U.S. patent application number 12/301906 was filed with the patent office on 2009-10-08 for composition and method for binding acetaldehyde in stomach.
This patent application is currently assigned to Biohit OYJ. Invention is credited to Martti Marvola, Mikko Salaspuro, Ville Salaspuro, Osmo Suovaniemi.
Application Number | 20090253793 12/301906 |
Document ID | / |
Family ID | 38436750 |
Filed Date | 2009-10-08 |
United States Patent
Application |
20090253793 |
Kind Code |
A1 |
Suovaniemi; Osmo ; et
al. |
October 8, 2009 |
COMPOSITION AND METHOD FOR BINDING ACETALDEHYDE IN STOMACH
Abstract
This invention relates to a non-toxic composition which bind
acetaldehyde present in the stomach, intestine and/or colon. The
composition comprises one or more acetaldehyde-binding compound(s)
comprising one or more free sulphhydryl and/or amino groups. The
compound(s) are mixed with a non-toxic carrier that effects
sustained release of said compound(s) in the gastrointestinal
tract. These compositions are of benefit in particular to patients
having atrophic gastritis or achlorhydric or low acid stomach.
Inventors: |
Suovaniemi; Osmo; (Helsinki,
FI) ; Salaspuro; Ville; (Helsinki, FI) ;
Marvola; Martti; (Helsinki, FI) ; Salaspuro;
Mikko; (Helsinki, FI) |
Correspondence
Address: |
SUGHRUE MION, PLLC
2100 PENNSYLVANIA AVENUE, N.W., SUITE 800
WASHINGTON
DC
20037
US
|
Assignee: |
Biohit OYJ
Helsinki
FI
|
Family ID: |
38436750 |
Appl. No.: |
12/301906 |
Filed: |
May 22, 2007 |
PCT Filed: |
May 22, 2007 |
PCT NO: |
PCT/FI07/50287 |
371 Date: |
November 21, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60802120 |
May 22, 2006 |
|
|
|
Current U.S.
Class: |
514/562 |
Current CPC
Class: |
A61K 9/2081 20130101;
A61K 9/2866 20130101; A61K 9/06 20130101; A61K 9/2846 20130101;
A61K 31/198 20130101; A61K 31/131 20130101; A61K 9/2077 20130101;
A61P 1/00 20180101; A61P 39/00 20180101; A61K 9/5026 20130101; A61K
9/5042 20130101; A61K 9/1635 20130101; A61K 47/02 20130101; A61K
9/1611 20130101; A61K 9/1652 20130101; A61K 9/2018 20130101; A61K
9/485 20130101; A61K 47/36 20130101; A61K 9/4866 20130101; A61K
9/2054 20130101; A61P 1/04 20180101; A61K 9/2009 20130101; A61K
9/2027 20130101; A61K 9/0095 20130101 |
Class at
Publication: |
514/562 |
International
Class: |
A61K 31/197 20060101
A61K031/197; A61P 35/00 20060101 A61P035/00 |
Foreign Application Data
Date |
Code |
Application Number |
May 22, 2006 |
FI |
20060501 |
Claims
1. A non-toxic composition in the form of a monolithic or
multiparticular preparation which binds acetaldehyde present in the
stomach or in the stomach, intestine and/or colon, wherein said
composition comprises one or more acetaldehyde-binding compound(s),
comprising one or more free sulphhydryl and/or amino groups,
wherein said compound(s) are mixed with a non-toxic carrier that
effects sustained release of said compound(s) in the
gastrointestinal tract.
2. The composition according to claim 1, wherein the non-toxic
carrier does not disintegrate in the stomach, forms a gel in the
stomach that floats in the contents of the stomach or attaches to
the mucous membrane of the stomach.
3. The composition according to claim 1 or 2, wherein the
composition comprises substances selected from the group comprising
one or more acetaldehyde-binding compound(s), a polymer(s) not
disintegrating in the stomach and a bulking agent(s).
4. The composition according to claim 3, wherein the amount of
acetaldehyde-binding compound(s) is 1 to 40 w-%, the amount of
polymer(s) not disintegrating in the stomach in the composition is
10-50 w-% and the amount of bulking agent(s) in the composition is
20-70 w-%.
5. The composition according to claim 3, wherein the polymer not
dissolving in the stomach is metacrylate polymer, such as Eudragit
L, S or RS, or ethyl cellulose or a combination of these.
6. The composition according to claim 5, wherein the polymer not
dissolving in the stomach forms a matrix, allowing said
acetaldehyde-binding compound(s) to diffuse in a sustained manner
into the stomach.
7. The composition according to claim 6, wherein the composition is
in the form of a matrix tablet or matrix granule.
8. The composition according to claim 1, wherein the composition is
coated with a water-soluble film, such as
hydroxypropylmethylcellulose (HPMC) film, or it may be within a
hard gelatine or HPMC capsule or tablet or other form of
preparation.
9. The composition according to claim 1, wherein the composition
comprises substances selected from the group comprising one or more
acetaldehyde-binding compound(s), a water-soluble bulking agent(s)
and at least two film forming agents coating the composition by a
film.
10. The composition according to claim 9, wherein the amount of
acetaldehyde-binding compound(s) is 1 to 50 w-% and the amount of a
water-soluble bulking agent(s) is 50 to 80 w-%.
11. The composition according to claim 9 or 10, wherein the first
of said film forming agents is water-insoluble and the second of
said film forming agents is water-soluble, said first film forming
agent forming a continuous film and said second film-forming agent
forming pores to the film allowing said acetaldehyde-binding
compound(s) to diffuse in a sustained manner into the stomach.
12. The composition according to claim 10, wherein the
water-soluble component in the film consists of hydroxypropyl
methylcellulose (HPMC) and said water-insoluble component in the
film consists of ethyl cellulose and/or Eudragit RS.
13. The composition according to claim 1, wherein each subunit of
the composition is protected in a form so that the compounds are
not released until in the colon.
14. The composition according to claim 13, wherein each subunit of
the composition is coated with a polymer film that dissolves in an
environment with a pH of 6.5 or higher.
15. The composition according to claim 1, wherein the composition
comprises a fraction binding acetaldehyde present in the stomach
and in addition a fraction of the composition protected in a form
so that the compounds are not released until in the colon.
16. The composition according to claim 15, wherein the relative
amount of fractions for stomach and for the colon is from 1:1 to
1:3.
17. The composition according to claim 1, wherein the composition
comprises a composition protected in a form so that the compound(s)
are not released until in the intestine.
18. The composition according to claim 17, wherein each subunit of
the composition is coated with a polymer film that dissolves in an
environment with a pH 5-6.
19. The composition according to claim 1, wherein the composition
comprises a fraction for binding acetaldehyde present in the
stomach and in addition a fraction protected in a form so that the
compounds are not released until in the intestine and in addition a
fraction protected in a form so that the compound(s) are not
released until in the colon.
20. The composition according to claim 19, wherein the relative
amounts of the fractions for the stomach and the fractions for the
intestine and the fractions for colon are selected from the group
comprising 2:1:1, 1:1:1, 1:1:2, 1:2:2, 1:2:3 and 1:1:3.
21. The composition according to claim 15, wherein the fractions
are in the form of a tablet or capsule, preferably a hard gelatine
or HPMC capsule.
