WO2010092467A1

WO2010092467A1 - Medicament comprising terpenoid cholinesterase inhibitor for treatment of dismotility disorder

Info

Publication number: WO2010092467A1
Application number: PCT/IB2010/000274
Authority: WO
Inventors: Carlo Ghisalberti
Original assignee: Carlo Ghisalberti
Priority date: 2009-02-13
Filing date: 2010-02-12
Publication date: 2010-08-19

Abstract

The present invention refers to the use of certain terpenoids having high cholinesterase inhibitory activity in the manufacturing of a composition to treat a foregut dysmotility disorder, wherein said terpenoids act as prokinetic agent by fastening the postprandial gastric empty. The composition may further comprise a gastric pH-modifier agent such as an antacid, a proton pump inhibitor, a H₂-receptor antagonist, or a parietal cell activator.

Description

MEDICAMENT COMPRISING TERPENOID CHOLINESTERASE INHIBITOR FOR TREATMENT OF DISMOTILY DISORDER

FIELD OF THE INVENTION The invention refers to a composition comprising a terpenoid cholinesterase inhibitor to treat gastroesophageal (foregut) dysmotility disorders with erosive and non-erosive manifestation.

BACKGROUND Non reflux and reflux dyspepsia (alias gastroesophageal reflux disease, or GERD) are common conditions affecting around 29% of the population with a significant impairment of their quality of life. Only 20% of those consult a doctor, but this accounts for 2-8% of all primary care consultations. Almost all of those who consult receive a prescribed medication, and half of all patients with dyspepsia take OTC medications Current standard therapies in said digestive disorders aim at suppressing gastric acid secretion to limit the exposure of the esophagus to acidic gastric contents, hence include proton pump inhibitors, histamine H2-receptor antagonists, prostaglandin analogues, and antacids.

A different approach is provided by prokinetic agents, drugs working by the increase of GI peristalsis, lowered esophageal sphincter pressure, stimulation of gastric motility and enhanced gastro-duodenal coordination. Antidopaminergic GI prokinetics such as bromopride, clebopride, domperidone, levosulpiride and metoclopramide are applied in the management of upper GI tract motility disorders, including functional dyspepsia, gastric stasis and emesis. The prokinetic effect is mediated by the blockade of enteric (neuronal and muscular) inhibitory D₂ receptors. Their pharmacological profiles differ in terms molecular structure, affinity at D₂ receptors, ability to interact with other receptor systems (5-hydroxytryptamine-3 (5-HT₃) and 5-HT₄ receptors for metoclopramide; 5-HT₄ receptors for levosulpiride) and ability to permeate the blood brain barrier "BBB" (compared with domperidone, which does not cross the BBB). The serotonergic (5-HT₄) component of some antidopaminergic prokinetics may enhance the therapeutic efficacy in functional dyspepsia and diabetic gastroparesis. However, the antagonism of central D₂ receptors can lead to both therapeutic, e.g. anti-emetic effect due to D₂ receptor blockade in the area postrema, and adverse effects, including extrapyramidal dystonic reactions and hyperprolactinaemia, the latter being a side-effect occurring with all antidopaminergic prokinetics although to different extents. Extrapyramidal reactions are commonly observed with compounds crossing the BBB, although with some differences amongst the various agents, due to their differentiated dissociation constant to D₂ receptors in the nigrostriatal pathway.

For these reasons, working alternatives to the current prokinetic drugs is in progress. For example U.S. Pat. No. 20090246233 recently disclosed a treatment of gastroparesis and nonulcer dyspepsia with GABA-B agonists, notably d-baclofen.

Another approach is the use of cholinesterase inhibitors as effective prokinetic agents, notably by alkaloidal ChE inhibitor such as neostigmine, with a therapeutic range of 0.01-lμM, as highlighted by Sanger et al.Pharm Res. 2008, 58:297-301.

Noteworthy, the AChE target is also known as "true cholinesterase" (E.C. 3.1.1.7), the other cholinesterase enzyme is butyrylcholinesterase (BChE) or "pseudocholinesterase"

(E.C. 3.1.1.8) which is differentiated from AChE in the reduced substrate specificity and susceptibility to inhibitors. While the role of AChE in neurotransmission - including its effect on GI motility - is well defined, the physiological function of BChE is less understood. The anti-BChE activity may be relevant in detoxication, e.g. scavenging of organophosphate and carbamate; inactivation of drugs such as cocaine, aspirin and amitriptyline; or activation of others such as bambuterol and heroin, as well as in regulating cholinergic transmission in paucity of AChE (e.g. in Alzheimer disease)

Actually the ChE inhibitors are studied as potential leads for drug development in CNS disorders, i.e. attractive targets in treatment of Alzheimer's disease, in the recovery of victims of nervine gas, as well as for their potential use as anti-plasmodial agents.

