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Gastrointestinal clinical pharmacology of peppermint oil
ARTICLE IN PRESS
Phytomedicine 12 (2005) 607–611 www.elsevier.de/phymed
REVIEW
Gastrointestinal clinical pharmacology of peppermint oil H.-G. Grigoleit, P. Grigoleit Johann-Sebastian-Bach-str. 27, 65193 Wiesbaden, Germany Received 13 September 2004; accepted 26 October 2004
Abstract In nine studies, 269 healthy subjects or patients underwent exposure to peppermint oil (PO) either by topical intraluminal (stomach or colon) or oral administration by single doses or 2 weeks treatment (n ¼ 19). 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 one exception, which show an unexplained potentiation of neostigmine stimulated colon activity, all other studies result in effects, indicating a substantial spasmolytic effect of PO of the smooth muscles of the gastrointestinal tract. Pharmacokinetic studies reveal that fractionated urinary recovery of menthol is dependent on the kind of formulation used for the application of PO. Optimal pH triggered enteric coated formulations start releasing PO in the small intestine extending release over 10–12 h thus providing PO to the target organ in irritable bowel syndrome, i.e. the colon. The hypothesis is supported by anecdotal observations in patients with achlorhydria or ileostoma, respectively. r 2005 Published by Elsevier GmbH. 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
Corresponding author. Tel.: +49 611 520509; fax: +49 611 5990443. E-mail address: [email protected] (H.-G. Grigoleit).
0944-7113/$ - see front matter r 2005 Published by Elsevier GmbH. doi:10.1016/j.phymed.2004.10.006
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
ARTICLE IN PRESS 608
H.-G. Grigoleit, P. Grigoleit / Phytomedicine 12 (2005) 607–611
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 monoand 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 (Colpermins and Mintecs) 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 Colpermins 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 Colpermins as compared to the gelatine capsule. It is concluded that PO from Colpermins 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 24 h sample. Patients simultaneously collected their ileostoma fluid (n ¼ 5 Colpermins, n ¼ 6 gelatine capsules) over the study period. In both fluids the menthol content was analyzed. Urinary menthol excretion after Colpermins in ileostoma patients is by more than 50% reduced as compared to healthy subjects whereas after gelatine capsules the reduction is o30%. 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 Colpermins 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 Colpermins and Mintecs, 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.
ARTICLE IN PRESS H.-G. Grigoleit, P. Grigoleit / Phytomedicine 12 (2005) 607–611
Table 1.
609
Summary of pharmacodynamic studies relevant to the use of peppermint oil (PO) in the GI tract
Reference
Design/no. of Dose PO/ subjects/route of or comparator application site
Sigmund and McNally (1969)
Open/n ¼ 34 healthy 15 drops of essence Manometrical subjects/gastric of peppermint/saline recording of lower lumen (n ¼ 7) esophageal (intrasphincteric) and gastric pressure Open, randomized/ 0.2 ml/placebo 15 min after 0.5 mg n ¼ 6 healthy i.m. neostigmine subjects/colonic colonic motility lumen recording by triple lumen catheter
Duthie (1981)
Method(s)
Leicester and Hunt (1982) Open/n ¼ 20 PO; dose not given patients undergoing diagnostic or therapeutic coloscopy/colonic lumen
Visual observation via colonoscope
Taylor et al. (1983)
Open, randomized/ n ¼ 6 healthy subjects/rectosigmoidal lumen
After 0.5 mg neostigmine i.m. intraluminal pressure recording
Rogers et al. (1988)
Open, randomized/ 0.1 ml/placebo n ¼ 5 healthy subjects/colonic lumen Matched pairs/n ¼ Enteric coated PO/ 19 IBS patients/oral placebo treatment 2 weeks
Wildgrube (1988)
Dalvi et al. (1991)
Sparks et al. (1995)
0.2 ml/placebo
30 min after 0.5 mg neostigmine intracolonic pressure recording for 30 min Oro-cecal transit time (hydrogen exhalation) and total gastrointestinal transit time (carmine red) Radiolabelled test meal and recording of gastric emptying by gamma camera
Results