22. The composition according to claim 1, wherein the composition
comprises 1-500 mg, preferably 10-300, more preferably 100-200 mg
of acetaldehyde-binding substance per single dose.
23. The composition according to claim 1, wherein the composition
is in the form of a tablet, a capsule, a granule or powder or a
combination of these.
24. The composition according to claim 23, wherein the composition
is in the form of a tablet or capsule the diameter of which is
about 7 mm, preferably 8-15 mm.
25. The composition according to claim 1, wherein said one or more
acetaldehyde-binding compound(s) comprises one or more free
sulphhydryl and amino groups.
26. The composition according to claim 1, wherein said one or more
acetaldehyde-binding compound(s) is represented by formula (I)
##STR00002## wherein R.sup.1 is hydrogen or an acyl group with 1-4
carbon atoms, R.sup.2 is a sulphhydryl or sulphone group, and n is
1, 2, 3 or 4, or is a salt or a derivative of any of these
compounds capable of binding acetaldehyde.
27. The composition according to claim 1, wherein the composition
comprises one or more acetaldehyde-binding compound(s) selected
from the group comprising L-cysteine, D-cysteine, cystine, cysteic
acid, cysteine glycine, threo-.beta.-phenyl-DL-cysteine,
erythro-.beta.-phenyl-DL-cysteine,
.beta.-tetramethylene-DL-cysteine, D-penicillamine or an N-terminal
dipeptide of D-penicillamine, semicarbazide, glutathione, reduced
glutathione, DL-homocysteine, N-acetylcysteine,
L-cysteinyl-L-valine, .beta.-.beta.-tetramethylene-DL-cysteine,
cysteinyl glycine, mercaptoethyl glycine,
tre(5)-.beta.-phenyl-DL-cysteine,
erythro-.beta.-phenyl-DL-cysteine, cysteine hydrochloride, thiamine
hydrochloride, sodium metabisulphite, serine, methionine,
.beta.mercaptoethylamine, arginine, lecithin, glycine, lycine,
ammonium chloride, 1,4-dithiothreitol and mercaptanes or a salt of
any of these compounds, and optionally at least one of the
substances selected from the group comprising vitamin B12, A-, D-,
E, -C-vitamin, niacin, biotin, thiamine, B2-, B5-, B6-vitamin,
folic acid, chromium, manganese, selenium, zink and iron.
28. The composition according to claim 1, wherein said one or more
acetaldehyde-binding compound(s) is L-cysteine, D-cysteine,
D-penicillamine, N-acetylcysteine, a compound converted to
cysteine, a salt or a structural analogue of these compounds
capable of binding acetaldehyde.
29. The composition according to claim 1, wherein the compound(s)
are released in the stomach for at least 30 minutes.
30. The composition according to claim 1, wherein the compound(s)
are released in the stomach for 0.5 to 8 hours, preferably 2 to 6
hours.
31. A method for decreasing the risk of developing cancer in the
gastrointestinal tract caused by acetaldehyde, wherein the
acetaldehyde present on these areas is locally bound by using the
composition according to claim 1 into a harmless form by
administering the composition to a person in need for such
treatment.
32. A method for decreasing the risk of developing cancer in the
gastrointestinal tract caused by acetaldehyde, wherein a
composition comprising acetaldehyde-binding compound(s) is
administered to a person having atrophic gastritis or achlorhydric
or low acid stomach.
33. The method according to claim 32, wherein a composition
comprising acetaldehyde-binding compound(s) is administered to a
person having at least one of the biomarkers of atrophic gastritis
or achlorhydric or low acid stomach selected from the group
comprising pepsinogen I, pepsinogen II, pepsinogen I/pepsinogen II
ratio, gastrin-17B (fast), gastrin-17S (stimulated) and HPAB
(Helicobacter pylori antibody), the values of said biomarkers being
outside the cut-off values or the reference ranges of these
values.
34. The method according to claim 32, wherein a composition
comprising acetaldehyde-binding compound(s) is administered to a
person having at least one of the biomarkers of atrophic gastritis
of corpus selected from the group comprising low pepsinogen I
value, low pepsinogen I/II ratio, high gastrin-17 B value and high
HPAB (Helicobacter pylori antibody) value compared to the cut-off
values or reference ranges.
35. The method according to claim 32, wherein a composition
comprising acetaldehyde-binding compound(s) is administered to a
person having at least one of the biomarkers of achlorhydric or low
acid stomach selected from the group comprising high pepsinogen I
value, high pepsinogen II value, high gastrin-17 B value and high
HPAB (Helicobacter pylori antibody) value compared to the cut-off
values or reference ranges.
36. The method according to claim 32, wherein the reference range
for pepsinogen I value is 30-120 .mu.g/l, for pepsinogen II 3-10
.mu.g/l, for PGI/PGII ratio 3-20, for Gastrin-17S (stimulated)
value 5-30 pmol/l, for Gastrin-17B (fast) 2-10 pmol/l and the
reference range for HPAB 0-30 EIU.
37. The method according to claim 32, wherein typical cut-off
values for the biomarkers are selected from the group comprising:
pepsinogen I 30 .mu.g/l, pepsinogen II 3 .mu.g/l, PGI/PGII ratio 3,
Gastrin-17S (stimulated) value 5 pmol/l, Gastrin-17B (fast) 2
pmol/l and HPAB 30 EIU.
38. A method for diagnosing and treating a patient having atrophic
gastritis and an increased risk for cancer in the stomach, said
method comprising: obtaining a serum sample from a patient;
quantitavely measuring the pepsinogen I, the pepsinogen II and
gastrin-17B (fast) from said serum sample and comparing the value
obtained to the cut-off values or reference ranges; whereby the
pepsinogen I concentration in said serum sample close to the lower
limit or below the reference range or cut-off value and PGI/PGII
ratio close to the lower limit or below the reference range or
cut-off value and gastrin-17B (fast) concentration close to the
upper limit or above the reference range or cut-off value is
indicative for atrophic gastritis of corpus leading to achlorhydric
or low acid stomach and to acetaldehyde production in the stomach;
administering to the patient a composition comprising an effective
amount of acetaldehyde-binding compound(s) in connection with
eating or in a continuous manner for a sufficient time; optionally
monitoring the effect of the treatment by testing the said values
after a sufficient time.
39. A method for diagnosing and treating a patient having
achlorhydric or low acid stomach due to acid suppression medication
and an increased risk for cancer in the stomach, said method
comprising: obtaining a serum sample from a patient; quantitavely
measuring the pepsinogen I, the pepsinogen II and gastrin-17 B from
said serum sample and comparing the value obtained to the reference
ranges or cut-off values; whereby the pepsinogen I concentration in
said serum sample close to the upper limit or above the reference
range or cut-off value and PGII ratio close to the upper limit or
above the reference range or cut-off value and gastrin 17B
concentration close to the upper limit or above the reference range
or cut-off value is indicative for achlorhydric or low acid stomach
leading to acetaldehyde production in the stomach; administering to
the patient a composition comprising an effective amount of
acetaldehyde-binding compound(s) in connection with eating or in a
continuous manner for a sufficient time; optionally monitoring the
effect of the treatment by testing the said values after a
sufficient time.
40. The method according to claim 38, wherein the method comprises
an assay to detect the presence of Helocobacter pylori
antibodies.
