WO2014184435A1

WO2014184435A1 - Cysteine or a derivative thereof for the treatment of atrophic gastritis

Info

Publication number: WO2014184435A1
Application number: PCT/FI2014/050351
Authority: WO
Inventors: Osmo Suovaniemi
Original assignee: Biohit Oy
Current assignee: Biohit Oy
Priority date: 2013-05-13
Filing date: 2014-05-12
Publication date: 2014-11-20
Anticipated expiration: 2015-11-13
Also published as: EA201591994A1; HK1223284A1; CN105492002A; EP2996687A4; FI20135503L; EP2996687A1; FI20135503A7

Abstract

The present invention concerns a pharmaceutically acceptable composition containing a cysteine selected from L-cysteine, D-cysteine and N-acetylcysteine, as an active agent, for use in treating atrophic gastritis, when administered in a dose of 300 to 1500 mg per day of said cysteine during a time period of at least 2 months, or for 3 months, or even 4 months. The invention also concerns a method for treating subjects suffering from atrophic gastritis, including administering to said subjects a composition according to the invention, including a cysteine as an active agent, using said dosage regimen.

Description

CYSTEINE OR A DERIVATIVE THEREOF FOR THE TREATMENT OF

ATROPHIC GASTRITIS

Background of the Invention

Field of the Invention

The present invention concerns a pharmaceutically acceptable composition containing a cysteine (either as L- or D-cysteine) or N-acetyl cysteine for the treatment of atrophic gastritis (in the corpus or antrum, or in both), using a specific dosage regimen.

Description of Related Art

Atrophic gastritis is a chronic inflammation of the stomach mucosa, leading to loss of gastric glandular cells and their eventual replacement by intestinal and fibrous tissues. Helicobacter pylori (H. pylori) infection is, in turn, the main pathogenic factor leading to atrophic gastritis (AG), which in turn is the single most important risk factor for carcinoma of the stomach (or gastric cancer). However, due to the fact that treatments of H. pylori infections are generally unsuccessful in treating the atrophic gastritis, the latter is generally considered to be an incurable disease, particularly if it has developed fully (i.e. is chronic).

In WO2012143608, a solution to the said problem is offered by including in the treatment of said H. pylori patients administration of a composition containing a semi-essential amino acid, cysteine, for 1-4 weeks duration. However, this treatment does not target the atrophic gastritis, which is not uncommon in the patients suffering from an H. pylori infection.

Atrophic gastritis, alone, is a well-known risk factor for gastric and esophageal cancer. About 1,469,000 cases of these cancer types are reported globally every year, i.e. they constitute almost 10% of all cancers. However, the curing rates of gastric and esophageal cancer are low.

Said type of gastritis is chronic and affects the mucosa of gastric corpus or antrum or both (i.e., corpus-antrum- or pangastritis). It is characterized histologically by chronic inflammation of the gastric mucosa with loss of glandular cells and replacement by intestinal-type epithelium (intestinal metaplasia) and fibrous tissue. Clinically, it is characterized by hypo- or achlorhydria and loss of intrinsic factor (IF) resulting in pernicious anemia.

Further, the absorption of several drugs such as dipyridamole, some iron products and antifungals (fluconazole, itraconazole), thyroxine and atazanavir is considerably impaired in an achlorhydric stomach. Particularly in senior citizens, the risk of severe intestinal infections (such as giardiasis, malaria, Clostridium difficile and E. coli EHEC) increases.

Globally, exposure to acetaldehyde is linked to more than three million new

gastrointestinal cancers per year, which represents approximately 25% of all cancers.

Using recently developed tests, such as the GastroPanel® test described in EP2203745, both atrophic gastritis and H. pylori infections can be diagnosed based on the levels of stomach-specific biomarkers in the blood. However, the conventional treatments for these conditions are not the same.

Although atrophic gastritis (AG) is mainly caused by H. pylori infections, it is not necessarily cured upon eradication of H. pylori.