Comments/ conclusions
25/27 1–7 min post dose decrease in intra-sphincteric pressure; no saline effect o2 min inhibition of motor activity up to 23 min (mean 12 min); po0:05 PO/ placebo
It is concluded that heartburn after PO is associated with the relaxation of lower esophageal sphincter
Within 30 s relieve of PO is useful in colonic spasms reducing spasms thus allowing easier passage of instrument or assisting in polypectomy Up to 20 min inhibition of colonic motor activity; placebo no effect Significant increase in colonic motor activity after PO
Oro-cecal transit time doubles from 40 to 80 min (po0:05); total transit time increase from 39 to 46.5 h (po0:05) Open/n ¼ 20 healthy 0.2 ml versus no Basal emptying: subject; 10 younger treatment 100 min young; (21 yr),10 older 160 min old; 227 min (40 yr); n ¼ 6 dyspepsia; after PO dyspepsia patients/ significant oral solution shortening: young 81,old 110, dyspepsia 148 min Double blind/141 0.24 ml PO in X-ray films reviewed No residual spasm in patients standard barium sulphate by 2 independent 60% with PO versus contrast barium contrast medium or radiologists for 35% with out enema examination; without PO colonic spasms (po0:001) n ¼ 71 standard barium preparation, n ¼ 70 standard plus PO/oral
Georg and Spilker (1998) Multiple cross over?/ Oral 90 mg PO or n ¼ 12 healthy caraway oil subjects/oral encapsulated/saline/ cisaprid/10 mg/ butyl- scopolamine rectal
Gastric and gall bladder emptying time by sonography; oro-cecal transit time (hydrogen expiration)
No influence of PO on gastric emptying time; oro-cecal transit time prolonged from 65 to 85 min (po0:05) by PO
Unexplained finding; in contrast to all other studies It is concluded that PO improves disturbed GI motility in IBS patients It is concluded that the spasmolytic property of PO is responsible for reduction of emptying time
It is concluded that PO added to barium suspension is a safe, simple and cheap method to relax the colon during barium enema examination
ARTICLE IN PRESS H.-G. Grigoleit, P. Grigoleit / Phytomedicine 12 (2005) 607–611
60 ***
35 -1
50 40
*** p<0.001 ** p<0.01 * p<0.02
Gelatine
30
Colpermin®
20
** **
10 0
Excretion rate (mg menthol h. )
mg menthol excreted per 2 hr. period
610
0-2
2-4
4-6
6-8
**
*
**
8-10 10-12 12-14
30 25 20 15 10 5 0
2
Mean total 24 h menthol urinary excretion was 95.5 mg for Colpermins and 130.9 mg for Mintecs (n.s.). The fractionated excretion pattern is shown in Fig. 2. Peak excretion was approximately 30 mg menthol/h for Mintecs at 3 h post dose with a sharp decline thereafter, whereas this rate was about 10 mg menthol/h for Colpermins extending over at least 12 h. This describes two distinct formulations. Lag time (1.07 h/0.5 h – Colpermins/Mintecs) and time to peak (5 h/2.8 h – Colpermins/Mintecs) are statistically different (po0:017 or po0:047) 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 Colpermins is not finalized within 24 h. It is interesting to note that five subjects had symptoms described as nausea and vague abdominal pain after Mintecs, 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 Colpermins 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
6
8
10
12
14
16
18
20
Mid-point of collection (h)
Mid-point of collection (h)
Fig. 1. Urinary excretion of menthol in six volunteers ingesting either two Colpermins capsules (open circles) or the equivalent amount of peppermint oil in soft gelatin capsules (closed circles).
4
Fig. 2. Mean excretion of menthol (in the form of its glucuronide metabolite), following ingestion of 0.6 ml of peppermint oil, either as Colpermins (closed circles) or Mintecs (open circles). n ¼ 13 per group.
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 4 h after ingestion with a release time of PO of up to 24 h meet such requirements. A t.i.d. regimen is thus possible and it can be assumed that over a 24 h period at the target site, i.e. the large bowel sufficient amount of PO is available to exert its pharmacological action(s).
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. Motilita¨tshemmende Wirkung von Ku¨mmel- und Pfefferminzo¨l: 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 channeldependent 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.