41. of acetaldehyde-binding compound(s) for preparing a composition
for decreasing the risk for cancer in stomach, said treatment being
directed to patients diagnosed to have atrophic gastritis by the
method comprising: obtaining a serum sample from a patient;
quantitavely measuring the pepsinogen I, the pepsinogen II and
gastrin-17B from said serum sample and comparing the value obtained
to the cut-off values or reference ranges; whereby the pepsinogen I
concentration in said serum sample close to the lower limit or
below the reference range or cut-off value and PGI/PGII ratio close
to the lower limit or below the reference range or cut-off value
and gastrin-17B concentration close to the upper limit or above the
reference range or cut-off value is indicative for atrophic
gastritis of corpus leading to achlorhydric or low acid stomach and
to acetaldehyde production in stomach; administering to the patient
a composition comprising an effective amount of
acetaldehyde-binding compound(s) in connection with eating or in a
continuous manner for a sufficient time; optionally monitoring the
effect of the treatment by testing the said values after a
sufficient time.
42. Use of acetaldehyde-binding compound(s) for preparing a
composition for decreasing the risk for cancer in stomach, said
treatment being directed to patients diagnosed to have achlorhydric
or low acid stomach due to acid suppression medication, said
patients being diagnosed by the method comprising: obtaining a
serum sample from a patient; quantitavely measuring the pepsinogen
I, the pepsinogen II and gastrin-17B (fast) from said serum sample
and comparing the value obtained to the reference ranges or cut-off
values; whereby the pepsinogen I concentration in said serum sample
close to the upper limit or above the reference range or the
cut-off value and PGII ratio close to the upper limit or above the
reference range or the cut-off value and gastrin-17B (fast)
concentration close to the upper limit or above the reference range
or cut-off value is indicative for achlorhydric or low acid stomach
leading to acetaldehyde production; administering to the patient a
composition comprising an effective amount of acetaldehyde-binding
compound(s) in connection with eating or in a continuous manner for
a sufficient time; optionally monitoring the effect of the
treatment by testing the said values after a sufficient time.
43. The method or use according to claim 31, wherein the
composition is a non-toxic composition which binds acetaldehyde
present in the gastrointestinal tract, wherein said composition
comprises one or more acetaldehyde-binding compound(s), comprising
one or more free sulphhydryl and/or amino groups, wherein said
compound(s) are mixed with a non-toxic carrier that effects
sustained release of said compound(s) in the gastrointestinal
tract.
44. The method or use according to claim 32, wherein the
composition is that of claim 1.
45. The method or use according to claim 31, wherein the
composition is administered to a person before, during or after
eating.
46. The method or use according to claim 31, wherein the
composition is administered to a person diagnosed to have
Helicobacter pylori infection or a risk for gastroesophageal reflux
disease, wherein the treatment is combined with PPI or other
treatment decreasing the acidity of stomach.
47. The method or use according to claim 31, wherein the
composition is administered to a person having one or more of the
conditions selected from the group comprising hangover,
achlorhydric or low acid stomach, atrophic gastritis of corpus,
cancer or risk for cancer and metabolic syndrome.
Description
[0001] This invention relates to a composition for binding
acetaldehyde in the stomach or in the stomach, intestine and/or
colon. This invention relates also to methods for decreasing the
risk of developing cancer in the gastrointestinal tract caused by
acetaldehyde.
[0002] Both alcohol and smoking are risk factors for upper
digestive tract cancers, and the combined use thereof multiplies
the risk of developing an upper digestive tract cancer to as much
as 150-fold (Salaspuro, M. Best Pract Res Clin. Gastroenterol
(2003) 17:679-94 and Francheschi et al. Cancer Res (1990)
50:6502-07).
[0003] The first metabolite of alcohol is acetaldehyde. It has been
shown to be carcinogenic both to test animals and humans
(Salaspuro, M. Crit Rev Clin Lab Sci (2003) 40: 183-208). Alcohol
is evenly distributed in the liquid phase of the organs. Hence,
after enjoying alcohol and as long as there is alcohol in the
organs, the alcohol content in blood, saliva, gastric juice and the
contents of the intestine is the same. In that case, the microbes
in the digestive tract are capable of oxidizing the alcohol to
acetaldehyde. For example, even after a moderate dose of ethanol
(0.5 g/kg), high acetaldehyde contents of a microbial origin
(18-143 .mu.M) have been found in human saliva; in other words,
acetaldehyde builds up in saliva as an intermediate product of the
microbial metabolism (Homann et al, Carcinogenesis (1997)
18:1739-1743). During active smoking, the acetaldehyde in saliva
was increased to a value of 261.4.+-.45.5 .mu.M from the basic
level (Salaspuro et al. (2004) Int J Cancer, 2004 Sep. 10;
111(4):480-3).
[0004] Asian heavy drinkers, who have a familial low-activity
modification of the aldehyde dehydrogenase-2 (ALDH2) enzyme, have
both an increased risk of developing a cancer of the mouth, the
pharynx and the digestive tract, and an increased acetaldehyde
content of the saliva after consuming alcohol (Vakevainen et al.
(2000) Alcohol Clin Exp Res 24:873-877). Even more common is the
ADH3*1 gene/allele (ADH1C at present), which predisposes the heavy
drinkers, who have this gene, to the upper digestive tract cancers
because of increased local acetaldehyde contents. (Visapaa J-P et
al. Gut. 2004 June; 53(6):871-6.)
[0005] In the organism, acetaldehyde is thus formed from alcohol as
a consequence of the hepatic metabolism and, locally, in the
digestive tract via microbial alcohol dehydrogenase (Salaspuro et
al, (1996) Ann Med 28:195-200). The average amount of saliva
secreted by a human is 1.5 litres per day. The areas of influence
of the acetaldehyde contained in the saliva include the mouth, the
pharynx, the oesophagus and the stomach. Consequently, the effects
of acetaldehyde may extend to the whole upper digestive tract area.
On the other hand, carcinogenic acetaldehyde can be produced also
endogenously by the oral microbes from various foodstuffs with high
sugar or carbohydrate content, especially in an achlorhydric
stomach. Atrophic gastritis and achlorhydria are well known risk
factors of gastric cancer.
[0006] As a consequence of the microbial metabolism, acetaldehyde
builds up in the stomach in the case, where the stomach is free
from acid or has been made acid-free by medication Vakevainen et
al. (2000) Alimentary Pharmacology Ther 14:1511-1518) describes an
experiment, where the pH of stomach fluid was raised from pH 1.3 to
6.1. Volunteers were given ethanol (0.6 g/kg as 15 vol % solution).
After 40 minutes incubation there were in the gastric juice 0.7 to
4.1% alcohol and 30 .mu.M to 100 .mu.M acetaldehyde. The
acetaldehyde content of the gastric juice was the higher the more
there were bacteria in the stomach. In the gastric juice there were
for example Streptococcus viridans--bacteria, which have been shown
to be excellent producers of acetaldehyde. Other effective
acetaldehyde producers in acid-free stomach have been shown to be
bacteria belonging to Neisseria, Rothia and Streptococcus
salivarius (Vakevainen (2002) et al. Scand J Gastroenterol
37:648-655).
