morcos SK. Does peppermint oil relieve spasm during barium enema? Br J Radiol 1995;68:841-3.

(12.) Holtmann G, Haag S, Adam B, Funk P, Wieland V, Heydenreich CJ. Effects of a fixed combination of peppermint oil and caraway oil on symptoms and quality of life in patients suffering from functional dyspepsia. Phytomedicine 2003;10(suppl 4):56-7.

(13.) Madisch A, Holtmann G, Mayr G, Vinson B, Hotz J. Treatment of functional dyspepsia with a herbal preparation. A double-blind, randomized, placebo-controlled, multicenter trial. Digestion 2004;69:45-52.

(14.) Melzer J, Rosch W, Reichling J, Brignoli R, Saller R. Meta-analysis: phytotherapy of functional dyspepsia with the herbal drug preparation STW 5 (Iberogast). Aliment Pharmacol Ther 2004;20:1279-87.

(15.) Gobel H, Schmidt G, Soyka D. Effect of peppermint and eucalyptus oil preparations on neurophysiological and experimental algesimetric headache parameters. Cephalalgia 1994;14:228-34.

(16.) Gobel H, Fresenius J, Heinze A, Dworschak M, Soyka D. Effectiveness of oleum menthae piperitae and paracetamol in therapy of headache of the tension type [German]. Nervenarzt 1996;67:672-81.

(17.) Schulz V, Hansel R, Tyler VE. Rational Phytotherapy: A Physician’s Guide to Herbal Medicine. 3rd ed. New York, N.Y. :Springer, 1998.

(18.) Dresser GK, Wacher V, Wong S, et al. Evaluation of peppermint oil and ascorbyl palmitate as inhibitors of cytochrome P4503A4 activity in vitro and in vivo. Clin Pharmacol Ther 2002;72:247-55.

(19.) Dresser GK, Wacher V, Ramtoola Z, Cumming K, Bailey DG. Peppermint oil increases the oral bioavailability of felodipine and simvastatin. Amer Soc Clin Pharmacol Ther Ann Meeting, March 24-27, 2002;TPII-95.

BENJAMIN KLIGLER, M.D., M.P.H., is associate professor of family medicine at Albert Einstein College of Medicine of Yeshiva University, Bronx, N.Y., and a faculty member at the Beth Israel Residency Program in Urban Family Practice, New York, N.Y. He also is the research director and codirector of fellowship programs at the Beth Israel Continuum Center for Health and Healing, New York, N.Y.

SAPNA CHAUDHARY, D.O., is an attending physician an attending physician in private practice at the Beth Israel Continuum Center for Health and Healing. She is a graduate of the Integrative Family Medicine Program at Beth Israel Medical Center

Address correspondence to Benjamin Kligler, M.D., M.P.H., Continuum Center for Health and Healing, 245 Fifth Ave., 2nd Floor, New York, NY 10016 (e-mail: bkligler@chpnet. org). Reprints are not available from the authors.

Author disclosure: Nothing to disclose.

BENJAMIN KLIGLER, M.D., M.P.H., Albert Einstein College of Medicine of Yeshiva University, Bronx, New York

SAPNA CHAUDHARY, D.O., Beth Israel Continuum Center for Health and Healing, New York, New York

SORT:  KEY RECOMMENDATIONS FOR PRACTICE

Evidence
Clinical recommendation  rating References

Peppermint oil seems to be a safeB  4, 9
alternative for reducing symptoms of
irritable bowel syndrome, although the
evidence supporting this use isunclear.
Peppermint oil given via enema can beB  10, 11
used for reducing colonic spasm
in patients undergoing barium enema.
In combination with caraway oil, B  12, 13
peppermint oil can be used for reducing
symptoms of non-ulcer dyspepsia.
Peppermint oil can be applied topically  B  15, 16
to relieve headache.

A = consistent, good-quality patient-oriented evidence;
B = inconsistent or limited-quality patient-oriented evidence;
C = consensus, disease-oriented evidence, usual
practice, expert opinion, or case series. For information
about the SORT evidence rating system, see page 957
or http://www.aafp.org/afpsort.xml.

Table 1. Key Points about Peppermint Oil

Effectiveness  Irritable bowel syndrome symptoms: probably
effective
Non-ulcer dyspepsia: probably effective
Reducing spasm during gastrointestinal
procedures: probably effective
Tension headache: probably effective

Adverse effectsCommon: allergic reactions, heartburn, perianal
burning, blurred vision, nausea, and vomiting
Rare: interstitial nephritis, acute renal
failure

Interactions   May inhibit the cytochrome P450 1A2 system

Contraindications  Hiatal hernia, severe gastroesophageal reflux,
gallbladder disorders; use with caution in
pregnant and lactating women

Dosage Adults: 0.2 to 0.4 mL of oil three times daily
in enteric-coated capsules
Children older than eight years: 0.1 to 0.2 mL
three times daily

Cost   $24 to $32 for one-month supply

Safe at proper dosages and moderately effective
in patients with functional gastrointestinal
conditions

The chronic and chronically recurring symptoms mostly require treatment for many years. Therefore, medical treatment should not only be effective, tolerable and safe, but also cost-effective.

Researchers found a combination of peppermint oil and caraway oil effective, as demonstrated by at least nine clinical trials.

Effects of a fixed combination of peppermint oil and caraway oil on symptoms and quality of life in patients suffering from functional dyspepsia. (Short Communication).

From:
Phytomedicine: International Journal of Phytotherapy &Phytopharmacology
Date:
May 1, 2003
Author:
Adam, B.; Funk, Petra; Haag, S.; Heydenreich, Claus-Jurgen; Holtmann, Gerald; Wieland, Veronika

See more articles from Phytomedicine: International Journal of Phytotherapy &Phytopharmacology

Functional gastrointestinal diseases represent a considerable socio-oeconomic problem, with complaints occurring in about 20-30% of the general population (Fuchs and Ritter, 1996). The chronic and chronically recurring symptoms mostly require treatment for many years. Therefore, medical treatment should not only be effective, tolerable and safe, but also cost-effective.

Various herbal extracts have been found to affect gastrointestinal function potentially linked to the development of symptoms of these disorders. Peppermint oil, e.g., has calcium antagonistic and thus spasmolytic properties (Hills and Aaronson, 1991) and caraway oil shows anti-meteoristic effects (empirical findings). From a combination of both oils synergistic effects and thus a positive influence on the variable symptoms in patients with functional dyspepsia can be expected.

By means of perfusion manometry it could be shown that a fixed combination of 90 mg peppermint oil (WS(r) 1340) and 50 mg caraway oil (WS(r) 1520) (FPCO; Enteroplant[R]) acts locally to cause smooth muscle relaxation (Micklefield et al. 2000) with both peppermint oil (WS(r) 1340) and caraway oil (WS[R] 1520) contributing to the efficacy (Micklefield et al. 2003). Goerg and Spilker (2003) reported a prolonged oroceacal transit time as well as a relaxing effect on the gall-bladder caused by both oils.

Thus, FPCO seems to be a promising combination which has been commercially available for many years. In a first placebo-controlled, double-blind multi-centre trial in dyspeptic patients, May et al. (1999) could show a significant superiority of FPCO (3 x 1 capsule daily) compared to placebo regarding the primary efficacy variables “change in pain intensity” and “global improvement” (Clinical Global Impressions, Item 2) after 4 weeks of treatment (p 0.0 15 and p = 0.008, respectively; one-sided U-test) as well as a statistically significant advantage for FPCO in that pain no longer occurred or occurred less frequently and in reducing the feeling of pressure, heaviness, tension and fullness (secondary efficacy variables; p = 0.04 and p = 0.005, respectively; two-sided U-test).

In their second placebo-controlled, double-blind multicentre trial administering FPCO (2 x 1 capsule daily) in patients with functional dyspepsia, May et al. (2000) observed a significant reduction in all three primary parameters (pain intensity, feeling of pressure, heaviness and fullness, CGI item 2; all p <0.001, one-sided U-test). >

Comparing FPCO (3 x 1 capsule daily) with an enteric soluble formulation with 36 mg WS(r) 1340 and 20 mg WS[R] 1520 in a randomized, double-blind multicentre trial, a statistically significant decline in pain intensity was observed in both groups (p <0.001; two-sided one-sample t-test) and equivalent efficacy of both preparations was demonstrated (Freise and Kohler, 1999). With respect to concomitant variables as CGI Item 2 and feeling of pressure, heaviness and fullness, similar results were obtained while the efficacy of FPCO was significantly better regarding pain frequency. >

Compared to cisapride (2 x 1 FPCO vs. 3 x 10 mg cisapride daily), equivalence was found for the mean reduction in the intensity of pain recorded on a visual analogue scale (primary efficacy variable; p = 0.021; test for equivalence) as well as in the frequency of pain (secondary efficacy variable; p = 0.0034; test for equivalence) (Madisch et al. 1999). Comparable results could be shown for further secondary efficacy variables as the CGI scales and the Dyspeptic Symptom Score.