Hence, the AChE and BChE inhibitory activities is being closely monitored and found out in several plant metabolite, e.g. in coumarin, anthroquinone, and stilbene derivatives

(Orhan, Z. Naturforsch. 2008; 63c:366-70); in abietane diterpene and other terpenoids

(Hougton, Planta Med 2004; 70:201-4); in anthrones and related substances (Lenta, Chem Pharm Bull. 2008; 56(2) 222-6), and in many other research and review articles. However, no teach has been given thereto on their potential use in gastric disorders.

It has been found out that an efficacious therapy in foregut dysmotility disorders may be carried out by compounds with a broad effect on the cholinergic system in upper GI, possibly without the noxious systemic effects, e.g., of the alkaloidal ChE inhibitor.

SUMMARY

The present invention is based on the discovery that an efficient treatment in digestive disorders is feasible by certain plant metabolites having cholinesterase inhibitory action.

Therefore, the present invention relates to a new medicinal use of terpenoids acting as cholinesterase (ChE) inhibitors, hereinafter 'terpenoid ChE inhibitor".

More particularly the invention relates to the use of certain terpenoid ChE inhibitors in the treatment of foregut dysmotility disorders, including functional dyspepsia, gastroparesis, non reflux dyspepsia, and reflux dyspepsia (alias GERD).

The present invention also provides the medicinal and functional food composition to treat the aforesaid digestive disorders comprising one or more ChE inhibitor.

The invention also provides the composition to treat the foregut dysmotility disorders comprising a terpenoid ChE inhibitor in combination with a gastric pH-modifier.

In one aspect, the gastric pH-modifier to be combined with a terpenoid ChE inhibitor is an antacid to promptly depress the stomach acidity. In another aspect, the gastric pH-modifier to be combined with a terpenoid ChE inhibitor is a proton pump inhibitor or a H₂-receptor antagonist to slowly depress the stomach acidity.

In a further aspect, the gastric pH-modifier to be combined with a terpenoid ChE inhibitor is a parietal cell activator to enhance the stomach acidity. The present invention furthermore provides a method for the treatment of a subject suffering from dyspepsia and related conditions which comprises administering a therapeutically effective amount of a terpenoid ChE inhibitor.

In a further aspect preferably a terpenoid ChE inhibitor is administered in combination with a gastric pH-modifier such as al) an antacid; a2) a proton pump inhibitor, or; b) a parietal cell activator in order to provide a fast, slow relief of the excess stomach acidity, or enhance thereof, respectively. DETAILED DESCRIPTION

The definition "terpenoid ChE inhibitor" as used herein means a mono-, sesqui-, di- and tri-terpene having a 50% inhibitory activity on AChE [ICso( AChE)] and/or BChE [IC₅o(BChE)] at micromolar concentration, i.e. less than 900μM, typically 0.1-900 μM.

In accordance with the invention, it has been found that terpenoid ChE inhibitor acting as specific AChE or mixed AChE/BChE inhibitor can be efficiently used to treat dyspepsia, including functional dyspepsia, gastroparesis, non reflux dyspepsia, and reflux dyspepsia. Suitable such terpenoids are listed herewith after.

Thymohydroquinone IC₅₀( AChEI) = 8 x 10² μM

(+/-)-α-Pinene IC₅₀(AChEI) = 5 x 10² μM

Eucalyptol IC₅₀(AChEI) = 4 x 10² μM

Carvacrol IC₅₀(AChEI) = 4 x 10² μM Thymoquinone IC₅₀(AChEI) = 3 x 10² μM

(+/-)-Carvone IC₅₀(AChEI) = 2 x 10² μM

Dihydrocarvone IC₅₀(AChEI) = 2 x 10² μM

3-Carene IC₅₀(A/ChEI) = 2 x 10² μM β-Caryophyllene IC₅₀(AChEI) = 1 x 10² μM Leucisterol IC₅₀(A/BChEI) = 5 x 10¹ μM

Nootkatone IC₅₀(AChEI) = 2 x 10¹ μM

Ursolic acic IC₅₀(AChEI) = 1 x 10° μM

Diterpenoids of Salvia mϊitiorrhiza^ IC₅₀(AChEI) = 1 - 150 x 10° μM Triterpenoids of Salvia sclareoides™ IC₅₀(AChEI) = 0.5 - 5 x 10° μM (^a) molecules and relevant structures in Planta Med. 2004; 70(3):201-4.