[0007] For atrophic gastritis patients, microbes produce high
acetaldehyde contents from ethanol and sugar in the stomach leading
to an enhanced gastric cancer risk among atrophic gastritis
patients (Vakevainen et al, Scand J Gastroenterol 2002 (6):
648-655). In the experiments of Vakevainen et al. sugar (3 ml/kg,
10 w-% glucose) or ethanol (0.3 g/kg; 15 vol-%) were infused to
stomach. After sugar infusion and 60 minutes incubation three
patients from 16 had 2.3 to 13.3 .mu.M endogenous acetaldehyde and
2.3 to 13.3 .mu.M ethanol in their stomach. After alcohol infusion
the average amount of acetaldehyde was 44.5 .mu.M which is 6.5
times more than what controls had.
[0008] Our recent studies show that in an achlorhydric stomach
alcohol fermentation can start very quickly by the bacteria
representing normal flora of the mouth or by yeasts present in the
foodstuffs, for example by common baker's or brewer's yeast. These
microbes can produce significant amounts of acetaldehyde and
ethanol for example from carbohydrate containing foodstuffs, such
as rice. This happens in particular, if the carbohydrate containing
foodstuff is sweetened. For example in Asian countries the use of
sweet sauces with rice is a very common practise. According to
epidemiological studies the eating of rice causes a high risk for
cancer in stomach.
[0009] In acid stomach the alcohol fermentation does not occur. On
the other hand Helicobacter pylori infection and certain
medicaments, such as Protein Pump Inhibitors (PPI) raise the pH of
the stomach.
[0010] About nearly 25% of the human population in the world
suffers from atrophic gastritis. From the Finnish population about
8 to 12% (depending on the age) suffers from atrophic gastritis and
the disease is even more common among elder people. The development
of achlorhydric stomach is a risk factor also for people having
oesophagus reflux disease, if it is treated by PPI medicamends.
About 25% of the human population in the world has this
disease.
[0011] One further risk factor are foodstuffs comprising
acetaldehyde. Our recent studies have shown that all sugar
(saccharose, maltose, lactose) containing foodstuffs including
beverages, can contain--or in the foodstuff is formed--significant
amounts of acetaldehyde, 5 to 2000 .mu.M and ethanol, 0.1 to 0.5
per mille. Some sour milks, yoghurts and juices contain
acetaldehyde and ethanol as such (PCT/FI2006/000104 incorporated
herein by reference).
[0012] It has also been shown that acetaldehyde builds up in the
large intestine, as its bacteria that represent the normal flora
are capable of converting ethanol into acetaldehyde (Jokelainen et
al, (1996) Gut 39:100-104). In the intestines, endogenous ethanol
can also be found, i.e. ethanol that is formed in the intestines in
oxygen-free conditions under the effect of microbes. Acetaldehyde
is formed, when this ethanol comes into contact with oxygen near
the mucous membrane, for example.
[0013] The prior art discloses pharmaceutical compositions which
contain compounds that bind acetaldehyde, their effect being based
on the reaction of the effective substances with the acetaldehyde
inside blood and/or cells, for example, U.S. Pat. No. 5,202,354,
U.S. Pat. No. 4,496,548, U.S. Pat. No. 4,528,295, U.S. Pat. No.
5,922,346.
[0014] Acetaldehyde, which is formed in the organism when alcohol
is consumed and thereafter, causes physiological symptoms called a
hangover. Previously, efforts have been made to decrease the
symptoms caused by acetaldehyde by taking preparations containing
ascorbic acid, thiamine, cysteine or cysteic acid, and flavonoids
or flavonoid complexes in a form of orally taken tablets in
connection with, before or after consuming alcohol. When swallowed,
the effective substances go to the stomach and small intestine and
from there into the blood circulation (Matsuoka, U.S. Pat. No.
5,202,354 and Moldowan et al, U.S. Pat. No. 4,496,548).
[0015] Suggestions have been made so as to use preparations
containing amino acids, such as L-cysteine, methionine, taurine or
arginine, ascorbic acid, vitamins A and E, which are sucked or
chewed in the mouth, to reduce the effect of detrimental free
radical compounds, which are formed when using tobacco products or
being exposed to the same. It is believed that, after being
absorbed, amino acids affect various tissues (Hersch, U.S. Pat. No.
5,922,346, Hersch, International Patent Application WO
99/00106).
[0016] Publication WO 02/36098 (incorporated herein by reference)
suggests the use of compounds containing a free sulfhydryl and/or
amino group for a local and long-term binding of acetaldehyde from
saliva, the stomach or the large intestine. The compounds were
mixed with a substance that enabled them to be released for at
least 30 minutes in the conditions of the mouth, the stomach or the
large intestine.
[0017] Publication WO 2006/037848 (incorporated herein by
reference) suggest a composition comprising one or more free
sulfhydryl and/or amino groups for removing or decreasing the
aldehyde content of the saliva during smoking.
[0018] As on the basis of our recent studies, acetaldehyde plays a
considerable part in the pathogenesis of the stomach cancers, in
particular by people having achlorhydric stomach or atrophic
gastritis. There is thus a need to find alternative ways to bind
acetaldehyde in the stomach and also lower part of digestive tract
in a harmless manner.
SUMMARY
[0019] It is an aim of the present invention to provide new
compositions, which can be used to reduce the acetaldehyde content
in the stomach. It is also an aim of the present invention to
provide new compositions, which can be used to reduce the
acetaldehyde content of small intestine (called here intestine)
and/or large intestine (called here colon).
[0020] It is also an aim of the present invention to provide new
methods and uses for binding acetaldehyde in the stomach and/or
intestine and/or colon.
[0021] It is also an aim of the present invention to provide new
methods and uses for binding acetaldehyde in the stomach and/or
intestine and/or colon of people having increased risk for cancer
in these areas.
[0022] It is also an aim of the present invention to provide new
methods and uses for treating people diagnosed to have increased
risk for cancer in the stomach and/or intestine and/or colon. In
particular, it is an aim of the invention to provide new methods
and uses for treating people having at least one of the biomarkers
of atrophic gastritis and/or achlorhydric or low acid stomach.
[0023] It is also an aim of the present invention to provide new
compositions, which mask the taste of the acetaldehyde-binding
compound)(s) in the composition. In particular, it is an aim of the
invention to protect the acetaldehyde-binding compound)(s) not to
be released too early, i.e. in mouth when they are consumed or if
they are mixed with a foodstuff, in the foodstuff.
[0024] These and other objects, together with the advantages
thereof over known compositions and methods are achieved by the
present invention, as hereinafter described and claimed.
[0025] One object of the present invention is thus a composition,
which comprises one or more acetaldehyde-binding compounds.
[0026] According to the invention the composition binds
acetaldehyde present in the stomach or in the stomach, intestine
and/or colon and comprises one or more acetaldehyde-binding
compound(s), which are bound to a non-toxic carrier that effects,
in the stomach, sustained release of said compound(s) into the
stomach.
[0027] To be more precise, the composition according to the
invention is characterized in that, what is stated in the
characterizing part of claim 1.
[0028] The method according to the invention is characterized in
that, what is stated in the characterizing part of claims 31, 32,
38, 39 and uses of claims 41 and 42.