In our own randomized, placebo-controlled, double-blind clinical trial, which is the first to investigate the effect of FPCO (2 x 1 capsule daily) on disease specific quality of life as measured by the validated Nepean Dyspepsia Index (NDI), the NDI subscores for pain and discomfort of the patients (primary efficacy variables) as well as the NDI symptom score and the NDI total score (secondary efficacy variables) improved significantly under FPCO compared to placebo (all p < 0.05, two-sided U-test) (Holtmann et al. 2001). We could also show that not only patients with severe pain but also patients with severe discomfort responded significantly better to FPCO (p < 0.001, two-sided U-test) than to placebo (Holtmann et al. 2002).

Moreover, even if the pathogenetic role of Helicobacter pylon is still unclear in functional dyspepsia and requires further elucidation, it can be concluded from several subgroup analyses that the response to FPCO is not negatively influenced by Helicobacter pylori status of the patient (May et al. 1999; Madisch et al. 2000; May et al. 2003).

Compared to placebo, FPCO did not show any adverse events which can clearly be attributed to the test preparation. A causal connection can only be presumed for substernal burning sensation with eructation and nausea in sensitive persons. Diarrhoea, which is a main adverse drug reaction under treatment with cisapride, has not been observed under FPCO.

* Conclusion

Based upon currently available data, FPCO has demonstrated efficacy in placebo-controlled trials, with significant reductions of symptoms and clear improvement of disease specific quality of life. Overall, efficacy of the fixed peppermint oil/caraway oil combination appears comparable to chemically defined treatment, e.g. with prokinetics. Due to its good tolerability and safety FPCO can be considered an alternative for the long-term management of these patients.

References

Freise J, Kohler S (1999) Pfefferminzol/Kummelol-Fixkombination bei nicht-saurebedingter Dyspepsie–Vergleich der Wirksamkeit und Vertraglichkeit zweier galenischer Zubereitungen. Pharmazie 54: 210-215

Fuchs K-H, Ritter M (1996) Non-ulcer-Dyspepsie. Pathophysiologie. In: Gastrointestinale Funktionsstorungen. Diagnose, Operationsindikation, Therapie (eds Fuchs KH, Stein HJ, Thiede A): 662-674. Springer, Berlin

Goerg KJ, Spilker T (2003) Effect of peppermint oil and caraway oil on gastrointestinal motility in healthy volunteers: a pharmacodynamic study using simultaneous determination of gastric and gall-bladder emptying and orocaecal transit time. Aliment Pharmacol Ther 17: 445-451

Hills JM, Aaronson PI (1991) The mechanism of action of peppermint oil on gastrointestinal smooth muscle. Gastroenterology 101: 55-65

Holtmann G, Gschossmann J, Buenger L, Wieland V, Heydenreich C-J (2001) Effects of a fixed peppermint oil/caraway oil combination (PCC) on symptoms and quality of life in functional dyspepsia. A multicenter, placebo-controlled, double-blind, randomized trial. Gastroenterology 120 (Suppl 1): A-237

Holtmann G, Gschossmann J, Buenger L, Wieland V, Heydenreich CJ (2002) Effects of a fixed peppermint oil/caraway oil combination (FPCO) on symptoms of functional dyspepsia accentuated by pain or discomfort. Gastroenterology 122 (Suppl 1): A-471

Madisch A, Heydenreich CJ, Wieland V, Hufnagel R, Hotz J (1999) Treatment of functional dyspepsia with a fixed peppermint oil and caraway oil combination preparation as compared to cisapride. Arzneimittelforschung 49 (II): 925-932

Madisch A, Heydenreich CJ, Wieland V, Hufnagel R, Hotz J (2000) Equivalence of a fixed herbal combination preparation as compared with cisapride in functional dyspepsia–influence of H. pylon status. Gut 47 (Suppl 1): A111

May B, Funk P, Schneider B (2003) Fixed peppermint oil] caraway oil combination in functional dyspepsia–efficacy unaffected by H. pylon status. Aliment Pharmacol Ther 17: 975-976

May B, Kohler S, Schneider B (2000) Efficacy and tolerability of a fixed combination of peppermint oil and caraway oil in patients suffering from functional dyspepsia. Aliment Pharmacol ther 14: 1671-1677

May B, Kuntz H-D, Kieser M, Kohler 5 (1996) Efficacy of a fixed peppermint oil/caraway oil combination in non-ulcer dyspepsia. Arzneimittelforschung 46: 1149-1153

Micklefield GH, Greving, I, May B (2000) Effects of peppermint oil and caraway oil on gastroduodenal motility. Phytother Res 14: 20-23

Micklefield G, Jung O, Greving, I, May B (2003) Effects of intraduodenal application of peppermint oil (WS[R] 1340) and caraway oil (WS[R] 1520) on gastroduodenal motility in healthy volunteers. Phytother Res 17:135-140

Gerald Holtmann (1)

S. Haag (1)

B. Adam (1)

Petra Funk (2)

Veronika Wieland (3)

Claus-Jurgen Heydenreich (4)

(1.) University of Essen, Department of Gastroenterology and Hepatology, Essen, Germany

(2.) Dr. Willmar Schwabe Pharmaceuticals, Clinical Research Department, Karlsruhe, Germany

(3.) General Medical Practice, Mannheim, Germany

(4.) Internal Medical Practice, Essen, Germany

Address

Gerald Holtmann, Universitatsklinik Essen, Zentrum fur Innere Medizin, Gastroenterologie/Hepatologie, HufelandstraBe 55, D – 45122 Essen, Germany

Keywords: Peppermint oil; Pharmacodynamics; Pharmacokinetics; Galenic formulations; Irritable bowel syndrome

Introduction

Peppermint oil (Menthae piperitae aetheroleum, PO) is obtained from the fresh leaves of peppermint, Mentha piperita L. by steam distillation. The major constituents of the oil include the terpenes (-)-menthol (30-55%), (-)-menthone (14-32%), (+)-isomenthone (1.5-10%), (-)-menthyl acetate (2.8-10%), (+)-menthofuran (1.0-9.0%) and 1,8-cineol (3.5-14%). Due to its calcium antagonistic properties (-)-menthol has been made responsible spasmolytic effect of PO (Hawthorn et al., 1988). The Food and Drug Administration lists peppermint and PO as “generally recognized as safe” (GRAS; Food and Drugs, 1998).

The purpose of this review is to analyze in detail the pharmacodynamic effects of PO on the gastrointestinal tract with a focus on its use in irritable bowel syndrome (IBS; ESCOP, 1997) as well as oral pharmacokinetics.

Pharmacodynamics

In Table 1 pharmacodynamic studies and results thereof relevant to the use of PO in the gastrointestinal tract are summarized. In nine studies 269 subjects underwent exposure to PO either by topical intraluminal (stomach or colon) or oral administration by single doses or 2 weeks (Wildgrube, 1988) treatment. Methods used to detect effects were oro-cecal transit time by hydrogen expiration, total gastrointestinal transit time by carmine red method, gastric emptying time by radiolabelled test meal or sonography, direct observation of colonic motility or indirect recording through pressure changes or relieve of colonic spasms during barium enema examination. The dose range covered in single dose studies is 0.1-0.24 ml of PO/subject. With the exception of the findings by Rogers et al. (1988 [dose 0.1 ml]), which show an unexplained potentiation of neostigmine stimulated colon activity, all other studies result in comparable data indicating a substantial spasmolytic effect of PO.

This effect commences as early as 0.5 min after topical (intestinal tract) application and may last up to 23 min. This is evidently a too short time period to treat e.g. IBS. To expose the target organ, i.e. the large bowel to a constant concentration of PO to maintain the short lasting effect a sustained release formulation is needed to secure constant exposure of the organ to constant concentrations of PO.