^(b) molecules and relevant structures in Chem & Biodiv. 2004; 1(6): 819-29. The afore said terpenoids can be used as supplied at high grade of purity, preferably at min. 90% of purity thereto obtained by suitable isolation method, e.g. distillation, from plant material or plant extracts comprising thereof. Pure terpenoids are ready available from vendors, e.g. eucalyptol, α-pinene, carvacrol, carvone, dihydrocarvone, nootkatone, β-caryophyllene, ursolic acid; whilst mixed terpenoid ChE inhibitors are obtained from extract of S. miltiorrhiza or S. sclareoides.

Further suitable ChE inhibitors are terpenoid and xanthones from Polygala alpestris (Z Naturforsch. 2004; 59c:335-8), Garcinia mangostana (Chem Pharm Bull. 2003; 51(7): 857-9); or from Gentiana campestris (Planta Med. 2004; 70(10): 1011-4).

Preferred terpenoid ChE inhibitors are β-caryophyllene and nootkatone.

The nutritional/pharmaceutical composition of invention can be prepared by conventional techniques with physiologically acceptable excipient(s) and carriers. As used herein, a composition or compound is "physiologically acceptable" if it is suitable for use with humans and/or other animals without undue adverse side effects such as toxicity, irritation, and allergic response.

The physiologically acceptable excipient can be solid diluents (e.g. lactose), disintegrants (e.g. corns tarch), granulating agents, lubricants (e.g. Mg stearate, talc), thickeners (e.g. paraffin, waxes), flavouring agents, colouring agents, wetting agents, emulsifying agents, dispensing agents, preservatives (e.g. parabens, benzoic and sorbic acid), isotonic agents (e.g. sugar, NaCl), fillers, sweeteners, antioxidants, coating materials, buffering agent, and so on.

The nutritional and pharmaceutical composition may use solid, semi-solid, or liquid carriers to facilitate the delivery of the active ingredients.

As used herein, the term "nutritional" refers to dietetic supplements and food products having nutritional/pharmaceutical benefits.

Examples of suitable unit dosage forms include, but are not limited to, a tablet, caplet, capsule (e.g., soft or hard gelatin capsule), microcapsule, pellet, pill, powder, syrup, gel, slurry, granule, suspension, dispersion, emulsion, liquid, solution, dragee, and bead.

The effective doses of the terpenoid ChE inhibitors that are applied in the unit dosage form may be ascertained by conventional method, such as in Example section. It is recommended that the unit dosage form is administered as soon as symptoms occur, preferably after a 30 minutes after meal when episodes are associated with dyspepsia. In another embodiment, the invention encompasses the use of those nutritional/ pharmaceutical composition for a medicament suitable for foregut dysmotility disorder such as functional dyspepsia, non reflux dyspepsia, and reflux dyspepsia (GERD).

The solid unit dosage form is preferably administered together with an amount of liquid that can be water, juice or any other beverage usually in the range from 100 to 500 ml. Depending on the dosage for, 1 to 4 tablets 4 times a day after meals and at bedtime or as needed are required, followed by half a glass of water or other liquid.

The liquid dosage form do generally not require the intake of an additional drink.

The actual dose an individual needs can be adjusted as a response to the amount of food or the individual's sensitivity to particular foods, beverages or spices.

The compositions of the present invention, in one embodiment, comprise at least of of the cited terpenoid ChE inhibitor as the active ingredient(s).

In another embodiment, however, the compositions can further comprise a gastric pH- modifier. The term "gastric pH modifier" as used herein includes over-the-counter (OTC) and prescription drugs as well as food-grade ingredients.

In one embodiment, a gastric pH-modifier is an antacid.

The term "antacid(s)" as used herein refers to any compound which ready react and neutralize hydrochloric acid. In the frame of the present invention antacids may be usefully added to exert a fast action on hyperacidity discomfort. Antacid agents are fully described in the following publications: G.B. 925,001, to Fielding et al., May 1,1963; and Remington: The Science and Practice of Pharmacy, Vol. II, 19^th Edition, 886-890 (1995). Antacids are already used to address the acute symptoms of several digestion- related disorders such as duodenal and gastric ulcers, stress gastritis, GERD, pancreatic insufficiency, biliary reflux, and constipation. Preferred antacids are metal alkali carbonates and bicarbonates such as sodium, potassium, magnesium and calcium carbonates and bicarbonates.