[0029] The invention provides considerable advantages. The
compositions comprising acetaldehyde-binding compounds can be used
to reduce the risk of developing the cancer of the stomach, the
intestine and/or colon of people having increased risk for cancer
in these areas. By the compositions and methods of the invention
can be treated in particular people suffering from atrophic
gastritis, achlorhydric and low acid stomach. More specifically, by
the method of the present invention can be treated people having
atrophic gastritis, atrophic gastritis of corpus or atrophic
gastritis of antrum or achlorhydric or low acid stomach or
Helicobacter pylori infection. In particular, the compositions
according to the invention can be used for decreasing the risk of
cancer or for treating people having at least one of the biomarkers
of atrophic gastritis. Such biomarkers are low pepsinogen I (PI)
level, low pepsinogen I (PI)/pepsinogen II (PII) ratio, high
gastrin-17 level compared to the reference range or cut-off values.
Furthermore, the compositions according to the invention can be
used for decreasing the risk of cancer or for treating people
having at least one of the biomarkers of achlorhydric or low acid
stomach. Such biomarkers are high gastrin-17 value, high PI value
and high PII value compared to the reference range values. High
HPAB (Helicobacter pylori antibody) value is a biomarker of
atrophic gastritis and achlorhydric and low acid stomach, since it
may raise the pH of the stomach. All these biomarkers can be tested
by commercially available GastroPanel.RTM..
[0030] Furthermore, the compositions of the present invention are
effective for binding acetaldehyde, in particular, when they are
consumed in connection of eating, before, during or after eating.
The composition is capable of releasing acetaldehyde-binding
compounds in stomach during the time the foodstuff is digested.
However, the compositions can be used also in a continuous manner,
for example after every 8 to 10 hours. The composition may comprise
a carrier that does not dissolve in the stomach or comprises a
water insoluble film releasing the effective substance only slowly.
Alternatively the composition may comprise substances which form a
gel in the stomach or which adhere the composition to the mucous
membrane of the stomach.
[0031] The compositions of the invention may be protected not to be
released too early, in mouth, but be released in the stomach. The
compositions may be covered or coated by a water-soluble film. This
hinders effectively the potentially unpleasant taste of
acetaldehyde-binding compound(s). Alternatively, the composition
may be in the form of a tablet or capsule, preferably a hard
gelatine or HPMC capsule.
[0032] Consuming the compositions according to the invention mainly
binds acetaldehyde locally, but it may also have a systemic
effect.
[0033] In addition, the compositions according to the invention can
be used for large-scale consumers of alcohol, or those who have
hangover, smokers and those, who have a familial low-activity
modification of the aldehyde dehydrogenase-2 (ALDH2) enzyme or the
ADH3*1 gene/allele (ADH1C*1 at present). The use of the
compositions according to the invention is also of benefit to those
who consume moderate amounts of alcohol or who consume foodstuffs
that contain small contents of alcohol or acetaldehyde.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0034] A composition comprising acetaldehyde-binding compound(s)
means in connection of this invention a composition which comprises
a non-toxic carrier(s), which is/are not harmful for human (or
animal) consumption. The composition may mean a functional food
additive comprising a liquid or solid material intended to be added
to a foodstuff or it may mean a product for reducing the risks for
diseases. The composition may also mean a pharmaceutical
composition comprising pharmaceutically acceptable carriers. The
compositions in particular suitable for oral administration. The
carriers as such may comprise the same substances and it depends on
the legislation of the country, whether the composition should be
called a food additive, a product for reducing the risks for
diseases or a pharmaceutical composition. The aim of the
composition is to decrease the risk for cancer in the
gastro-intestinal tract.
[0035] The composition comprises an effective amount of
acetaldehyde-binding compound(s). An effective amount means an
amount capable of binding or inactivating the amount of
acetaldehyde present in a foodstuff or formed during the digesting
of a foodstuff in the stomach after eating. An effective amount may
mean also an amount capable of binding or inactivating the amount
of acetaldehyde present in the stomach due to acetaldehyde formed
from alcohol or for other reasons in stomach or in intestine and/or
colon.
[0036] "A composition for binding acetaldehyde present in the
stomach" means here a composition, which comprises one or more
acetaldehyde-binding compound(s). Preferably said compound(s)
comprise one or more free sulphhydryl and/or amino groups, more
preferably one or more free sulphhydryl and amino groups. Instead
of sulphhydryl group may be used sulphone group.
[0037] The composition comprises a non-toxic carrier that effects,
in the stomach, sustained release of said compound(s) in the
stomach. Sustained or prolonged release means the release of
effective substances for at least 30 minutes in the conditions of
the stomach. Preferably the effective substances release for 0.5 to
8 hours, preferably 2 to 6 hours, most preferably 2 to 4 hours.
[0038] According to a preferred embodiment of the invention the
compositions are taken in connection of eating, preferably during
the eating, before the eating or after eating. The composition can
be for example mixed to the foodstuff or it can be taken before or
after eating. The composition preferably releases the effective
compound(s) the time the foodstuff is in the stomach i.e. during
the digestion of the food. This time is typically 2 to 4 hours.
[0039] According to some embodiments of the invention the dosage
may be renewed by 4 to 10 hour intervals, preferably at 6 to 8-hour
intervals.
[0040] The composition according to the invention may be in the
form of a preparation, for example a tablet, a capsule, a granule,
powder, or a tablet or a capsule comprising powder or granules. The
composition may be in a form of a monolithic or multiparticular
preparation, such as tablet or capsule or granule.
[0041] A single dose of the preparation may be a tablet or capsule
or suitable amount of granules or a tablet or capsule comprising
granules or powder.
[0042] It is of advantage if the composition is in the form of a
preparation, the diameter of which is at least 7 mm, preferably 8
to 15 mm, more preferably 11 to 15 mm. This assists the preparation
to stay in the stomach sufficient time for the sustained release of
acetaldehyde-binding compound(s).
[0043] The amount of compound(s) released in the conditions of the
stomach is preferably 40-80 mg in an hour.
[0044] The task of the carrier in the composition is sustained
release of the effective compound(s) in the conditions of the
stomach.
[0045] According to one preferred embodiment of the invention the
composition comprises a carrier that does not dissolve or dissolves
only poorly in the stomach. Alternatively the composition may be
covered by a water insoluble film.
[0046] According to another embodiment of the invention the carrier
may form a gel in the stomach that floats in the contents of the
stomach.
[0047] According to one further embodiment of the invention the
preparation may be a liquid preparation taken orally (mixture), the
physical structure of which is a gel.
[0048] According to one further embodiment of the invention the
preparation may attach to the mucous membrane of the stomach.
[0049] According to one preferred embodiment of the invention the
composition comprises a carrier that does not dissolve in the
stomach. Such a carrier may be a polymer, such as metacrylate
polymer, for example Eudragit RS or S, or ethyl cellulose.
[0050] The composition may comprise substances selected from the
group comprising one or more acetaldehyde-binding compound(s), a
polymer not dissolving in the stomach and a bulking agent.
[0051] The composition preferably comprises acetaldehyde-binding
compound(s) 1 to 40 w-%, preferably 5 to 40, more preferably 10 to
30 w-%. Typically the amount is 20 to 25 w-%.
[0052] The composition preferably comprises polymers 10-50 w-%
preferably 20 to 40 w-%, more preferably 20 to 30 w-%.
[0053] The composition preferably comprises bulking agents 20-70
w-%, preferably 40 to 60 w-%, most preferably about 50 w-%.