Oro-cecal transit time is prolonged after both acute and chronic use. A low dose of the oil (90 mg; approximately 0.1 ml) has no influence on gastric emptying (Georg and Spilker, 1998), after 0.2 ml a significant reduction is found (Dalvi et al., 1991). The findings are in line with the antispasmodic effect. Also, as an additive to a barium sulphate suspension PO exerts a spasmolytic effect on the colon in patients undergoing barium enema examination (Sparks et al., 1995).

Heartburn, one of the major adverse events of oral PO may be caused to a large extent by inappropriate release of the oil in the upper GI tract (Sigmund and McNally, 1969) resulting in relaxation of the lower esophageal sphincter thus facilitating reflux. To minimize these adverse events an appropriate delayed release formulation may be useful.

Pharmacokinetics

In rats PO is relatively rapidly absorbed and eliminated mainly via the bile. The major biliary metabolite is menthol glucuronide, which undergoes enterohepatic circulation. The urinary metabolites result from hydroxylation at the C-7 methyl group at C-8 and C-9 of the isopropyl moiety, forming a series of mono- and dihydroxymenthols and carboxylic acids, some of which are excreted in part as glucuronic acid conjugates (Yamaguchi et al., 1994).

Menthol (30-55% of natural PO) and other plant mono-terpenes in PO are highly fat soluble and therefore rapidly absorbed from the proximal gut (Somerville et al., 1984; White et al., 1987). Thus, to secure availability of unmetabolised PO at the target organ in IBS, i.e. the lumen of the lower intestinal tract, the oil requires an appropriate galenic formulation (sustained release in the lower intestinal tract) to reach the target. In addition, such a formulation may be useful to minimize one of the more frequent adverse events of PO, i.e. heartburn. The kinetic properties of such formulations (Colpermin[R] and Mintec[R]) were analyzed in two studies, comparing also soft gelantine capsules as a model formulation for upper gastrointestinal release of PO.

Somerville et al. (1984) investigated in a cross over study in six healthy volunteers urinary excretion of menthol in the form of its major metabolite menthol glucuronide after oral ingestion of either two capsules of Colpermin[R] or two soft gelatine capsules without enteric coating, containing each a total of 0.4 ml of PO. Urine was collected in 2-hourly intervals up to 14 h plus one 10 h sample up to 24 h.

In the pooled 24 h sample urinary menthol excretion was essentially identical for both groups (64 mg/74 mg). In Fig. 1 the fractionated menthol excretion is illustrated showing a sustained release pattern for Colpermin[R] as compared to the gelatine capsule. It is concluded that PO from Colpermin[R] is released to a significant extent in the lower digestive tract and in the colon, the target organ to exert antispasmodic effects. The gelantine capsule release pattern does not meet the therapeutic requirements.

The study was extended in six patients, each with an ileostoma. Urine was collected in a single 24h sample. Patients simultaneously collected their ileostoma fluid (n = 5 Colpermin[R], n = 6 gelatine capsules) over the study period. In both fluids the menthol content was analyzed.

Urinary menthol excretion after Colpermin[R] in ileostoma patients is by more than 50% reduced as compared to healthy subjects whereas after gelatine capsules the reduction is <30%. It is interesting to note that Rhodes (1976) describes a patient suffering from achlorhydria. After ingestion of enteric coated PO the patient complained of heartburn and eructation; investigations demonstrated that the capsule disintegrated in the stomach due to the high pH. McKenzie and Gallacher (1989) describe a patient who had only 10 cm of jejunum anastomosed to the left colon. Repeated ingestion of Colpermin[R] capsules resulted in them being passed unchanged per rectum. Both observations and the study by Somerville et al. (1984) underline that efficacy and tolerance may be dependent on effective enteric coating. >

White et al. (1987) studied in 13 healthy subjects in a randomized cross over study the urinary pharmacokinetic profiles of Colpermin[R] and Mintec[R], another enteric coated PO formulation, after ingestion of each three capsules (0.6 ml PO) each. Urine was collected in 2-hourly intervals up to 14 h and in a 10 h sample up to 24 h. Menthol and its glucuronide metabolite were determined in urine.

Mean total 24h menthol urinary excretion was 95.5 mg for Colpermin[R] and 130.9 mg for Mintec[R] (n.s.). The fractionated excretion pattern is shown in Fig. 2.

[FIGURE 1 OMITTED]

Peak excretion was approximately 30 mg menthol/h for Mintec[R] at 3h post dose with a sharp decline thereafter, whereas this rate was about 10 mg menthol/h for Colpermin[R] extending over at least 12 h.

This describes two distinct formulations. Lag time (1.07 h/0.5 h–Colpermin[R]/Mintec[R]) and time to peak (5h/2.8h–Colpermin[R]/Mintec[R]) are statistically different (p < 0.017 or p < 0.047) for the two formulations. Absorption half life, terminal elimination half life and AUC’s are not different. The difference in total urinary menthol excretion (~35%) may indicate that PO release from Colpermin[R] is not finalized within 24 h. It is interesting to note that five subjects had symptoms described as nausea and vague abdominal pain after Mintec[R], whereas no such events were reported after the comparator. This may underline the need for a release of PO in the lower gastrointestinal tract to ensure both efficacy and clinical tolerance, as e.g. demonstrated for the Colpermin[R] formulation.

Discussion

There is reasonable evidence that PO exerts a spasmolytic effect on the smooth vasculature of the intestinal tract. The duration of effect is limited to approximately 20 min. Furthermore, there is evidence that the typical adverse events of PO (e.g. heartburn) do occur if PO is released in the upper gastrointestinal tract. If the target organ like in IBS is the colon immediate release formulations are inadequate. A sustained release formulation is required which releases PO in the lower GI tract, thus also avoiding typical adverse events of PO. Such formulations are available as described in pharmacokinetic studies (Somerville et al., 1984; White et al., 1987). A sustained release formulation having its peak release at about 4h after ingestion with a release time of PO of up to 24h meet such requirements. A t.i.d. regimen is thus possible and it can be assumed that over a 24h period at the target site, i.e. the large bowel sufficient amount of PO is available to exert its pharmacological action(s).

[FIGURE 2 OMITTED]

References

Dalvi, S.S., Nadkarni, P.M., Pardesi, R., Gupta, K.C., 1991. Effect of peppermint oil on gastric emptying in man: a prelimary study using a radiolabelled solid test meal. Indian J. Physiol. Pharmacol. 35 (3), 212-214.

Duthie, H.L., 1981. The effect of peppermint oil on colonic motility in man. Br. J. Surg. 68, 820.

ESCOP (European Scientific Cooperative on Phytotherapy), 1997. Monograph: Menthae Piperitae Aetheroleum (Peppermint Oil). Exeter, UK.

Food and Drugs, 1998. Substances generally recognized as safe, 21 C.F.R. Sect. 182.10 and Sect. 182.20 (April 1, 1998).

Georg, K.J., Spilker, Th., 1998. Motilitatshemmende Wirkung von Kummel- und Pfefferminzol: simultane kombinierte Messung mit Sonographie und H2-Atemtest. (Motility inhibitory effect of caraway and peppermint oil: combined simultaneous measurement by sonography and H2-expiration test) Abstract Phytopharmakaforschung 2000, Bonn 27-28.11.98.

Hawthorn, M., Ferrante, J., Luchowski, E., et al., 1988. The actions of peppermint oil and menthol on calcium channel-dependent processes in intestinal, neuronal and cardiac preparations. Aliment Pharmacol. Therap. 2, 101-118.

Leicester, R.J., Hunt, R.H., 1982. Peppermint oil to reduce colonic spasm during endoscopy. Lancet, 989.

McKenzie, J., Gallacher, M., 1989. A sweet smelling success. Nur. Times 85, 48-49.

Rhodes, J., 1976. Open clinical study of peppermint oil in patients with colonic symptoms. Clinical trial report

Rogers, J., Tay, H.H., Misiewicz, J.J., 1988. Peppermint oil. Lancet, 98-99.

Sigmund, C.J., McNally, E.F., 1969. The action of a carminative on the lower esophageal sphincter. Gastroenterology 56, 13-18.

Somerville, K.W., Richmond, C.R., Bell, G.D., 1984. Delayed release peppermint oil capsules (Colpermin) for the spastic colon syndrome: a pharmacokinetic study. Br. J. Clin. Pharmacol. 18, 638-640.