Other factors associated with AG include autoimmune disorders, pernicious anemia (PA) and achlorhydria, both leading to microbial colonization of the stomach. This can also take place after eradication of H. pylori. There are considered to be about 500 million people in the world suffering from atrophic gastritis / an achlorhydric stomach.

With the development of the said biomarker test (GastroPanel®), it has become possible to determine, whether H. pylori eradication has been successful, and whether this therapy has also been successful in treating AG. Importantly, however, until now, no successful treatments are available for treating AG, in cases where it fails to recover after H. pylori eradication therapy.

Several of the microbes formed in the stomach as a result of achlorhydria (e.g. due to AG) are able to produce significant amounts of acetaldehyde by oxidation from ingested alcohol. Under anaerobic conditions, these microbes are able to produce acetaldehyde also from glucose. Acetaldehyde present in alcoholic beverages and formed from ethanol endogenously has been classified by I ARC as Group 1 carcinogen in humans.

Acetaldehyde can be eliminated from saliva or the stomach after alcohol intake and during smoking using a semi-essential amino acid, cysteine, particularly in the form of L-cysteine. More specifically, it has been shown that a formulation releasing e.g. L-cysteine in a controlled manner (e.g. the formulation known as Acetium^®) can be used to decrease the acetaldehyde concentration formed during alcohol exposure, thus minimizing the exposure to carcinogenic acetaldehyde (as described in EP 1339394). However, this decrease of acetaldehyde concentration is targeted only to the time period during alcohol exposure, whereby the effect is short-term (a couple of hours in an optimal situation), and the dose is designed only for this immediate need.

Thus, there is a need for novel dosage regimens that would be capable of targeting and treating AG, in addition to eradicating H. pylori, the major causative agent of AG.

Summary of the Invention

It is an objective of the present invention to develop a pharmaceutically acceptable composition to be administered as a dosage regimen effective for recovery of AG.

Another objective of the present invention is to develop a dosage regimen of a

pharmaceutically acceptable composition that is effective in eradicating H. pylori. These and other objectives, together with the advantages thereof over known compositions and dosage regimens, are achieved by the present invention, as described and claimed hereinafter.

This invention is based on the finding that a semi-essential amino acid, cysteine, in the form of either L- or D-cysteine (or as N-acetylcysteine), is capable of reverting (or healing, or inducing recovery of) atrophic gastritis, both in the corpus and in the antrum, when administered during a sufficient period of time. The present invention concerns a pharmaceutically acceptable composition containing one or more cysteines (selected among L-cysteine, D-cysteine and N-acetylcysteine), for use in treating AG (or an H. pylori infection), when administered in a dose of 300 to 1500 mg per day during a period of at least 2 months, often up to 2 years, and possibly for longer, preferably using a reduced dose after the first 2 - 12 months.

More specifically, the pharmaceutically acceptable composition and the dosage regime of the present invention are characterized by what is stated in the characterizing part of Claim 1.

Considerable advantages are obtained by means of the invention in that it provides an effective (but gentle) treatment of AG, which is a condition that so far has lacked any effective treatments. The invention also provides means for treating both an H. pylori infection and AG using the same composition.

Further, the said composition in the used dose has the advantage of being completely harmless to the subject.

Next, the invention will be described more closely with reference to the following detailed description.

Detailed Description of the Embodiments of the Invention

The present invention concerns a pharmaceutically acceptable composition containing a semi-essential amino acid, cysteine, particularly L-cysteine, D-cysteine or N- acetylcysteine, or a combination of 2 or 3 of these, as an active agent, for use in treating atrophic gastritis (AG) in a subject with a dose of 300 to 1500 mg per day, administered to the subject for at least 2 months.

The subjects likely to benefit from the said treatment can be sorted out using a histological sample obtained by gastroscopy, but preferably the diagnosis is carried out using a noninvasive bio marker test (such as the GastroPanel® test) on samples of body fluid (preferably blood samples) collected among selected subjects (preferably being subjects at risk for AG and its complications).

Further, the effects of the said treatment are most suitably monitored at 2-4-month intervals using stomach-specific markers (such as the biomarkers of the GastroPanel® test).