[0054] According to one preferred embodiment of the invention the
composition comprises matrix granules not dissolving in stomach.
The composition may comprise for example:
TABLE-US-00001 Asetaldehyde binding 5 to 40 w-% (preferably 25 w-%)
compound(s) Polymer not dissolving in 10 to 50 w-% (preferably 20
to 30 w-%) stomach Inert bulking agent 20 to 70 w-% (preferably 40
to 60 w-%) Ethanol q.s.
[0055] The polymer not dissolving in stomach may be any in
pharmaceutical industry commonly used additive, such as metacrylate
polymer, for example Eudragit RS or S, or ethyl cellulose (EC). The
inert bulking agent may be for example dicalcium hydrogen
phosphate, microcrystalline cellulose (MCC), or other corresponding
non-swelling agent. The solid substances are mixed and moistured by
ethanol. The moisture mixture is granulated by using in
pharmaceutical industry well known methods and devices. The dried
granules can be used as such or distributed into dosages, for
example into capsules.
[0056] According to another preferred embodiment of the invention
the composition comprises matrix tablets not dissolving in stomach.
The composition may comprise for example:
TABLE-US-00002 Asetaldehyde binding 5 to 40 w-% (preferably 25 w-%)
compound(s) Polymer not dissolving in 10 to 50 w-% (preferably 20
to 30 w-%) stomach Inert bulking agent 20 to 70 w-% (preferably 20
to 50 w-%)
[0057] The polymer not dissolving in stomach may be any in
pharmaceutical industry commonly used additive, such as metacrylate
polymer, for example Eudragit RS or S, or ethyl cellulose (EC). The
inert bulking agent may be for example dicalcium hydrogen
phosphate, microcrystalline cellulose (MCC), or other corresponding
non-swelling agent. The solid substances are mixed and the mixture
is granulated by using for example ethanol or hydrophilic polymer
solution. The granules are pressed to tablets by in pharmaceutical
industry well known methods and devices. The release of the
effective compound(s) is now based on the diffusion of the
water-soluble effective compound(s) from the pores formed to the
tablet matrix.
[0058] According to one preferred embodiment of the invention the
composition may be protected in a form so that the compounds are
not released in mouth. The granules, tablets and capsules may be
covered by a water-soluble film, which effectively covers or masks
the taste of acetaldehyde-binding compound(s).
[0059] According to another preferred embodiment of the invention
the composition may comprise substances selected from the group
comprising one or more acetaldehyde-binding compound(s),
water-soluble bulking agent(s) and porous film forming agent(s) for
coating the preparation.
[0060] The composition preferably comprises acetaldehyde-binding
compound(s) 1 to 50 w-preferably 5 to 40 w-%, more preferably 20 to
50 w-%, still more preferably 20 to 30 w-%. Typically the amount is
about 20 to 25 w-%.
[0061] The composition preferably comprises bulking agent(s) 10-80
w-% preferably 40 to 80 w-%, more preferably 50 to 60 w-%.
[0062] The composition preferably comprises porous film forming
agents, such as ethyl cellulose and hydroxypropyl methylcellulose.
The relative amount of EC to HPMC may be 3/2 to 7/3.
[0063] Preparation, preferably tablets, covered by a film not
dissolving in stomach. The composition may comprise for
example:
TABLE-US-00003 Asetaldehyde binding 1 to 50 w-% (preferably 20 to
50 w-%) compound(s) Water-soluble bulking agent(s) 50 to 80 w-%
(preferably 30 to 60 w-%) Porous film forming agent(s) q.s.
[0064] The water-soluble bulking agent may be for example lactose
or some other in pharmaceutical industry commonly used
water-soluble bulking agent. The solid substances are mixed and the
mixture is pressed to tablets by in pharmaceutical industry
well-known methods and devices. The porous film may be prepared
from a water-soluble polymer, such as hydroxypropyl methyl
cellulose (HPMC) and water-insoluble polymer, such as ethyl
cellulose (EC). The relative amount of the film forming substances,
for example EC and HPMC, may be 2-5 parts EC and 1-2 parts HPMC. In
the conditions of the stomach the water-soluble polymer dissolves
and pores are formed to the water insoluble polymer. The release of
the effective compound(s) is now based on the diffusion of the
water-soluble effective compound(s) from the pores formed to the
film. The film forming substances effectively mask also the taste
of acetaldehyde binding compound(s).
[0065] Since acetaldehyde is formed also in the large intestine,
for example in connection of drinking alcoholic beverages, it is of
advantage, if the composition is protected in a form so that the
compounds are not released until in the large intestine. Such a
protection may be a polymer film that dissolves in an environment
with a pH of 6.5 or higher, typically at pH 6.0-7.5, preferably
6.5-7.0.
[0066] A film coating, which does not dissolve in the acidic
environment of the stomach, but dissolves at a pH value of 7.5 at
the latest, can be made both on the tablet or the granules or the
capsules. In making the preparation, it is also possible to use
polysaccharides that degrade under the effect of microbes of the
large intestine, or polymers generated by azo bonds. The form of
preparation known by the trade name Oros.TM. can also be used, when
its opening is first covered with an enteric polymer, the solution
pH of which is .apprxeq.7.
[0067] Useful enteric polymers include, for example, the grades of
hydroxypropyl methylcellulose phthalate, hydroxypropyl
methylcellulose succinate or hydroxypropyl
methylcellulose-acetatesuccinate (HPMC-AS) or the like, such as
sold by the trade name Aqoat.TM., Aqoat AS-HF.TM. in particular, a
cellulose acetatephtalate (CAP) grade sold by the trade name
Aquateric.TM., and methacrylic acid derivative, methacrylic
acid-methylmethacrylate copolymers, the grade sold by the trade
name Eudragit-S.TM. in particular.
[0068] The composition according to the invention may have at least
one ingredient, which adjusts the release of the effective
substance not to take place until at the end of the small intestine
or in the large intestine. This component can be a polymer that
dissolves depending on the pH (=enteric polymer) or a polymer that
degrades under the effect of the enzymes secreted by the bacteria
of the large intestine. The polymer that controls the place of
release can form a film around the entire preparation. It can also
form a film around the particles (granules) contained by the
multiple-part preparation. The polymer that degrades under the
effect of the enzymes secreted by the bacteria of the large
intestine can also be as a filler in a monolithic preparation, or
as a filler in the granules or in a multiple-unit preparation
prepared from these granules. See also WO 02/36098.
[0069] The preparation one embodiment of the invention the
preparation may be an enteric tablet, the film coating of which
does not dissolve until at the end of the small intestine or at the
beginning of the large intestine. The dissolution pH of the polymer
that forms the film may be 6.0-7.5, preferably 6.5-7.0. The amount
of enteric polymer that forms the film may be 5-20%, preferably
10-15% of the whole mass of the tablet. The filler of the tablet
can comprise pharmaceutical additives that do not swell, such as
calcium hydrogen phosphate.
[0070] The preparation according to the invention can also be
granules that comprise an acetaldehyde-binding compound(s) and are
coated with an enteric film, the dissolution pH of the film-forming
polymer being 6.0-7.5, preferably 6.5-7.0. The amount of
film-forming enteric polymer of the entire mass of the granule may
be 5-30%, preferably 15-25%. The granule can comprise 20-40%,
preferably about 30% of filler poorly soluble in water, such as
calcium hydrogen phosphate.