Sparks, M.J.W., O’Sullivan, P., Herrington, A.A., Morcos, S.K., 1995. Does peppermint oil relieve spasm during barium enema? Br. J. Radiol. 68, 841-843.

Taylor, B.A., Duthie, H.L., Oliveira, R.B., Rhodes, J., 1983. Ultrasound used to measure the response of colonic motility to essential oils. Proceedings of the International Motility Symposium, Aix-en-Provence, France, pp. 441-448.

White, D.A., Thompson, S.P., Wilson, C.G., Bell, G.D., 1987. A pharmacokinetic comparison of two delayed-release peppermint oil preparations, Colpermin and Mintec, for treatment of the irritable bowel syndrome. Int. J. Pharmaceutics 40, 151-155.

Wildgrube, H.J., 1988. Untersuchung zur Wirksamkeit von Pfefferminzol auf Beschwerdebild und funktionelle Parameter bei Patienten mit Reizdarm-Syndrom (Studie) [Investigation of the efficacy of peppermint oil on the symptoms and functional parameters of patients with irritable bowel syndrome (study)]. Naturheilpraxis 41, 2-5.

Yamaguchi, T., Caldwell, J., Farmer, P.B., 1994. Metabolic fate of [[.sup.3]H]-l-menthol in the rat. Drug Metabol. Dispos. 22, 616-624.

H.-G. Grigoleit*, P. Grigoleit

Johann-Sebastian-Bach-str. 27, 65193 Wiesbaden, Germany

Received 13 September 2004; accepted 26 October 2004

*Corresponding author. Tel.: +49 611 520509; fax: +49 611 5990443.

E-mail address: Dr.Grigoleit@t-online.de (H.-G. Grigoleit).

Table 1. Summary of pharmacodynamic studies relevant to the use of
peppermint oil (PO) in the GI tract

Design/no. of
subjects/route ofDose PO/
Reference   or application site  comparator Method(s)

Sigmund and Open/n = 34 healthy  15 drops ofManometrical
McNally (1969)  subjects/gastric essence of recording of lower
lumenpeppermint/esophageal
saline (n =(intrasphincteric)
7) and gastric pressure
Duthie (1981)   Open, randomized/n   0.2 ml/15 min after 0.5 mg
= 6 healthy  placeboi.m. neostigmine
subjects/coloniccolonic motility
lumen   recording by triple
lumen catheter
Leicester and   Open/n = 20  PO; dose not   Visual observation
Hunt (1982) patients undergoing  given  via colonoscope
diagnostic or
therapeutic
coloscopy/colonic
lumen
Taylor et al.   Open, randomized/n   0.2 ml/After 0.5 mg
(1983)  = 6 healthy  placeboneostigmine i.m.
subjects/   intraluminal
rectosigmoidal  pressure recording
lumen
Rogers et al.   Open, randomized/n   0.1 ml/30 min after 0.5 mg
(1988)  = 5 healthy  placeboneostigmine
subjects/colonicintracolonic
lumen   pressure recording
for 30 min
Wildgrube   Matched pairs/n =EntericOro-cecal transit
(1988)  19 IBS patients/ coated PO/ time (hydrogen
oral treatment 2 placeboexhalation) and
weeks   total
gastrointestinal
transit time
(carmine red)
Dalvi et al.Open/n = 20 healthy  0.2 ml versus  Radiolabelled test
(1991)  subject; 10 younger  no treatment   meal and recording
(21 yr), 10 older   of gastric emptying
(40 yr); n = 6  by gamma camera
dyspepsia patients
oral solution
Sparks et al.   Double blind/141 0.24 ml PO in  X-ray films reviewed
(1995)  patients standardbarium by 2 independent
contrast barium  sulphate   radiologists for
enema examination;   contrast   colonic spasms
n = 71 standard  medium or
barium preparation,  without PO
n = 70 standard
plus PO/oral
Georg and   Multiple cross   Oral 90 mg PO  Gastric and gall
Spilker (1998)  over?/n = 12 or caraway bladder emptying
healthy subjects/oiltime by sonography;
oral encapsulated/  oro-cecal transit
saline/time (hydrogen
cisaprid/10expiration)
mg/butyl-
scopolamine
rectal

Reference   ResultsComments/conclusions

Sigmund and 25/27 1-7 min post It is concluded that heartburn
McNally (1969)  dose decrease in   after PO is associated with the
Intrasphincteric   relaxation of lower esophageal
pressure; no salinesphincter
effect
Duthie (1981)   <2 min inhibition of
motor activity up to
23 min (mean 12 min);
p >< 0.05 PO/placebo
Leicester and   Within 30s relieve of  PO is useful in reducing spasms
Hunt (1982) colonic spasms thus allowing easier passage of
instrument or assisting in
polypectomy
Taylor et al.   Up to 20 min
(1983)  inhibition of colonic
motor activity;
placebo no effect
Rogers et al.   Significant increase   Unexplained finding; in contrast
(1988)  in colonic motor   to all other studies
activity after PO
Wildgrube   Oro-cecal transit  It is concluded that PO improves
(1988)  time doubles from 40   disturbed GI motility in IBS
to 80 min (p < 0.05);  patients
total transit time
increase from 39 to
46.5 h (p < 0.05)
Dalvi et al.Basal emptying: 100It is concluded that the
(1991)  min young; 160 min spasmolytic property of PO is
old; 227 min   responsible for reduction of
dyspepsia; after POemptying time
significant
shortening: young 81,
old 110, dyspepsia
148 min
Sparks et al.   No residual spasm in   It is concluded that PO added to
(1995)  60% with PO versus barium suspension is a safe,
35% with out (p <  simple and cheap method to relax
0.001) the colon during barium enema
examination
Georg and   No influence of PO on
Spilker (1998)  gastric emptying
time; oro-cecal
transit time
prolonged from 65
to 85 min (p <
0.05) by PO

From:
Phytomedicine: International Journal of Phytotherapy &Phytopharmacology
Date:
August 1, 2005
Author:
Grigoleit, H.-G.; Grigoleit, P.

“Average response rates in terms of “overall success” are 58% (range
39-79%) for PO and 29% (range 10-52%) for placebo. The three studies
versus smooth muscle relaxants did not show differences between
treatments hinting for equivalence of treatments. Adverse events
reported were generally mild and transient, but very specific. PO
caused the typical GI effects like heartburn and anal/perianal burning
or discomfort sensations, whereas the anticholinergics caused dry mouth
and blurred vision. Anticholinergics and 5HT3/4-ant/agonists do not
offer superior improvement rates, placebo responses cover the range as
in PO trials. Taking into account the currently available drug
treatments for IBS PO (1-2 capsules t.i.d. over 2-4 weeks) may be the
drug of first choice in IBS patients with non-serious constipation or
diarrhea to alleviate general symptoms and to improve quality of life.”

[c] 2005 Elsevier GmbH. All rights reserved.

Keywords: Peppermint oil; Irritable bowel syndrome; Clinical trials; Efficacy; Safety; Treatment alternatives

Introduction

The lack of efficacious and safe medications for irritable bowel
syndrome (IBS) warrants a review of the quite extensive peppermint oil
(PO) clinical database in IBS, taking into account the significant
prevalence of the disease and its enormous costs as well as the
potential cost effectiveness of PO and its clinical safety.

The current definition of IBS (Rome II criteria) is listed below (Thompson et al., 1999).

At least 12 weeks, which need not to be consecutive, in the preceding
12 months of abdominal discomfort or pain that has two out of three
features:

* relieved with defecation; and/or

* onset associated with a change in frequency of stool; and/or

* onset associated with a change in form (appearance) of stool.

Symptoms that cumulatively support the diagnosis of IBS:

* abnormal stool frequency (for research purposes ‘abnormal’ may be
defined as greater than three bowel movements per day or less than
three bowel movements per week),

* abnormal stool form (lumpy/hard or loose/watery stool),

* abnormal stool passage (straining, urgency, incomplete evacuation),

* passage of mucus,

* bloating or feeling of abdominal distension.

PO exerts an antispasmodic action via interference of menthol, the main
component of PO, acting as a calcium antagonist (Hawthorn et al., 1988)
and anti-flatulent effects of currently unexplained nature (WHO, 2002).

Data base

A total of 15 published studies as
listed in Table 1 using PO in IBS were found in a literature search. A
further study (Kline and Barbero, 1997) refers to recurrent abdominal
pain in children. It was included due to the spasmogenic nature of the
underlying symptomatology. In Table 1 key information for all studies
is summarized.