Said subjects can be either human or animal patients, preferably human patients. For documentation of the long-term efficacy and for control of eventual recurrence, it is preferred to continue the said treatment (with the said composition) for 3-, 4-, or 6 months, or up to 2 years, even after a negative biomarker test result, possibly with declining cysteine dose of 300 to 900 mg per day, after the first 6 months. Similarly, it is preferred to continue administration of the composition as a prophylactic (even after cure of AG) using a dose of 100 to 300 mg of the active cysteine agent, administered prior to drinking any alcoholic drink, with intention to decrease the risk of recurrent AG or H. pylori infection. This is also likely to decrease the risk of future gastric cancer.

In addition to the said cysteine component, the composition may also contain other active agents, e.g. conventional antibiotics, chelating agents and alpha-hydroxy acids (HICAs), or other acids (such as betaine hydrochloride or glutamic acid), or pepsin or both, to relieve any conditions related to an achlorhydric stomach and/or H. pylori infection, and with a further intention to prevent the conversion of cysteine to less reactive cystine.

The composition is preferably formulated into monolithic or multi-particular tablets, capsules, lozenges, chewing gums, or granules as such, or into the physical structure of a gel. Primarily, the formulation is intended to provide a local action by delivering the active agent(s) to its(their) desired site of action, i.e., the stomach. Thus, at least one of the carriers of the composition will be selected among those known to facilitate controlled, and particularly sustained release of the active agent(s). The term "carrier" here also includes fillers and binders. Thus, the optimal carriers are preferably selected among those capable of maintaining an effective concentration of the pharmaceutically active agent(s) in the stomach during a period of at least 30 minutes using one unit dose, targeting AG, preferably as a mono therapy.

More preferably, the used carriers are selected from those capable of controlling the releasing speed of the active agent(s) so that these compounds are released, locally, in the stomach during a period of 60-120 minutes. Examples of such carriers are substances, which are selected from the group of various chitosans, alginates, such as sodium alginate, aluminium hydroxide, sodium

carboxymethyl cellulose, sodium hydrogen carbonate, and enteric polymers, preferably from enteric polymers. Such carriers may be used either alone, particularly when the intended release time is 30-60 minutes, or as combinations of two or more substances, in cases when the intended release times exceed 60 minutes.

A single unit, or formulation, of the composition preferably comprises 50-500mg, more preferably between 50-300mg, and most suitably between 100-200mg of the cysteine(s), whereby the required daily dose of cysteine can be provided using one or more units or formulations, preferably 2-6 units or formulations per day. In this context, the "unit" or "formulation" may implicate one tablet, capsule, lozenge or chewing gum, or one measurable unit of a gel or a gel-forming liquid.

The optional further active agent(s) (such as HICAs, acid or pepsin) can be added to the formulation in amounts of 1 to 50 weight-% of the total amount of active agent(s), preferably 10 to 40 weight-%, most suitably 20 to 30 weight-%.

Thus, the composition according to the invention, which releases its contents in the stomach, contains at least one - preferably two - polymers, in the form of additives, such as carriers, fillers or binders, which have the task of keeping the formulations (and the active agent(s)) as long as possible, for two hours minimum, in the stomach, generally by forming a gel that floats in the contents of the stomach. A specific task of the polymers is to prolong the release of the active agent(s). The composition is preferably in the form of an encapsulated composition comprising a mixture of powder or granules that form a gel in the stomach. In addition to cysteine(s), the composition comprises said polymers and optional further additives. This encapsulated composition is most suitably formulated to be swallowed by the subject.

The amount of such polymers in the composition is preferably 10-50%, preferably 15-40%, and most preferably 20-30%.

According to one preferred option, cysteine(s) in the composition are mixed with the fillers needed and, after that, granulated by using enteric polymers as binders. According to this alternative, the composition can include, for example granules contained in an HPMC capsule, the granules containing a suitable filler and a suitable binder, as well as, optionally, further conventional pharmaceutical additives. An exemplary granule composition might contain:

L- or D-Cysteine or N-acetylcysteine 100 mg

Calcium hydrogen phosphate 30-50 mg

Eudragit RS-PO 40-60 mg

titanium dioxide 5-10 mg

A particularly preferred active agent is L-cysteine.