Other preferred antacids are magnesium and aluminium hydroxides.

The amount of antacid to be combined with the terpenoid ChE inhibitors is 50-2000 mg, more preferably 100-1000 mg, and even most preferably 150-500 mg per unit dose. The concomitant action of a terpenoid ChE inhibitors and at antacid produce a fast response to reflux (acid) dyspepsia while the residence time in the stomach is reduced. While the afore mentioned combinations aims to decrease the stomach acidity, there are several functional dyspepsia and gastroparetic subject in need of acidic activation. Therefore, in another embodiment, the gastric pH-modifier is a parietal cell activator.

Suitable parietal cell activators (hereinafter "PCA") include four-carbon (4C-) dicarboxylic acids, methylxanthines, and aromatic aminoacids.

The 4C-dicarboxylic acids are succinic acid (HO₂C-CH₂-CHJ-COJH); maleic acid and fumaric acid

either in their acid form, and mono or double salt thereof, e.g. Na, Ca, Mg and K salts and the hydrates, e.g. mono-sodium hexahydrate.

A preferred 4C-dicarboxylic acids for the use in the present invention is maleic acid, more preferably a maleate salt such as sodium, potaqssium and calcium maleates.

Others PCA are methylxanthines such as caffeine, theophylline, and theobromine. Others PCA are aromatic aminoacids such as tyrosine, phenylalanine, and tryptophan.

The amount of the PCA to be combined with the terpenoid ChE inhibitors is 10-1000 mg, and more preferably 150-500 mg per unit dose. The concomitant action of terpenoid AChE inhibitors and PCA induces the parietal cells to boost the gastric acid (hydrochloric acid) production in response of both stimuli. The high acidic environment allows pepsinogen to unfold and cleave autocatalytically to generate pepsin, which is the active form of the first-line proteolytic en2yme. The process as described herein end up with better and faster gastric emptying. In another embodiment, the terpenoid ChE inhibitor are used in conjunction or in combination with "drug-type" gastric pH-modifier such as a proton pump inhibitor or a H2 Receptor antagonists (H2RAs).

Suitable proton pump inhibitors include: omeprazole (Prilosec™), lansoprazole (Prevacid™); dexlansoprazole (Kapidex™), esomeprazole (Nexium™); pantoprazole (Protonix™); rabeprazole (Rabecid™).

These drugs act by irreversibly blocking the hydrogen/potassium adenosine triphosphatase enzyme system (the H⁺ZK⁺ ATPase, alias gastric proton pump) of the gastric parietal cell.

The amount of proton pump inhibitor to be used in conjunction or in combination with the terpenoid ChE inhibitors is 10-80 mg; and more preferably 20-40 mg per unit dose. Suitable H^-receptor antagonists include ranitidine (Zantac™), cimetidine (Tagamet™), famotidine (Pepcid™), and nizatidine (Axid™).

The amount of H2 Receptor antagonist to be used in conjunction or in combination with the terpenoid ChE inhibitors is 50-300 mg; and more preferably 75-150 mg per unit dose.

These GERD drugs provide short-term relief. The OTC preparations should not be used for more than a few weeks at a time. The prescription strength preparations may be taken longer, simply because they are taken under the supervision of a doctor since H₂- receptor antagonists work for about 50% of those patients with GERD symptoms. The invention also refers to a method of treating dysmotility disorders in foregut, dyspepsia, slow digestion, gastroparetic and digestive syndromes as described above comprising the administration of a composition or a functional food of invention during the digestive episodes. The method is based on the action of terpenoid ChE inhibitors. Preliminary evidences seem to be confirmatory of the aforesaid pattern. The invention will be elucidated by way of the following, non-restrictive examples.

EXAMPLES Dose finding for terpenoid ChE inhibitors

Level of inhibition of AChE and BChE can be assessed by the colorimetric method of Ellman (Biochem. Pharmacol. 1961 , 7,88-95).