Nine out of 16 studies were randomized double
blind cross over trials with (n = 5) or without (n = 4) run in and/or
wash out periods, five had a randomized double blind parallel group
design and two were open labeled studies. A total of 651 patients were
enrolled. A sex distribution for patients enrolled is available for
half of all studies. In general, there is a prevalence of women, which
is in line with current literature. Inclusion criteria appear to be
adequate, mentioning in 15 out of 16 studies IBS or relevant symptoms,
taking into account that some studies started in the 1980s before
definition of the Rome criteria. Qualitative efficacy rating by either
or both patient and physician included symptoms of IBS and overall
success judgments. Mostly per protocol analyses were done. Treatment
duration ranged from 2 to 11 weeks, in one open study it was 6 months.
As comparators served placebo (n = 12 studies; 1 study compares placebo
and an anticholinergic), smooth muscle relaxants (anticholinergics, n =
3 studies; 1 study compares placebo and an anticholinergic) and
psychotherapy (n = 1 study; stress management program). Placebo was
usually matching the active treatment or double dummy technique was
used were needed (anticholinergics). Out of these 13 trials refer to
investigations with enteric-coated PO and three to PO formulations
without galenic specification, the latter being presumably also enteric
coated. Treatments were administered 1-2 capsules t.i.d., each capsule
containing between 182 and 200 mg of PO, treatment duration was usually
2-4 weeks. Compliance was monitored in four studies. It was
approximately 60-75%.

Assessment of efficacy

In
11 out of 16 studies there was a daily patient rating of a whole set or
only selected symptoms (e.g. abdominal pain, distension, assessment of
winds, stool frequency, urgency, bloating, stool quality, frequency of
attacks, severity of attacks). The symptom catalogue essentially
followed the “Rome” criteria. In two studies rating by patients ensued
at regular intervals of 2 weeks, in two studies the interval is not
given and in one study there was the physician rating at the end of
each study week (open trial).

To make all these variations
comparable the variable “overall success” (overall benefit, global
improvement, overall assessment) was used (% of responders). This
parameter is either rated by investigators/patients or could be
calculated from the data available. Also, this variable is used in
recent IBS drug study meta-analyses (Poynard et al., 1994; Pittler and
Ernst, 1998) and review articles (Camilleri and Choi, 1997) to achieve
data comparability.

Results

In Table 2 all
overall success data from the 16 studies reviewed are summarized.
Placebo response is in the range from 10% to 52% (mean 29%) for all
studies. The open studies (Fernandez, 1990, Shaw et al., 1991) mark the
extremes of PO response, i.e. 18% or 93%. The double blind cross over
trials with (n = 5) or without (n = 4) run in and/or wash out periods
and the five randomized double blind parallel group design trials show
PO efficacy in the range from 39% to 79% (mean 58%). Eight out of 12
placebo controlled studies show statistically significant effects in
favor of PO. Where no response data versus placebo are recorded (n = 3
studies) statistical information reveals significance (n = 2) in favor
of or a borderline effect of PO. The three double blind cross over
studies versus smooth muscle relaxants did not show differences between
treatments hinting for equivalence of treatments, although a placebo
arm is missing with the exception of one trial (Carling et al., 1989).

There is reasonable evidence that enteric-coated PO. 180-200 mg t.i.d.,
given over 2-4 weeks, in IBS is efficacious as compared to placebo and
the smooth muscle relaxants investigated.

Adverse events
reported were generally mild and transient, but very specific. PO
caused the typical GI effects like heartburn (n = 14) and anal/perianal
burning or discomfort sensations (n = 26), whereas the anticholinergics
caused dry mouth (n = 21) and blurred vision (n = 14). There is no dose
or time dependent pattern for either active treatment. Tolerance in the
children study was good.

A total of 71 patients dropped out.
The vast majority (n = 58) due to events unrelated to study drugs (e.g.
protocol violations, failure to report back). Other reasons were: n = 6
worsening of symptoms (PO or placebo), n = 2 nausea and vomiting (PO),
n = 3 perianal burning (PO) and n = 2 peppermint taste and pyrosis.

Discussion

Data analysis of PO clinical data in IBS reveals that in a sufficient
number of studies with appropriate design the oil is safe and
efficacious as a symptomatic remedy. Average response rates are 58%
(range 39-79%) and 29% (range 10-52%) for placebo. This is in line with
the data compiled by Camilleri and Choi (1997) quoting 73% (range
39-89%) for various active treatments and 41% (range 13-69%) placebo
response. In a meta-analysis focusing on smooth muscle relaxants
Poynard et al. (1994) calculate 62% for active treatment and 35% for
placebo from 25 drug studies. Mertz (2003) quotes a 20 [right arrow]
50% response rate for placebo. The significant variability of response
to any treatment in IBS may underline the multi-causal etiology of the
disease.

It is interesting to note that also with recently
developed more targeted drugs like tegaserod (Mertz, 2003), alosetron
(SCRIP, 2000) or cilansetron (Pink Sheet, 2004) versus placebo response
rates cover the same range (52/42%, 41/29%, 60/45%). Only cilansetron
appears to be effective in both sexes. In 2000 (FDA Talk Paper, 2000)
alosetron was withdrawn from the US market because of ischemic colitis.
In 2002, the drug was re-launched for women with serious IBS under a
restricted distribution program (Pink Sheet, 2004). Also for tegaserod,
in an FDA Talk Paper (2004) new risk information was announced
referring to serious diarrhea, ischemic colitis and other forms of
intestinal ischemia. The drug is only approved for short-term treatment
of women. Also cilansetron, a new chemical in this group may have
comparable risks (Pink Sheet, 2004).

In a recent
meta-analysis assessing the global improvement of IBS by PO Pittler and
Ernst (1998) identified eight randomized placebo controlled trials.
Five studies were eligible for a meta-analysis and calculation shows a
beneficial effect of the oil (p < 0.001). This is in line with the
results of this review. The discussion touches a number of significant
issues (e.g. inclusion criteria, carry over effects) and it is stated
that definitive conclusions concerning efficacy cannot be inferred.

A critical view has to be made on: (1) The authors missed four
randomized trials versus placebo (Evans, 1982; Weiss and Kolbl, 1988;
Liu et al., 1997; Kline and Barbero, 1997 [children]), irrespective of
their eligibility for meta-analysis. (2) No wash out period in cross
over trials is addressed as a serious concern (carry over effect). It
is stated that only the study by Schneider and Otten (1990) had an
appropriate wash out period. But also the eligible double blind cross
over studies by Dew et al. (1984) and Rees (1979) must have had
variable wash out periods because the authors explicitly write that
“each treatment began when active symptoms developed”. (3) Whether the
study by Shaw et al. (1991) does not corroborate the positive findings
of other studies remains an open question because 6 months
psychotherapy are compared to drug treatment in an open design. There
is only 18% drug and 72% psychotherapy response. The drug rate is at
the very low end of placebo response, and it may be speculated that
drug patients aggravated their symptoms.

The data presented
in this review depict the current knowledge of PO in IBS, providing
evidence that the oil, administered orally in an enteric coated form,
is a safe, efficacious and cost-effective symptomatic short term
treatment in reducing global symptoms and pain due to its spasmolytic
and antiflatulent effect. The adverse event pattern of PO is distinct
from that of anticholinergics and 5HT3/4-ant/agonists with a low
frequency and mild symptoms, which in general do not require any
intervention, thus resulting in a positive benefit/risk ratio. Taking
into account the currently available drug treatments for IBS PO may be
the drug of first choice in IBS patients with non-serious constipation
or diarrhea to alleviate the general symptoms and to improve quality of
life, e.g. pain or bloating. Anticholinergics and 5HT3/4-ant/agonists
do not offer increased improvement rates, but the latter appear to be
useful under tight medical supervision in patients with serious
constipation or diarrhea.

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H.-G. Grigoleit*, P. Grigoleit

Johann-Sebastian-Bach-Str.27, 65193 Wiesbaden, Germany

Received 13 September 2004; accepted 26 October 2004

*Corresponding author. Tel.: +49611 520509; fax: +49611 5990443.

E-mail addresses: Dr.Grigoleit@t-online.de (H.-G. Grigoleit), Dr.Grigoleit@t-online.de (P. Grigoleit).