According to another option, the used carriers are selected among those that are capable of controlling the releasing speed of the active agent(s) so that these compounds are released, locally, in the mouth during a period of 60-120 minutes. Thus, the release will be controlled also by the conditions in the mouth.

Examples of carriers suitable for this kind of formulations include substances, which are selected from the group of various chitosans, alginates, such as sodium alginate, aluminium hydroxide, sodium carboxymethyl cellulose, and sodium hydrogen carbonate. Such carriers may be used either alone or as combinations of two or more substances.

This composition, which releases at least a portion of its contents already in the mouth, contains at least one - preferably two - polymers, in the form of additives, such as carriers, fillers or binders, which have the task of keeping the drug as long as possible, for two hours minimum, in the mouth so that it forms a gel that adheres to the mucous membranes. Another task of the polymers is to prolong the release of the active agent(s). Such a formulation is preferably in the form of a tablet, capsule, lozenge or chewing gum, forms a gel when placed in contact with the saliva, and is most suitably formulated to be kept in the mouth, by the subject placing it under the tongue, sucking on it or chewing on it. In addition to cysteine(s), the composition of the said formulation comprises the said polymers and optional further additives. The amount of polymers in this formulation is 10- 50%, preferably 15-40%, and most preferably 20-30%.

In general, the composition according to the present invention is formulated for release of at least a portion of its active agent(s) in the contents of the stomach. Said release is typically controlled, for example using one or more carriers.

Such a composition preferably contains also a filler in the form of calcium hydrogen phosphate (CaFffC^), which has the advantage of i) not swelling in the stomach content and ii) being suitable for direct compression. The amount of such a filler in the

composition is preferably 30-70%), most suitably 40-60%).

Further, such a composition preferably contains a binder selected among any known enteric polymers, preferably a methacrylate derivative, e.g. Eudragit, and most suitably Eudragit RS-PO. The amount of enteric polymer in the composition is preferably 2-5%, most preferably 3-4% of the entire composition.

Such a composition can also contain other conventional additives, such as titanium dioxide, preferably in minor amounts of 2- 5% of the entire composition.

In case of using polymers as carriers, it is particularly preferred to mix the polymer(s) or the active agent(s) with 10-30%), preferably 20%> of sodium hydrogen carbonate of the weight of the polymer(s).

The total amount of polymers in the composition is then, generally, 10-50%, preferably 15- 40%, and most preferably 20-30% of the total weight of the composition. A formulation intended to be swallowed by the subject is suitably in the form of a tablet or a capsule, particularly comprising a mixture of powder or granules. Most preferably, it is in the form of capsules comprising granules.

In case of the formulation being in the form of, or containing, granules (for example contained in capsules), these granules contain binders preferably selected from enteric polymers, e.g. methacrylate derivatives, the solution pH of which is 6-7 and the total amount of the weight of the preparation is 2-5%, preferably 3-4%.

Generally, the formulation prepared according to the present invention is intended to be administered to patients (subjects) suffering from AG. Using the said composition, a long- term treatment is possible and large doses can be used, because the composition of the invention contains no substances that even in large concentrations are harmful or toxic.

According to the present invention, the units or formulations are administered to a subject using a daily dose of 300 to 1500 mg of cysteine(s).

According to a preferred embodiment of the invention, the units or formulations are administered using a single dose of 50 to 300 mg, between meals, such as at 3- to 6-hour intervals, preferably at around 4-hour intervals, 2-6 times a day, preferably 4-6 times a day, most suitably to an empty stomach, e.g. at least 1 hour, preferably at least 2 hours (or within 2-5 hours) after the previous meal. According to another alternative, the daily dose of the composition of the present invention is, however, administered as a single dose, prior to bedtime, to allow the active agent(s) to react while the subject is asleep.