If more than one ChE inhibitor is used, the following formula can be applied:

wherein for each i^nth component, its IC₅₀ is expressed as inhibitory activity in mM or μM x 1000, and MW is the molecular weight of the given ChEj inhibitor. The resulting combination achieve at least 50% inhibitory of the cholinesterase activity in a gastroesophageal volume of around 1 liter, i.e. calculated after meal intake. Preliminary tests on the composition in subjects suffering from gastroesophageal dysmotility disorder indicate a significant reduction of the symptoms and discomfort associated with dyspepsia and/or heartburn. The improved upper GI transit may be monitored by the decrease of the orocaecal transit time determined by the non-invasive lactulose H₂ breath test using a Micro-H₂ apparatus by Micromedical Ltd (Northbrook, IL, USA). As soon as lactulose reaches the colon, the metabolism of the non-absorbable disaccharide starts and the pulmonary H₂ excretion in expirate increases. Orocaecal transit is considered accomplished when an increased H₂ concentration of at least 15 ppm over basal concentration is recorded. The following composition are carried out according standard formulation techniques.

Example 1 - Tablets for mild dyspepsia

Ingredients Ouantitv ( per tablet)

Carvacrol 40% adsorbed on silica (*) 75 mg

Ursolic acid 2 mg

Salvia sclareoides extract 25 mg

Sorbitol 100 mg

Corn starch / 35.2 mg

Talc 6 mg

Magnesium stearate 1 mg

Colloidal silica 2 mg

Lemon flavour 2 mg

Ethanol 95° q.s. for granulation

(*) Macroporous silica Sipemat™ 2200 from Degussa (Germany)

Example 2 — Hard gel capsules for mild GERD Ingredients Ouantitv (per capsule^*) β-Caryophyllene 40% adsorbed on silica (*) 125 mg Magnesium hydrate 250 mg

Cellulose (microcristalline) 50 mg

Colloidal silica lO mg

PVP K 30 0.5 mg Purified water q.s. for granulation Other ingredients: succinated gelatin (capsules).

(*) Macroporous silica Sipernat™ 2200 from Degussa (Germany)

Example 3 - Medicated capsules with proton pump inhibitor The same composition of Example 2 is prepared with 40 mg of omeprazole instead of the 250 mg of magnesium hydrate.

Example 4 - Medicated capsules with a H?-receptor antagonist

The same composition of Example 5 is prepared with 150 mg of ranitidine instead of the 250 mg of magnesium hydrate..

Example 5 - Hard gel capsules for functional dyspepsia

Ingredients Quantity (per capsule)

Eucalyptol 40% adsorbed on silica (*) 125 mg α-Pinene 40% adsorbed on silica (*) 50 mg

Maleic acid 150 mg

Theophylline 25 mg

Cellulose (microcristalline) 75 mg

Colloidal silica 10 mg PVP K 30 0.5 mg

Purified water q.s. for granulation

Other ingredients: succinated gelatin (capsules).

(*) Macroporous silica Sipernat™ 2200 from Degussa (Germany)

Example 6 - Hard gel capsules for hypogastric gastroparesis

Ingredients Quantity (per capsule)

Carvacrol 40% adsorbed on silica (*) 75 mg

Nootkatone 5 mg _.

Maleic acid 150 mg

Caffeine 25 mg 1-Tyrosine 50 mg

Colloidal silica 10 mg

PVP K 30 0.5 mg

Purified water q.s. for granulation (*) Macroporous silica Sipernat™ 2200 from Degussa (Germany)

Example 7 - Tablets for reflux dyspepsia

Ingredients Quantity (per tablet)

Dihydrocarvone 40% adsorbed on silica (*) 15 mg P o Iy gala alpestris extract 50 mg

Gentiana campestris extract 20 mg

Calcium carbonate 1000 mg

Sucralose 4 mg

Corn starch 30 mg Dextrose 100 mg

Magnesium stearate 2 mg

Maltodextrin lO mg

Mannitol 40 mg

Cellulose (microcristalline) 50 mg Sodium croscarmellqse. 4 mg^"

(*) Macroporous silica Sipernat™ 2200 from Degussa (Germany)

Example 8 - Liquid suspension with high buffering capacity Ingredients Quantity (per 10 ml) Eucalyptol 15 mg β-Caryophyllene 40 mg

Magnesium hydroxide 200 mg

Aluminum hydroxide 200 mg

Hydroxypropyl methylcellulose 50 mg Dextrose monohydrate 30 mg Sucralose 0.5 mg

PEG-castor oil (Cremophor™ RH40) 50 mg

Parabens (methyl & propyl) 0.02 mg

Purified water q.b. to 10 ml (*) Macroporous silica Sipernat™ 2200 from Degussa (Germany)

Example 9 — Soft gel capsules for hypogastric gastroparesis

Ingredient Quantity (per capsule)

Carvacrol 30 mg β-Caryophyllene 20 mg Maleic acid 50 mg Polisorbate 80 lO mg PEG-castor oil (Cremophor™ RH40) 15 mg Caprilic/carpic tryglicerides q.b. to 0.5 ml Other ingredients: gelatin (capsules).