<br />Table 1. Summary of study information <br /> <br />   Study drug(s) <br />Study no./Ref. Design  Peppermint oil <br /> <br /> 1 Rees (1979) db, co, wash outOne to two <br />   period  capsules <br />   t.i.d. (b) <br /> 2 Evans et al. (1982) db, co, randomized, One to two <br />   wash out?   capsules <br />   t.i.d. (d) <br /> 3 Dew et al. (1984)   db, co, wash outOne to two <br />   period  capsules <br />   t.i.d. (b) <br /> 4 Nash et al. (1986)  db, co, no wash out,Two capsules <br />   randomized  t.i.d. (a) <br /> 5 Munst et al. (1987) db, co, wash out,   One capsule <br />   double dummy,   t.i.d. (a) <br />   randomized <br /> 6 Weiss and Kolbl (1988)  db, pg, randomized  One capsule <br />   t.i.d. (a) <br /> 7 Lawson et al. (1988)db, co, no wash out One capsule <br />   t.i.d. (b) <br /> 8 Lech et al. (1988)  db, pg, randomized  One capsule <br />   t.i.d. (d) <br /> 9 Wildgrube (1988)Matched pairs, db pg,   Capsules (c) <br />   randomized <br />10 Carling et al. (1989)   db, 3 way co, wash out  One to two <br />   capsules <br />   t.i.d. (a) and <br />   matching placebo <br />11 Schneider and Otten (1990)  db, co, wash out,   One capsule <br />   randomized  t.i.d. (a) <br />12 Fernandez (1990)OpenOne capsule <br />   t.i.d. (b) <br />13 Ambross (1990)  db, co, randomized  Not specified (d) <br />14 Shaw et al. (1991)  Open, pg, randomizedOne capsule <br />   t.i.d. (a) <br />15 Liu et al. (1997)   db, pg, randomized  One capsule <br />   t.i.d. or <br />   q.i.d. (a) <br />16 Kline and Barbero (1997)db, pg, randomized  One to two <br />   capsules <br />   t.i.d. (a) <br /> <br />   Study drug(s)  Treatment  Patients <br />Study no./Ref. Comparator(s)  weeks  enrolled <br /> <br /> 1 Rees (1979) Placebo 1-23/  18 <br />   capsules t.i.d.treatment <br /> 2 Evans et al. (1982) Placebo2/  20 <br />  treatment <br /> 3 Dew et al. (1984)   Placebo 1-22/  29 <br />   capsules t.i.d.treatment <br /> 4 Nash et al. (1986)  Pacebo 2   2/  41 <br />   capsules t.i.d.treatment <br /> 5 Munst et al. (1987) Matching   3/  16 <br />   mebeverine treatment <br />   135 mg 1 tablet <br />   t.i.d. <br /> 6 Weiss and Kolbl (1988)  Placebo, 1 3   60 <br />   capsule t.i.d. <br /> 7 Lawson et al. (1988)Placebo, 1 4   25 <br />   capsule t.i.d. <br /> 8 Lech et al. (1988)  Placebo, 1 4   47 <br />   capsule t.i.d. <br /> 9 Wildgrube (1988)Matching placebo   2   40 <br />   capsules <br />10 Carling et al. (1989)   Hyoscyamine 0.22/  40 <br />   mg and matchingtreatment <br />   placebo, 1-2 <br />   tablets t.i.d. <br />11 Schneider and Otten (1990)  Placebo 1 capsule  6/  60 <br />   t.i.d. treatment <br />12 Fernandez (1990)   4   50 <br />13 Ambross (1990)  Alverine citrate   11/ 18 <br />  treatment <br />14 Shaw et al. (1991)  Stress management  24  35 <br />   program, median 6 <br />   psychotherapy <br />   sessions of each <br />   40 min/patient <br />15 Liu et al. (1997)   Placebo 1 capsule  4  110 <br />   t.i.d. or q.i.d. <br />16 Kline and Barbero (1997)Placebo 1-22   42 <br />   capsules t.i.d. <br /> <br />db = double blind, co = cross over, pg = parallel groups. <br />(a) Colpermin[R]. <br />(b) Enteric-coated PO capsule. <br />(c) Mentacur[R]. <br />(d) Unspecified PO formulation. <br /> <br />Table 2. Summary of "overall success" data for peppermint (PO) oil in <br />IBS <br /> <br />Study  Overall success (%)   Overall success <br />no.peppermint oil   Comparator   comparator (%) <br /> <br /> 1 50   Placebo  13 <br /> 2 No numerical dataPlacebo  No numerical data <br /> 3 41   Placebo  10 <br /> 4 39   Placebo  52 <br /> 5 No numerical dataMebeverine   No numerical data <br /> 6 74   Placebo  17 <br /> 7  Placebo <br /> 8 68   Placebo  26 <br /> 9 No numerical dataPlacebo  No numerical data <br />10 57   Placebo  37 <br />Hyoscyamine  38 <br />11 57   Placebo  39 <br />12 93 <br />13 No numerical dataAlverine No numerical data <br />14 18   Stress   72 <br />management <br />program <br />15 79   Placebo  32 <br />16 70   Placebo  43 <br /> <br />Study <br />no.Comments <br /> <br /> 1 p < 0.01 <br /> 2 Overall success in favor of PO (p < 0.025) <br /> 3 p < 0.001 <br /> 4 n.s. <br /> 5 Except for "fullness" no difference between treatments <br /> 6 p < 0.001 <br /> 7 Increase in stool frequency (p < 0.05), formulation problem <br /> 8 p < 0.02 <br /> 9 All symptoms improved in favour of peppermint oil (p < 0.05) <br />10 Symptom score before/after PO p < 0.01; placebo and hyoscyamine <br />   p>0.05 <br />11 Difference n.s. p = 0.08 <br />12 Open study <br />13 No difference between treatments <br />14 Strongly in favour of psychotherapy after 6 months <br />15 Overall success calculated from mean improvement values of <br />   symptoms, single symptoms all p < 0.05 <br />16 Children/recurrent abdominal pain, p < 0.002 <br />

Peppermint oil has been extensively researched for its effect on the
digestive system. An article in Phytomedicine details the
pharmacodynamics the fact on the gastrointestinal tract as an antispasmodic effect on smooth muscle. The authors describe the metabolism and elimination of menthol and peppermint oil.

“The principal pharmacodynamic effect of peppermint oil relevant to the
gastrointestinal tract is a dose-related antispasmodic effect on the
smooth musculaturedue to the interference of menthol with the movement of calcium across
the cell membrane. The choleretic and antifoaming effects of peppermint
oil may play an additional role in medicinal use.”

“Peppermint oil is relatively rapidly absorbed after oral administration
and eliminated mainly via the bile. The major biliary metabolite is
menthol glucuronide, which undergoes enterohepatic circulation. The
urinary metabolites result from hydroxylation at the C-7 methyl group
at C-8 and C-9 of the isopropyl moiety, forming a series of mono- and
dihydroxymenthols and carboxylic acids, some of which are excreted in
part as glucuronic acid conjugates. Studies with tritiated I-menthol in
rats indicated about equal excretion in feces and urine. The main
metabolite indentified was menthol-glucuronide. Additional metabolites
are mono- or di-hydroxylated menthol derivatives.”

[c] 2005 Published by Elsevier GmbH.

Keywords: Peppermint oil; Spasmolysis; Calcium antagonist; Antifoaming activity; Choleresis; Pharmacokinetics

Introduction

Peppermint oil has a long history of safe use both in medicinal
preparations and as a flavoring agent in foods and confectionery.
Peppermint oil is indicated for both external and internal use. In an
ESCOP monograph in 1997 (ESCOP, 1997) the medicinal use is summarized
and FDA granted the oil a so-called “generally recognized as safe”
(GRAS) status (Food and drugs, 1998).

The major constituents
of the oil include the terpenes (-)-menthol (30-55%), (-)-menthone
(14-32%), (+)-isomenthone (1.5-10%), (-)-menthyl acetate (2.8-10%),
(+)-menthofuran (1.0-9.0%) and 1.8-cineol (3.5-14%).

The
purpose of this review is to summarize preclinical research data with
peppermint oil or its constituents, relevant to the gastrointestinal
tract.