The present invention also introduces a novel method of treating subjects with atrophic gastritis, by administering to the said subjects (for at least 2 months), one or more units of the composition of the present invention, with a daily dose of 300 to 1500 mg of cysteine(s). To sort out the subjects most likely to benefit from the said treatment, it is preferred to screen the subjects at risk using a non- invasive test (such as the GastroPanel® test) based on stomach- specific biomarkers (such as blood biomarkers). This GastroPanel® test (Biohit Oyj) determines (by ELISA) the levels of pepsinogen I (PGI), pepsinogen II (PGII), gastrin- 17 (G-17) and H. pylori antibodies (HpAb; IgG, IgA or both), and enables calculation of the PGI/II ratio in the sample.

If the patient has developed severe atrophic gastritis, the condition is typically permanent, and the patient will require follow-up tests due to an increased risk of gastric cancer. These patients can reduce their risk of developing gastric and/or oesophageal cancer by taking units of the composition according to the invention.

Measures to reduce this risk can also include screening, e.g. using the GastroPanel® test. According to the present invention, these measures are recommended for subjects with an achlorhydric or low-acid stomach caused by atrophic gastritis resulting from H.pylori infection or an autoimmune disease (500 million subjects affected worldwide).

Thus, according to an embodiment of the present invention, the subjects to undergo treatment with the composition of the invention are selected using a simple blood test, which optionally is processed to give a serum or plasma sample. Preferably, the test is carried out on a fasting sample, most suitably a fasting plasma sample.

Particularly, the test includes a step of quantitatively measuring the biomarkers indicative for H. pylori infection or AG using the said test, these biomarkers comprising pepsinogen I (PGI), pepsinogen II (PGII), pepsinogen I/II ratio (PGI/II), gastrin- 17 (G-17) and H. pylori antibodies (HpAb).

The H. pylori antibodies are preferably IgG or IgA antibodies, or both. The combination of IgA and IgG antibodies has the advantage of increased reliability as compared to testing for one antibody only. Since patients with atrophic gastritis often suffer also from an H. pylori infection, determining whether the patient has this infection using the same bio marker test is advantageous. Nearly all H. pylori -infected individuals (>90%) exhibit H. /r /orz-specific IgG antibodies, and most (approximately 70%) of these individuals also exhibit IgA antibodies. However, approximately 7% of infected individuals are positive for IgA antibodies but negative for IgG antibodies.

The most suitable cut-off values for the above named biomarkers have been selected as follows: pepsinogen I 30 μg/l, for the PGI/PGII ratio 3.0, for Gastrin- 17 2 or 5 pmol/1, and for HpAb 30 EIU (enzyme immunoassay units), while the reference ranges have been selected as follows: pepsinogen I 30 - 160 μg/l, pepsinogen II 3-20 μg/l, the PGI/PGII ratio < 3.0, Gastrin- 17 2-30 pmol/1 and HpAb 0 - 30 EIU. It is particularly preferred to measure the Gastrin- 17 value from either a stimulated sample to give a Gastrin- 17S value, with a cut-off value of 5 pmol/1 (reference range of 5-30 pmol/1), or from a fasting sample to give a Gastrin-17B value, with a cut-off value of 2pmol/l (reference range of 2-10 pmol/1). The normal reference values (for healthy subjects in large clinical series) are:

PGI 30-165 ug/1

PGII 3-10 ug/1

G-17B 1-10 pmol/1

IgG-Hp <30 EIU

Using the combination of these four biomarkers, it is possible to reliably diagnose AG of the corpus or antrum or in both (pangastritis).

The bio marker values indicative for AG in the corpus are: pepsinogen I or II concentration in blood sample being below the reference range, the PGI/PGII ratio being below the reference range, and gastrin- 17 concentration being above the reference range. The H. pylori IgA and IgG antibodies, in turn, function as markers of H. pylori infection

Using the conventional tests for H. pylori infection and PG I and PG II concentrations, it is not possible to obtain information on the function the whole stomach mucosa, because the PG I level and PGI/II ratio only reveal AG of the gastric corpus, not in the antrum. The assessment of the function and structure of antrum mucosa is extremely important because AG in most cases has its onset in the distal stomach (antrum and angulus), from where it may extend to the corpus. More precisely, the level of PGI and the PGI/II ratio are markers of the function and structure of corpus mucosa, while the level of G-17 and the levels of the H. pylori IgA and IgG antibodies function as markers of the function and structure of antrum mucosa. The H. pylori antibodies, of course, also indicate an active H. pylori infection.