ARTICLE IN PRESS H.-G. Grigoleit, P. Grigoleit / Phytomedicine 12 (2005) 607–611
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
611
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 Pfefferminzo¨l 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 [3H]-l-menthol in the rat. Drug Metabol. Dispos. 22, 616–624.
Phytomedicine 12 (2005) 607–611 www.elsevier.de/phymed
REVIEW
Gastrointestinal clinical pharmacology of peppermint oil H.-G. Grigoleit, P. Grigoleit Johann-Sebastian-Bach-str. 27, 65193 Wiesbaden, Germany Received 13 September 2004; accepted 26 October 2004
Abstract In nine studies, 269 healthy subjects or patients underwent exposure to peppermint oil (PO) either by topical intraluminal (stomach or colon) or oral administration by single doses or 2 weeks treatment (n ¼ 19). 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 one exception, which show an unexplained potentiation of neostigmine stimulated colon activity, all other studies result in effects, indicating a substantial spasmolytic effect of PO of the smooth muscles of the gastrointestinal tract. Pharmacokinetic studies reveal that fractionated urinary recovery of menthol is dependent on the kind of formulation used for the application of PO. Optimal pH triggered enteric coated formulations start releasing PO in the small intestine extending release over 10–12 h thus providing PO to the target organ in irritable bowel syndrome, i.e. the colon. The hypothesis is supported by anecdotal observations in patients with achlorhydria or ileostoma, respectively. r 2005 Published by Elsevier GmbH. 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
Corresponding author. Tel.: +49 611 520509; fax: +49 611 5990443. E-mail address: [email protected] (H.-G. Grigoleit).
0944-7113/$ - see front matter r 2005 Published by Elsevier GmbH. doi:10.1016/j.phymed.2004.10.006
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
ARTICLE IN PRESS 608
H.-G. Grigoleit, P. Grigoleit / Phytomedicine 12 (2005) 607–611
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 monoand 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 (Colpermins and Mintecs) 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 Colpermins 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 Colpermins as compared to the gelatine capsule. It is concluded that PO from Colpermins 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 24 h sample. Patients simultaneously collected their ileostoma fluid (n ¼ 5 Colpermins, n ¼ 6 gelatine capsules) over the study period. In both fluids the menthol content was analyzed. Urinary menthol excretion after Colpermins in ileostoma patients is by more than 50% reduced as compared to healthy subjects whereas after gelatine capsules the reduction is o30%. 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 Colpermins 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 Colpermins and Mintecs, 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.
ARTICLE IN PRESS H.-G. Grigoleit, P. Grigoleit / Phytomedicine 12 (2005) 607–611
Table 1.
609
Summary of pharmacodynamic studies relevant to the use of peppermint oil (PO) in the GI tract
Reference
Design/no. of Dose PO/ subjects/route of or comparator application site
Sigmund and McNally (1969)
Open/n ¼ 34 healthy 15 drops of essence Manometrical subjects/gastric of peppermint/saline recording of lower lumen (n ¼ 7) esophageal (intrasphincteric) and gastric pressure Open, randomized/ 0.2 ml/placebo 15 min after 0.5 mg n ¼ 6 healthy i.m. neostigmine subjects/colonic colonic motility lumen recording by triple lumen catheter
Duthie (1981)
Method(s)
Leicester and Hunt (1982) Open/n ¼ 20 PO; dose not given patients undergoing diagnostic or therapeutic coloscopy/colonic lumen
Visual observation via colonoscope
Taylor et al. (1983)
Open, randomized/ n ¼ 6 healthy subjects/rectosigmoidal lumen
After 0.5 mg neostigmine i.m. intraluminal pressure recording
Rogers et al. (1988)
Open, randomized/ 0.1 ml/placebo n ¼ 5 healthy subjects/colonic lumen Matched pairs/n ¼ Enteric coated PO/ 19 IBS patients/oral placebo treatment 2 weeks
Wildgrube (1988)
Dalvi et al. (1991)
Sparks et al. (1995)
0.2 ml/placebo