Dynamics and mode of action

The
antipasmodic activity of 2.5 and 10.0 ml/l of alcoholic extracts of
Melissa officinalis, Rosmarinus officinalis, Mentha piperita,
Matricaria chamomilla, Foeniculum vulgare, Carum carvi and Citrus
aurantium prepared from 1 part of the plant and 3.5 parts of ethanol
(31% w/w) was tested employing the guinea pig ileum and using
acethylcholine and histamine as spasmogens (Forster et al., 1980). Most
of the extracts shifted the dose response curves of acetylcholine and
histamine to the right in a dose-dependent manner. Extracts from Carum
carvi, Mentha piperita, Citrus aurantium and Matricaria chamonilla
showed a significant rise of the D[E.sub.50] of acetylcholine-induced
contractions and a significant decrease of the maximal possible
contractility. In histamine-induced contractions, all plant extracts
except Extractum Melissae exhibited a significant increase of the
D[E.sub.50], and all extracts used decreased the maximal possible
contractility produced by histamine. The alcoholic extract of Mentha
piperita was most effective when tested with acetylcholine and the
extract of Citrus aurantium was most active when tested with histamine.
Melissa officinalis did not show significant antispasmodic activity.
When the antispasmodic activities of the most effective plant extracts
were compared with the activity of atropine, it was evident that their
effects were less than that of the usual therapeutic dosage of atropine
in man. The most pronounced effects with 10 ml/l Extractum Citrus
aurantii and 10 ml/l Extractum Menthae piperitae correspond to the
effect of 0.07 resp. 0.13 mg atropine.

The antispasmodic
effects of peppermint oil have been directly demonstrated in vitro in a
series of experiments with smooth muscle fibres isolated from the
guinea pig, including the trachea and ileum (Reiter and Brandt, 1985;
Taddei et al., 1988) and the sphincter of Oddi (Giachetti et al.,
1988). Peppermint oil was shown to be effective in reducing muscle tone
in all three systems either at rest or following electrical stimulation
or morphine treatment. The effects of peppermint oil were shown to be
due largely to its menthol constituent.

Evans et al. (1975)
studied the effect of menthol on the colonic motility in dogs.
Biological activity was estimated on colonic motility using mongrel
dogs with an exteriorized terminal ileum which allowed direct access to
the colon and which had been kept in continuity with both the ileum and
the remainder of the large intestine. Each dog was given an enema on
the day prior to experimentation and colonic motility was examined by
recording intra-luminal pressure with three water-filled polyethylene
tubes inserted through the ileal stoma into the proximal, medial and
distal regions and linked to a multi-channel pen-recorder. A recording
of the normal pattern of colonic motility was first obtained following
the introduction of 30 ml normal saline into the colon. A similar
volume of menthol, at a concentration of 1.0 mg/ml, was then introduced
into the colon and the effect on intra-luminal pressure recorded. It
produced an immediate decrease in colonic motility, which lasted from
20-25 min, before the normal pattern of motility was restored.
Decreased motility was observed as a reduction in intra-luminal
pressure.

Hills and Aaronson (1991) studied the mechanism of
action of peppermint oil on gastrointestinal smooth muscle in isolated
organs. Peppermint oil relaxed carbachol-contracted guinea pig taenia
coli (I[C.sub.50] 22.1 [micro]g/ml) and inhibited spontaneous activity
in the guinea pig colon (I[C.sub.50] 25.9 [micro]g/ml) and rabbit
jejunum (I[C.sub.50] 15.2 [micro]g/ml). Peppermint oil markedly
attenuated contractile responses in the guinea pig taenia coli to
acetylcholine, histamine, 5-hydroxytryptamine, and substance P.
Peppermint oil reduced contractions evoked by potassium depolarization
and calcium contractions evoked in depolarizing Krebs solutions in
taenia coli. Potential-dependent calcium currents recorded using the
whole cell clamp configuration in rabbit jejunum smooth muscle cells
were inhibited by peppermint oil in a concentration-dependent manner.
Peppermint oil both reduced peak current amplitude and increased the
rate of current decay. The effect of peppermint oil resembled that of
dihydropyridine calcium antagonists. The authors concluded that
peppermint oil relaxes gastrointestinal smooth muscle by reducing
calcium influx.

Taylor et al. (1985) studied in guinea pig
isolated ileum and human isolated taenia coli the relaxant activity of
peppermint oil and its constituents. Carbachol was used as antagonist.
Doses required to bring about 50% relaxation (I[D.sub.50]) were then
compared. Menthol (3.0 X [10.sup.-5] w/w) was the most active
constituent, being more active than peppermint oil (4.4 X [10.sup.-5]
w/w) while menthone, menthyl acetate and cineole were considerable less
active than peppermint oil. Using strips (30 X 3 mm) of human isolated
taenia coli suspended in normal Krebs’ solution bubbled with 5%
C[O.sub.2] in [O.sub.2] at 37[degrees]C, peppermint oil and menthol
inhibited basal tone and contractions to carbachol
([10.sup.-7]-[10.sup.-4]M) and to potassium chloride (5-150 mM) in a
non-competitive manner. In calcium-free, depolarizing Krebs’ solution
(mM: NaCl 82.7; KCL 40.0; NaHC[O.sub.3] 25.0; Na[H.sub.2]P[O.sub.4]
1.4; glucose 11.5) parallel shifts in dose response curves to calcium
(0.1-20 mM) indicated that peppermint oil and menthol posses specific
calcium antagonist activity. To further investigate this effect the
influx of [.sup.25][Ca.sup.2+] ([micro] mol/kg wet weight) into
carbachol ([10.sup.-6] M) or potassium (80 mM) stimulated rings of
guinea pig ileum (7-15 mg) suspended in buffered HEFES solution
containing [.sup.45][Ca.sup.2+] ([10.sup.-5] = Ci/ml) was studied.
Following carbachol or potassium stimulation the extracellular
concentration of [CA.sup.2+] increased significantly (p < 0.001).
However, in the presence of menthol (0.64 = M) no such influx was
observed. The calcium antagonist, verapanil ([10.sup.-5] M) likewise
inhibited [.sup.45][Ca.sup.2+] uptake in response to carbachol and
potassium stimulation. In addition, peppermint oil and menthol
inhibited carbachol-induced contractions of the guinea pig isolated
ileum suspended in calcium-free Tyrode’s solution in the readmission of
calcium ions, further indicating that peppermint oil and menthol are
able to inhibit carbachol-induced influx of extracellular calcium ions.

The effect of peppermint oil and menthol on isolated human
coli was investigated by Taylor et al. (1984). A total of 50 strips of
taenia, approximately 30 X 3 mm, were dissected from 20 resections for
carcinoma. Peppermint oil and menthol produced both inhibition of
spontaneous activity and decrease in basal tone in all tissues in a
dose-dependent manner. Under isotonic conditions (tension 2g),
I[D.sub.50] values (concentration of antagonist producing 50% reduction
in response to carbachol, [10.sup.-6] M) were calculated for menthol
(0.29 [+ or -] 0.11 mM; n = 5) and for peppermint oil (0.41 [+ or -]
0.06 mM; n = 5: estimated MW 160). Under isometric conditions,
dose-response curves to carbachol ([10.sup.-7]-[10.sup.-4]M and to
potassium (5-150 mM) demonstrated non-competitive inhibition by both
peppermint oil and menthol, this effect being rapidly reversible on
wash-out. In calcium-free, depolarizing Kreb’s solution (mM; NaCl 82.7;
KCL 40.0; NaHC[O.sub.3] 25.0; Na[H.sub.2]P[O.sub.4] 1.4; glucose 11.5),
dose-response curves to calcium (0.1-20 mM) showed a specific calcium
antagonist effect of menthol, which was dose-related and rapidly
reversible.

Beesley et al. (1996) studied the influence of
peppermint oil on absorptive and secretory processes in rat small
intestine using both intestinal sheets mounted in Ussing chambers and
brush border membrane vesicles. Peppermint oil in the intestinal lumen
inhibited enterocyte glucose uptake via a direct action on the brush
border membrane. Intestinal secretion was inhibited by peppermint oil,
which is consistent with a reduced availability of calcium.

The action of menthol and/or peppermint oil as a calcium channel
antagonist has been demonstrated in vitro by Hawthorn et al. (1988).
These investigators used 45[Ca.sup.2+] uptake and radioligand-binding
assays to measure the effects of menthol and peppermint oil in a range
of mammalian tissues. Both showed [Ca.sup.2+] channel-blocking activity
in guinea-pig ileum, rat and guinea-pig cardiac muscle, rat brain
synaptosomes and also in chick retinal neurones. The results of binding
studies supported a [Ca.sup.2+] channel-specific effect in both cases.