Thus, the patients with an H. pylori infection and a low G-17 value either have atrophic antral gastritis, and/or so-called antral predominant gastritis characterized by a high acid output and a high risk of peptic ulcer disease. To confirm the diagnosis, these patients should undergo gastroscopy and biopsy examinations, because of an increased risk for precancer lesions or early cancer of the antrum. Such patients may also be at increased risk for gastroesophageal reflux disease (GERD) and its complications.

After initial results from the said described biomarker tests (e.g. the GastroPanel test), AG of the antrum can be confirmed or excluded by assaying the concentration of protein- stimulated G-17 in the plasma. In case of antrum atrophy, the fasting level of G-17 is low due to the absence of the G-cells and the protein stimulation cannot increase the G-17 level. Gastric acid in turn inhibits the secretion of G-17, and in cases with high intra-gastric acidity alone, protein stimulation clearly raises the plasma level of G-17 (the G cell population in antrum is normal).

It is thus possible to distinguish the subjects with AG in the antrum from those whose low fasting concentration of G-17 is entirely due to high acid secretion. If the antrum is not atrophied, protein stimulation increases the level of G-17 in the blood to over 5,0 pmol/1. In contrast, if the protein- stimulated G-17 concentration remains below 5.0 pmol/1 and the subject has a H. pylori infection, it is very likely that the patient has AG of the antrum.

The relation between low G-17, antrum atrophy and high acid secretion is explained by the well-known physiological feedback mechanism between the antrum and the corpus. Subjects without an H. pylori infection and with G-17 fasting values of less than 2.0 pmol/1, who have increased G-17 levels following protein stimulation, may be at risk for the severe complications of GERD, i.e., erosive esophagitis and Barrett's oesophagus. This risk is significantly more likely if the fasting level of G-17 is 1.0 pmol/1 or lower. The PG I level is generally normal or high in these subjects. The detection of G-17 and subsequent early diagnosis of AG of the antrum provides possibilities to find subjects at significant risk for cancer in the gastric antrum, as well as subjects at particular risk for peptic ulcer diseases. Bleeding peptic ulcers are severe complications of peptic ulcer disease and constantly increasing due to the use of NSAID (non-steroid anti-inflammatory drugs) medication.

It is also important that the diagnosis of AG, limited to gastric corpus (low PGI and low PG I/II ratio), is confirmed by the high G-17 level. This is due to the physiological feedback mechanism between the corpus and antrum, where lack of PGI and the consequent lack of acid secretion results in increased G-17 production and secretion.

On the other hand, a low plasma level of G-17 with a low level of PGI (and/or low PGI/II ratio) enable to delineate the subjects at highest risk for gastric cancer; i.e., those with extended and severe AG in both the antrum and corpus.

A subject with moderate or severe AG in the antrum (low levels of G-17 and positive H. pylori IgA and IgG antibodies) has an 18-times higher risk for gastric cancer than a healthy subject. A subject with moderate or severe AG in the corpus (low level of PG I and /or low PG I/II ratio and high level of G-17) has "only" a 5-times higher risk for cancer than a healthy subject. If both the corpus and antrum have moderate or severe atrophic gastritis, however, the risk of gastric cancer is increased by 90 times.

The described biomarker tests (e.g. the GastroPanel analysis) also identifies asymptomatic subjects who are at risk of complications due to GERD (approx. one third of GERD patients are asymptomatic). Among GERD subjects with heartburn symptoms, NERD (non-erosive reflux disease) is likely if the levels of the present biomarkers are normal. ERD (erosive reflux disease) in turn is likely if the levels of the other biomarkers are normal, except for low G-17 level (< 1 pmol/1). ERD is a serious complication, which in some cases may predispose to development into Barrett^'s oesophagus and even

oesophageal cancer.