[0071] The binder of the granule coated with the enteric film,
according to the invention, can be an enteric polymer, the
dissolution pH of which is 6.0-7.5, preferably 6.5-7.0. The amount
of binder in the granule may be 2-5%, preferably 3-4%.
[0072] The preparation according to the invention can also be a
tablet comprising the enteric coated granules described above, on
which an enteric film has also been made. The tablet made for such
a preparation not only comprises enteric granules, but also a
filler suitable for direct compression, such as microcrystalline
cellulose, the amount of which in the tablet is 30-70%, preferably
40-60%.
[0073] The composition of the enteric tablet, which comprises
enteric granules and binds acetaldehyde in the desired way, can be
as follows, for example: [0074] Enteric granules:
TABLE-US-00004 [0074] Acetaldehyde-binding substance 100 mg Filler,
e.g., calcium hydrogen phosphate 30-50 mg Enteric polymers 40-60
mg
[0075] Enteric tablet:
TABLE-US-00005 [0075] Enteric granules 170-210 mg Microcrystalline
cellulose 170-210 mg Lubricants (e.g. magnesium stearate 5-10 mg
and talcum) Enteric polymers 30-50 mg
[0076] Since acetaldehyde is formed also in the small intestine,
for example in connection of drinking alcoholic beverages or is
carried there from the stomach, it is of advantage, if the
composition is protected in a form so that the compounds are not
released until in the small intestine. Such a protection may be a
polymer, such as Eudragit L, that dissolves in an environment with
a pH of pH 5 to 6.
[0077] The composition of the present invention can also be in a
form of a preparation comprising a fraction for binding
acetaldehyde present in the stomach and in addition a fraction
protected in a form so that the compounds are not released until in
the large intestine. The ratio of the composition for stomach and
the composition for the large intestine may be 1:1 to 1:3,
typically 1:2.
[0078] The composition of the present invention can also be in a
form of a preparation comprising a fraction for binding
acetaldehyde present in the stomach and in addition a fraction
protected in a form so that the compounds are not released until in
the small intestine and in addition a fraction protected not
released until in the large intestine. The ratio of the composition
for stomach and the composition for the small intestine and for the
large intestine may 2:1:1 to 1:3:3, typically it may be 2:1:1,
1:1:1, 1:1:2, 1:1:3, 1:2:2, 1:2:3, 1:1:3 or 1:3:3.
[0079] The preparation may comprise the substances intended for a
preparation for binding acetaldehyde in the stomach. Optionally the
preparation may be in the form of a capsule, such as HPMC capsule
or gelatine, particularly hard gelatine.
[0080] According to another embodiment of the invention the carrier
may form a gel in the stomach that floats in the contents of the
stomach.
[0081] According to one further embodiment of the invention the
preparation may be a liquid preparation taken orally (mixture), the
physical structure of which is a gel.
[0082] According to one further embodiment of the invention the
preparation may attach to the mucous membrane of the stomach.
[0083] For these embodiments the carrier may be selected from the
group comprising various chitosans, alginates, such as sodium
alginate, aluminium hydroxide, sodium hydrogen carbonate, sodium
carboxymethyl cellulose, and sodium hydrogen carbonate as described
in WO 02/36098.
[0084] The composition may be monolithic or multiparticular tablet
or capsule or granule as such, which, when wetted under the
influence of the gastric juices adhere to the mucous membrane of
the stomach or form a gel that floats in the contents of the
stomach, as a consequence of which their residence time in the
stomach is prolonged and thus enables a prolonged release in and a
local effect of the drug on the stomach. The long-acting
preparation that locally acts on the stomach can be a liquid
preparation taken orally (mixture), the physical structure of which
is a gel.
[0085] A special property required of the pharmaceutical
composition that has a local effect on the stomach is that it
remains in the stomach for as long time as possible. Technically,
this can be solved in two ways: by making a preparation that
adheres to the mucous membrane of the stomach or making a
preparation that floats in the contents of the stomach. The
preparation can be rendered fixable to the mucous membrane of the
stomach by using as additives cationic polymers, such as various
chitosan grades. Preparations that float in the stomach are
provided by using polymers, such as alginic acid, that form a gel
and by adding to the preparation sodium hydrogen carbonate, which
under the influence of gastric acid releases carbon dioxide, which
in turn forms gas bubbles inside the gel. A liquid gel that floats
in the stomach can also be prepared from sodium alginate, aluminium
hydroxide, sodium hydrogen carbonate, and water, to which the
acetaldehyde-binding compound can be added. A corresponding liquid
preparation is also obtained by adding an acetaldehyde-binding
substance to an aqueous dispersion of chitosan. Another preparation
that remains in the stomach for a long time is a preparation, which
is known as HBS.TM. (hydrodynamically balanced system). The
preparation can remain in the stomach for a long time, when a
relatively large tablet is made of it (with a diameter of at least
7-10 mm) and it is coated with a film, which does not decompose in
the alimentary tract, and which, however, releases an effective
substance (Oros.TM.) through a hole which has been made to it, for
example. Preferably such a preparation is consumed before, during
or after eating.
[0086] When needed, the dosage may be renewed at 4 to 10-hour
intervals, preferably at 6 to 8-hour intervals.
[0087] The amount of compound released in the conditions of the
stomach is preferably 40-80 mg in an hour.
[0088] The preparation according to the invention, which releases
in the stomach, has at least one--often two--polymers, which have
the task of keeping the drug as long time as possible, for two
hours minimum, in the stomach either so that it attaches the
preparation to the mucous membrane of the stomach or forms a gel
that floats in the contents of the stomach. Another task of the
polymers is to prolong the release of the effective substance.
[0089] The preparation that locally binds acetaldehyde in the
stomach can be a tablet that forms a gel in the stomach or a
capsule comprising a mixture of powder or granules that forms a
gel. In addition to the acetaldehyde-binding substances, the
preparation comprises polymers that form a gel in the stomach, such
as chitosans, alginates, sodium carboxy-methylcellulose grades,
carbomers or aluminium hydroxide. To advance floating in the
stomach, the preparation can also comprise sodium hydrogen
carbonate.
[0090] The amount of polymers in the preparation may be 10-50%,
preferably 15-40%, and most preferably 20-30%.
[0091] The amount of sodium hydrogen carbonate may be 10-30%,
preferably 20% of the amount of polymers.
[0092] The preparation that locally binds acetaldehyde in the
stomach can be a tablet or granule preparation, wherein the
acetaldehyde-binding substance is mixed with the fillers needed
and, after that, granulated by using enteric polymers as binders.
The binder used can be any known enteric polymer, preferably a
polymer with a solution pH of 6-7, and most preferably the polymer
is any of the methacrylate derivatives, which are known by the
trade names Eudragit L and Eudragit S. The amount of enteric
polymer in the preparation is preferably 2-5%, most preferably
3-4%.
[0093] The preparation that locally binds acetaldehyde in the
stomach can be a liquid preparation, i.e., a mixture comprising, in
addition to the acetaldehyde-binding substance, also sodium
alginate, aluminium hydroxide, sodium hydrogen carbonate, and
water. The amount of water in the whole preparation is 70-90%, most
preferably about 75-85%. The amount of sodium alginate in the
preparation is preferably 2-10%, most preferably about 5%, and the
amount of aluminium hydroxide is preferably 5-15%, most preferably
about 10%.