Palade et al. (1989) classified menthol as activator of the
[Ca.sup.2+]-induced [Ca.sup.2+] release in sarcoplasmatic reticulum,
which more than doubled the control rate of ruthenium red-insensitive
unidirectional 45Ca efflux. Rampe and Triggle (1990) reviewed new
ligands for L-type [Ca.sup.2+] channels of different chemical
structure, among them menthol. The identity of the binding site has not
yet been established; however, such ligands were proposed for new
directions of [Ca.sup.2+] channel drug structures. Zygmunt et al.
(1993) performed structure activity studies on the calcium antagonistic
properties of terpenes and suggested that these substances represent a
new chemical class of calcium antagonists, which interact with
dihydropyridine binding sites.

Using isolated ganglia from
Helix pomatia and cultured dorsal root ganglion cells from chick and
rat embryos, Swandulla et al. (1986, 1987), Schafer et al. (1988) found
that menthol blocks currents through the low-voltage-activated Ca
channel, and facilitates inactivation gating of the classical high
voltage-activated Ca channel. Schafer et al. (1995) reported similar
findings in afferent discharges from electroreceptor organs of catfish.

These results indicate that the spasmolytic effect of
peppermint oil on the intestinal smooth musculature appears to involve
calcium antagonism. Menthol, which is the major constituent of
peppermint oil exerts its effect most probably via a calcium channel
antagonistic effect. This leads to antispasmodic activity observed in
pharmacodynamic studies with peppermint oil or menthol. The activity
appears to be dose dependent. The mechanism by which this is brought
about is associated with the ability of menthol to decrease the influx
of extracellular calcium ions through potential dependent channels.

Antifoaming activity

Harries et al. (1978) studied in an apparatus specially designed to
assess foams in digestive fluids in vitro the antifoaming effect of
various carminatives. The effects of caraway, cinnamon, dill, orange
and peppermint oils on gastric and intestinal foams were examined.
Reductions in foam volume were observed in every case, although the
effects were not as great as those produced by a combination of
dimethicone and silica. m-Cresol, p-hydroxybenzaldehyde, isobutanol,
menthol and phenoxyethanol also reduced foam volume. It is suggested
that carminative action is a combination of effects, one of which is a
reduction of gastrointestinal foam.

Choleretic activity

A choleretic action has traditionally been ascribed to peppermint oil,
in keeping with the occasional use of menthol in the treatment of
gallstones (Leuschner et al., 1988). Increases in bile production of
1.3-2.4-fold were recorded (Mans and Pentz, 1987) after oral doses of
0.1-1.0 g/kg bw in male rats. Trabace et al. (1993) found dose- and
time-dependent choleretic effects of peppermint oil and menthol in
anesthetized rats and used these as standards for testing other
essential oils. The mechanism of action underlying the observed
choleretic activity of menthol or other constituents of peppermint oil
is not clearly understood, but may result from the marked biliary
output of metabolized menthol (Mans and Pentz, 1987).

Pharmacokinetics

Mans and Pentz (1987) studied the pharmacokinetic behaviour of menthol
administered orally at a range of doses (0.1-1.0 g/kg b.w.) in male
rats. Plasma levels and biliary and renal excretion of unchanged versus
conjugated menthol were measured. The levels of unchanged compound were
low in plasma, bile and urine, with a preponderance of the glucuronide
(60%) present in the urine and of the sulphate (60-90%) present in the
bile. Renal recovery of total menthol within 24 h was dose dependent,
ranging from 5.4% (0.1 g/kg) to 2.1% (1 g/kg). The recovery in bile
over 8 h was substantially higher, ranging from 16% to 6% at the
corresponding dose levels. Dose-related increases in volume of both
urine and bile were recorded.

Biotransformation

Madyastha and Srivatsan (1988) investigated the metabolism of l-menthol
in rats both in vivo and in vitro. Metabolites isolated and
characterized from the urine of rats after oral administration (800
mg/kg) of l-menthol were the following: p-menthane-3,8-diol,
p-menthane-3,9-diol, 3,8-oxy-p-menthane-7-carboxylic acid, and
3,8-dihydroxy-p-menthane-7-carboxylic acid. Repeated administration of
800 mg/kg l-menthol to rats for 3 days resulted in the increase of both
liver mitochondrial cytochrome P-450 content and NADPH-cytochrome C
reductase activity by nearly 80%. Rat liver microsomes readily
converted l-menthol to p-menthane-3,8-diol in the presence of NADPH and
O2. A metabolic pathway of l-menthol in rats was proposed. Yamaguchi et
al. (1994) administered [3-3H]-l-menthol by oral gavage to intact and
bile duct-cannulated male Fischer 344 rats at a dose level of 500
mg/kg. Excreta were collected for up to 48 h and metabolites in urine
and bile analysed by TLC, solid phase extraction, GLC, and GC/MS. In
intact rats, some 71% of the dose was recovered in 48 h with
approximately equal amounts in urine and feces. In total, 74% of the
dose was recovered from bile duct-cannulated rats, with 67% in the bile
and 7% in the urine. The major biliary metabolite was menthol
glucuronide, which undergoes enterohepatic circulation. The urinary
metabolites resulted from hydroxylation at the C-7 methyl group at C-8
and C-9 of the isopropyl moiety, resulting in a series of mono- and
dihydroxymenthols and carboxylic acids, some of which are excreted in
part as glucuronic acid conjugates. The results enabled the
construction of a metabolic map for menthol in the rat.

A
twofold difference in the formation rate of glucuronides of (+)- and
(-)-menthol by rat liver slices and by rat liver microsomes was found
by Caldwell (1995). The plasma elimination half-life of (-)-menthol is
2.4h compared with 4.0 h for (+)-menthol, with the plasma AUC of
(-)-menthol being threefold less than for the (+)-isomer. These
pharmacokinetic differences arise from the enormous difference between
the isomers in terms of the biliary excretion of their glucuronides:
69% of a dose of the more rapidly cleared (-)-menthol is excreted in
the bile in 24 h compared with only 32% for (+)-menthol.

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H.-G. Grigoleit*, P. Grigoleit

Johann-Sebastian-Boch-Str. 27, 65193 Weisbaden, Germany

Received 13 September 2004; accepted 26 October 2004

*Corresponding author. Tel.: +49 611 520509; fax: +49 611 5990443.

E-mail address: Dr.Grigoleit@t-online.de (H.-G. Grigoleit).

Green Tea Polyphenol Epigallocatechin-3-Gallate Suppresses Collagen Production and Proliferation in Keloid Fibroblasts via Inhibition of the STAT3-Signaling Pathway.

J Invest Dermatol. 2008 May 8. Park G, Yoon BS, Moon JH, Kim B, Jun EK, Oh S, Kim H, Song HJ, Noh JY, Oh C, You S.

Keloids are benign skin tumors characterized by collagen accumulation and hyperproliferation of fibroblasts. To find an effective therapy for keloids, we explored the pharmacological potential of (-)-epigallocatechin-3-gallate (EGCG), a widely investigated tumor-preventive agent. When applied to normal and keloid fibroblasts (KFs) in vitro, proliferation and migration of KFs were more strongly suppressed by EGCG than normal fibroblast proliferation and migration (IC(50): 54.4 muM (keloid fibroblast (KF)) versus 63.0 muM (NF)). The level of Smad2/3, signal transducer and activator of transcription-3 (STAT3), and p38 phosphorylation is more enhanced in KFs, and EGCG inhibited phosphorylation of phosphatidylinositol-3-kinase (PI3K), extracellular signal-regulated protein kinase 1/2 (ERK1/2), and STAT3 (Tyr705 and Ser727). To evaluate the contribution of these pathways to keloid pathology, we treated KFs with specific inhibitors for PI3K, ERK1/2, or STAT3. Although a PI3K inhibitor significantly suppressed proliferation, PI3K and MEK/ERK inhibitors had a minor effect on migration and collagen production. However, a JAK2/STAT3 inhibitor and a STAT3 siRNA strongly suppressed proliferation, migration, and collagen production by KFs. We also found that treatment with EGCG suppressed growth and collagen production in the in vivo keloid model. This study demonstrates that EGCG suppresses the pathological characteristics of keloids through inhibition of the STAT3-signaling pathway. We propose that EGCG has potential in the treatment and prevention of keloids.Journal of Investigative Dermatology advance online publication, 8 May 2008; doi:10.1038/jid.2008.103.