A feature that is particularly relevant for the present invention is that, using the

GastroPanel® biomarker test, it is also possible to specifically distinguish between subjects who suffer from H. pylori -related gastritis and subjects who suffer from only chronic AG. The former usually have normal PGI, elevated PGII, elevated G-17 and elevated HpAb IgG, while the latter generally have reduced levels of PGI and PGII, a PGI/II ratio of < 3.0, a variable G-17 level and a negative result for the HpAb IgG.

Further, unlike the H. pylori tests in current use (¹³C urea breath test and stool antigen test) for diagnosing dyspepsia (various upper abdominal complaints), the above described GastroPanel biomarker test reliably detects H. pylori infection and reveals atrophic gastritis and associated cancer and other risks.

The 13C urea breath test (UBT), stool antigen test and antibody tests alone do not detect atrophic gastritis of the corpus caused by H. pylori infection or autoimmune disease, or atrophic gastritis of the antrum caused by H. pylori infection.

In addition, the 13C urea breath test and stool antigen test may give up to 40% false negative results.

As much as 20-40%) of the Western population suffers from dyspepsia, which, according to conventional medical practice, requires gastroscopy. There are no resources available, nor is there any need for such examinations or high-risk experimental medications. The GastroPanel biomarker test allows only ill and at-risk patients to be referred for

gastroscopy and treatment. This increases patient safety, and saves 40-70%) of scarce and expensive endoscopy capacity to be used for colonoscopies to prevent colorectal cancer. Particularly with elderly people, problems in the colon are often the cause of dyspepsia complaints. It is therefore advisable to supplement GastroPanel with a Colon View test in these elderly patients to select at-risk patients for colonoscopy. Researchers further recommend screening also asymptomatic patients.

Biomarker tests are non- invasive, and thus particularly suitable for diagnosing and screening atrophic gastritis and related risks in both asymptomatic patients and patients with abdominal discomfort.

The following non-limiting example is intended merely to illustrate the advantages obtained with the embodiments of the present invention. Example 1 - Treatment of AG according to the present invention

A study was conducted on 13 human volunteers, who all suffered from total AG, confirmed on endoscopy. At baseline, GastroPanel® examination (measuring the blood concentration of pepsinogen I, pepsinogen II, the PGI/II ratio, gastrin- 17 as well as H. pylori IgG and IgA antibodies) also revealed significantly reduced levels of PGI in the said volunteers, combined with increased levels of G-17.

The patients were given 3 units of the "test composition" of the invention, to be swallowed before every meal, continued for 3 months.

The test units were HPMC capsules each containing lOOmg L-cysteine, mixed into a granular composition that also included Eudragit RS-PO (about 50mg), calcium hydrogen phosphate (about 40mg) and titanium dioxide (about 8mg).

After completion of the treatment, the patients were re-tested with the GastroPanel® assay, with the results shown in Table 1.

Table 1. The results of a 3 -month treatment with the composition of the present invention of 13 patients with severe AG of the gastric corpus (PGI and PGII indicated in μg/l, and G-

17 in pmol/1)

Age Sex PGI PGI G-17 G-17 PGII PGII

(F / M) To Ti To Ti To Ti

1 42 F 5.2 9.3 34 27 5.8 3.1

2 51 F 9.6 14.2 62 46 7.6 9.2

3 27 F 6.3 9.5 51 47 9.3 6.3

4 46 M 8.5 10.2 47 43 10.5 9.2

5 44 F 10.3 16.3 33 21 8.4 8.9

6 43 F 14.5 15.2 39 34 5.2 6.3

7 38 F 18.2 19.3 56 57 8.9 7.7

8 43 F 3.2 6.4 29 27 6.3 6.8

9 50 F 7.4 10.3 33 24 10.2 9.2 10 43 F 4.3 5.6 41 33 6.7 6.2

1 1 51 F 5.1 7.9 24 21 5.8 8.3

12 47 M 7.8 10.1 50 44 7.3 6.4

13 55 F 1.9 1.2 9.8 2.2 5.7 3.5

As compared with the baseline values, PGI levels were markedly increased (p=0.0039, Wilcoxon test) in 12 of the 13 subjects, whereas the levels of G-17 were markedly decreased (p=0.0078) in 12 of the 13 subjects. Similarly, the PGI/II ratio was markedly increased in 12 of the 13 subjects.