Example 10 - Alcoholic solution for non-erosive reflux dyspepsia

Ingredient Quantity (per 25 ml dose)

Dihydrocarvone 20 mg Salvia miltiorrhiza extract 25 mg

Salvia sclareoides extract 25 mg

Glycerine 0.5 g

Caramellose 0.1 mg

Parabens (methyl & propyl) 0.02 mg Sucrose 0.4 g Vanillin 0.25 g Hvdroalcholic solution 32° q.b. to 10 ml

Claims

' 1. Use of a terpenoid acting as cholinesterase ("ChE") inhibitor for the preparation of a composition to treat a gastroesophageal dysmotility disorder.

2. A pharmaceutical or nutritional composition to treat a gastroesophageal dysmotility disorder such as functional dyspepsia, non reflux dyspepsia, and reflux dyspepsia

(GERD) according to claim 1 comprising a terpenoid that is a ChE inhibitor, characterized in that said terpenoid has an inhibitory activity (IC₅₀) on AChE [ICso( AChE)] at less than 900 μM and in that it is selected from the group consisting of eucalyptol, α-pinene, carvacrol, carvone, dihydrocarvone, carene, β- caryophyllene, leucisterol, nootkatone, ursolic acic, diterpenoids of Salvia miltiorrhiza, and triterpenoids of Salvia sclareoides.

3. The composition according to claim 2 wherein said terpenoid ChE inhibitor is β- caryophyllene or nootkatone.

4. The composition according to claim 2 wherein said terpenoid ChE inhibitors are in admixture with xanthones such as in the extracts from Polygala alpestris, Garcinia mangostana, and Gentiana campestris.

5. The composition of according to any claims 2 to 4 wherein the terpenoid ChE inhibitor is in quantity sufficient to inhibit at least 50% of cholinesterase activity calculated on single ChE inhibition potency normalized to 1 litre volume.

6. The composition of according to claim 5 in a form of tablet, caplet, capsule, microcapsule, pellet, pill, powder, syrup, gel, slurry, granule, suspension, dispersion, emulsion, gelled liquid, solution, dragee, and bead.

7. Method for the treatment of a subject suffering from a foregut dysmotility disorder which comprises administering to said subject a composition according to any claims 2 to 6 comprising a therapeutically effective amount of a terpenoid ChE inhibitor.

8. The composition of according to any claims 2 to 6 further comprising a gastric pH- modifier.

9. The composition according to claim 8 wherein the gastric pH-modifϊer is an antacid.

10. The composition according to claim 9 wherein said antacid is a metal alkali carbonate or bicarbonate, and a magnesium or aluminium hydroxide in amount from 100 to 1000 mg per unit dose.

11. The composition according to claim 8 wherein the gastric pH-modifier is a proton pump inhibitor.

12. The composition according to claim 11 wherein the proton pump inhibitor is selected from the group consisting of omeprazole, lansoprazole; dexlansoprazole, esomeprazole, pantoprazole, and rabeprazole in amount from 20 to 40 mg per unit dose.

13. The composition according to claim 8 wherein the gastric pH-modifier is a H₂- receptor antagonist.

14. The composition according to claim 11 wherein the H₂-receptor antagonist is selected from the group consisting of include ranitidine, cimetidine, famotidine, and nizatidine in amount from 75 mg to 150 mg per unit dose.

15. Method for the treatment of a subject suffering from a foregut dysmotility disorder with predominant hyperacid reflux dyspepsia (GERD) which comprises administering to said subject a composition according to any claims 9 to 14 wherein the terpenoid ChE inhibitor is combined with at least an antacid, a proton pump inhibitor or a H₂-receptor antagonist.

16. The composition according to claim 8 wherein the gastric pH-modifier is a parietal cell activator.

17. The composition according to claim 14 wherein said parietal cell activator is selected from maleic acid, a methylxanthine, or an aromatic aminoacid, and mixture thereof in a amount from 50 to 250 mg per unit dose.

18. Method for the treatment of a subject suffering from a foregut dysmotility disorder with predominant non-acid functional dyspepsia (gastroparesis) which comprises administering to said subject a composition according to claims 14 and 15 wherein the terpenoid ChE inhibitor is combined with at least a parietal cell activator .