30 min after 0.5 mg neostigmine intracolonic pressure recording for 30 min Oro-cecal transit time (hydrogen exhalation) and total gastrointestinal transit time (carmine red) Radiolabelled test meal and recording of gastric emptying by gamma camera
Results
Comments/ conclusions
25/27 1–7 min post dose decrease in intra-sphincteric pressure; no saline effect o2 min inhibition of motor activity up to 23 min (mean 12 min); po0:05 PO/ placebo
It is concluded that heartburn after PO is associated with the relaxation of lower esophageal sphincter
Within 30 s relieve of PO is useful in colonic spasms reducing spasms thus allowing easier passage of instrument or assisting in polypectomy Up to 20 min inhibition of colonic motor activity; placebo no effect Significant increase in colonic motor activity after PO
Oro-cecal transit time doubles from 40 to 80 min (po0:05); total transit time increase from 39 to 46.5 h (po0:05) Open/n ¼ 20 healthy 0.2 ml versus no Basal emptying: subject; 10 younger treatment 100 min young; (21 yr),10 older 160 min old; 227 min (40 yr); n ¼ 6 dyspepsia; after PO dyspepsia patients/ significant oral solution shortening: young 81,old 110, dyspepsia 148 min Double blind/141 0.24 ml PO in X-ray films reviewed No residual spasm in patients standard barium sulphate by 2 independent 60% with PO versus contrast barium contrast medium or radiologists for 35% with out enema examination; without PO colonic spasms (po0:001) n ¼ 71 standard barium preparation, n ¼ 70 standard plus PO/oral
Georg and Spilker (1998) Multiple cross over?/ Oral 90 mg PO or n ¼ 12 healthy caraway oil subjects/oral encapsulated/saline/ cisaprid/10 mg/ butyl- scopolamine rectal
Gastric and gall bladder emptying time by sonography; oro-cecal transit time (hydrogen expiration)
No influence of PO on gastric emptying time; oro-cecal transit time prolonged from 65 to 85 min (po0:05) by PO
Unexplained finding; in contrast to all other studies It is concluded that PO improves disturbed GI motility in IBS patients It is concluded that the spasmolytic property of PO is responsible for reduction of emptying time
It is concluded that PO added to barium suspension is a safe, simple and cheap method to relax the colon during barium enema examination
ARTICLE IN PRESS H.-G. Grigoleit, P. Grigoleit / Phytomedicine 12 (2005) 607–611
60 ***
35 -1
50 40
*** p<0.001 ** p<0.01 * p<0.02
Gelatine
30
Colpermin®
20
** **
10 0
Excretion rate (mg menthol h. )
mg menthol excreted per 2 hr. period
610
0-2
2-4
4-6
6-8
**
*
**
8-10 10-12 12-14
30 25 20 15 10 5 0
2
Mean total 24 h menthol urinary excretion was 95.5 mg for Colpermins and 130.9 mg for Mintecs (n.s.). The fractionated excretion pattern is shown in Fig. 2. Peak excretion was approximately 30 mg menthol/h for Mintecs at 3 h post dose with a sharp decline thereafter, whereas this rate was about 10 mg menthol/h for Colpermins extending over at least 12 h. This describes two distinct formulations. Lag time (1.07 h/0.5 h – Colpermins/Mintecs) and time to peak (5 h/2.8 h – Colpermins/Mintecs) are statistically different (po0:017 or po0:047) 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 Colpermins is not finalized within 24 h. It is interesting to note that five subjects had symptoms described as nausea and vague abdominal pain after Mintecs, 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 Colpermins 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
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Mid-point of collection (h)
Mid-point of collection (h)
Fig. 1. Urinary excretion of menthol in six volunteers ingesting either two Colpermins capsules (open circles) or the equivalent amount of peppermint oil in soft gelatin capsules (closed circles).
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Fig. 2. Mean excretion of menthol (in the form of its glucuronide metabolite), following ingestion of 0.6 ml of peppermint oil, either as Colpermins (closed circles) or Mintecs (open circles). n ¼ 13 per group.
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 4 h after ingestion with a release time of PO of up to 24 h meet such requirements. A t.i.d. regimen is thus possible and it can be assumed that over a 24 h period at the target site, i.e. the large bowel sufficient amount of PO is available to exert its pharmacological action(s).
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