Of these subjects, only 2 reported some post-prandial distress at the time of the 3-month follow-up, while the others were asymptomatic. This treatment was continued and the situation monitored for a total period of 6 months, whereafter two exemplary subjects displayed the results shown in the following Table 2.

Table 2. The results of a 6-month treatment with the composition of the present invention of 2 patients originally having severe AG of the gastric corpus

Thereby, it is clear that the improvement in the gastric condition of the subjects continues. The treatment and the monitoring was continued even beyond this 6-month treatment (at least for a full year), whereby the values were normal in a majority of the subjects after 2 years had passed from the onset of the study. The regular administration of the medication was discontinued after one year from the onset of the study, when the subjects had normal levels of PGI and G-17, while commonly a different dosage regime was adopted (self- administration of the test composition in connection with meals and consumption of alcoholic drinks).

Claims

1. A pharmaceutically acceptable composition containing one or more cysteines selected from L-cysteine, D-cysteine and N-acetylcysteine, as active agent(s), for use in treatment of atrophic gastritis, with a daily dose of 300 to 1500 mg of cysteine(s), administered for at least 2 months.

2. The composition according to claim 1, characterized in that it is administered for at least 3 months, preferably at least 4 months.

3. The composition according to claim 1 or 2, characterized in further containing one or more carriers selected among the carriers that are capable of maintaining an effective concentration of the pharmaceutically active agent in the stomach contents for at least 30 minutes using one unit dose.

4. The composition according to any of claims 1 to 3, characterized in that the carrier is selected from carriers that are capable of controlling the releasing speed of the active agent(s), to enable their release in the upper gastrointestinal tract, particularly in the stomach, during a period of 30-120 minutes, and preferably within 60-120 minutes.

5. The composition according to any of claims 1 to 4, characterized in being developed for use as mono -therapy.

6. The composition according to any of claims 1 to 5, characterized in that a single unit dose of the composition comprises 50-500mg, preferably 50-300mg, and most preferably

100-200mg of the active agent(s).

7. The composition according to any of claims 1 to 6, characterized in that the carrier comprises one or more substances, selected among the group of chitosans, alginates, e.g. sodium alginate, aluminium hydroxide, sodium carboxymethyl cellulose, and sodium hydrogen carbonate, as well as enteric polymers, preferably at least one or more polymers from said group.

8. The composition according to claim 7, characterized in that the composition comprises 10-30%, preferably 20% sodium hydrogen carbonate of the weight of the polymers.

9. The composition according to claim 7 or 8, characterized in containing a total amount of polymers adjusted to 10-50%), preferably 15-40%), and most preferably 20-30%> of the weight.

10. The composition according to any of claims 1 to 9, characterized in that it comprises granules containing, as binders, enteric polymers, preferably methacrylate derivatives, with a solution pH of 6-7 and a total weight of 2-5%, preferably 3-4%, of the composition.

11. The composition according to any of claims 1 to 10, characterized in that it is in the form of monolithic or multi-particular tablets or capsules, or granules as such, or it has the physical structure of a gel, preferably a tablet or a capsule comprising a mixture of powder or granules.

12. The composition according to any of claims 1 to 11, characterized in that it is in the form of capsules, intended for daily use at 4-hour intervals, particularly 6 times a day, preferably to an empty stomach at least 1 hour, more preferably 2-5 hours after the previous meal.

13. Treatment of a subject suffering from atrophic gastritis, including administering to said subject a composition according to any of claims 1 to 12, with at least one of L,-D-, and N- acetylcysteine as active agent(s), using daily dose of 300 to 1500 mg of the active agent(s), and administered for at least 2 months.