[0094] The relative composition of the preparation comprising
granules can be as follows, for example:
TABLE-US-00006 Acetaldehyde-binding substances 60 parts Chitosan
10-40 parts Calcium hydrogen phosphate 0-30 parts
[0095] The relative composition of the liquid preparation can be as
follows, for example:
TABLE-US-00007 Acetaldehyde-binding substances 10 parts Sodium
alginate 2-10 parts Aluminium hydroxide 5-15 parts Sodium hydrogen
carbonate 1-2 parts Water 70-80 parts
[0096] An "acetaldehyde-binding compound(s)" refers to a
compound(s) containing one or more free sulphhydryl and/or amino
groups, preferably one or more sulphhydryl and amino group(s), most
preferably in close proximity to each other (1,2- or 1,3
disubstituted aminothiols). Instead of sulphhydryl group may be
used sulphone group. "Compound" may be used to refer to one or more
compounds. Also compounds comprising one or more SH-group(s) and/or
one or more amino group(s) function in suitable concentrations.
[0097] The "binding of acetaldehyde" preferably refers to a
chemical reaction between the acetaldehyde and the compound that
has a free sulphhydryl and/or amino group, wherein the acetaldehyde
jointly with the "acetaldehyde-binding substance" forms a larger
molecule and water can be formed in the reaction. Instead of
sulphhydryl group may be used sulphone group For example, when
reacting with cysteine, the acetaldehyde binds itself both to the
sulphhydryl and the amino group and forms
2-methyl-L-thiazolidine-4-carboxylic acid and water. The
acetaldehyde can bind itself to the amino group of almost any
protein, whereby Schiffs base or a 2-methyl-imidazole ring is
formed.
[0098] According to the invention, the compounds obtained from
acetaldehyde by chemically binding are safe for the organism.
[0099] Suitable compounds for binding acetaldehyde in the organism
also include the compounds according to the formula (I):
##STR00001##
wherein R.sup.1 is hydrogen or an acyl group with 1-4 carbon atoms;
R.sup.2 is a sulphhydryl or sulphone group; n is 1, 2, 3 or 4.
[0100] The scope of the invention also includes the salts of the
compounds of Formula I, specifically pharmaceutically acceptable
salts, in particular water-soluble salts.
[0101] The scope of the invention also includes derivatives of the
compounds of Formula I, specifically pharmaceutically acceptable
derivatives, in particular water-soluble derivatives, capable of
binding acetaldehyde in the similar manner as cysteine.
[0102] The substances according to the following formula are
capable of binding acetaldehyde:
R--NH.sub.2 (II)
wherein R is derived from a protein (e.g., haemoglobin, albumin or
tubuline).
[0103] In a reaction of the compound according to the formula (II)
with acetaldehyde, a Shiff's base according to the formula (III) is
formed,
R--N.dbd.CHCH.sub.3 (III)
wherein R is derived from a protein (e.g., haemoglobin, albumin or
tubuline).
[0104] Amino acids or other compounds or the salts thereof that
suitably bind acetaldehyde and contain a free sulphhydryl and/or
amino group (instead of sulphyhydryl group may be used sulphone
group) include, for example:
L-cysteine,
D-cysteine,
[0105] cystine, cysteic acid, cysteine glycine, threo or
erythro-.beta.-phenyl-DL-cysteine,
.beta.-tetramethylene-DL-cysteine, methionine, serine,
D-penicillamine and its dipeptides with N-terminals, peptide or a
protein with terminal cysteine semicarbazide, glutathione, reduced
glutathione, .beta.-mercaptoethylamine,
D,L-homocysteine,
[0106] D,L-homocysteic acid,
N-acetylcysteine,
L-cysteinyl-L-valine,
[0107] .beta.-.beta.-tetramethylene-DL-cysteine, cysteinyl-glycine,
mercaptoethylglycine, tre-(5)-.beta.-phenyl-DL-cysteine,
erythro-.beta.-phenyl-DL-cysteine, cysteine hydrochloride,
thiaminhydrochloride, sodiummetabisulphite, arginine, glycine,
lycine, ammonium chloride, 1,4-dithiothreitol, mercaptanes.
[0108] It is of advantage to add to the compositions of the present
invention at least one of the substances selected from the group
comprising chromium, vitamin B12, A-, D-, E, -C-vitamins, niacin,
biotin, thiamine, B2-, B5-, B6-vitamins and folic acid and trace
elements, such as chromium, manganese, selenium, zink and iron.
[0109] However, only those acetaldehyde-binding compounds, which
are non-toxic and suitable for human consumption, can be applied to
the compositions according to the present invention. These
compounds should not cause a health hazard in the amounts used.
[0110] Cysteine and its derivatives are especially well suited to
the purpose according to the invention. The most suitable amino
acids for the use according to the invention comprise L- and
D-cysteines, compounds that are converted to cysteine or compounds
which function in the same way as the L- or D-cysteines, the
derivatives or salts of cysteine, especially water-soluble
derivatives or salts, The most preferred compound)(s) are in
addition to L-cysteine and D-cysteine, D-penicillamine,
.beta.-mercaptoethylamine and N-acetylcysteine, a compound
converted to cysteine, or a salt or a structural analogue of these
compounds capable of binding acetaldehyde. The most preferred
compound is L-cysteine and the salts thereof.
[0111] Useful compound to be added to the composition of the
invention and for binding acetaldehyde is also lecithin.
[0112] A "harmful/carcinogenic content of acetaldehyde" in the
human mouth, oesophagus, stomach, small intestine and large
intestine is 20 to 800 .mu.mol/l of saliva or the contents of the
intestine, a content of as low as about 20 to 50 .mu.M causing
carcinogenic mutations on the cell level. Hence, it would be
advisable to aim at a zero concentration of acetaldehyde in these
areas.
[0113] Keeping the acetaldehyde content essentially lower than
without the use of the composition means that the acetaldehyde
content should be kept at a level that is at least 20%, preferably
over 40%, and most preferably over 60% lower than when not using
the composition according to the description of the invention.
[0114] Such a harmful or carcinogenic content of acetaldehyde in
the human mouth, oesophagus, stomach or small intestine or large
intestine can be obtained in connection with consuming alcoholic
drinks, particularly strong alcoholic drinks, or foodstuffs
containing alcohol, as a consequence of smoking, when consuming
products containing acetaldehyde and in particular in people having
atrophic gastritis or achlorhydric stomach.
[0115] "Alcoholic drinks" are ethanol-containing drinks, their
ethanol content varying within 0.7% by volume and 84% by
volume."
[0116] "Alcoholic foodstuffs" refer to foodstuffs containing at
least 0.7% of ethanol. Such foodstuffs can be, for example,
fermented juices or preserves, or foodstuffs preserved with small
amounts of alcohol, pastries, jellies, and mousse seasoned with
liqueur or corresponding products containing alcohol.
[0117] "Acetaldehyde comprising foodstuffs" refers to foodstuffs
containing acetaldehyde. Acetaldehyde is contained in foodstuffs,
which have ethanol that is generated in connection with
fermentation, such as beer, cider, wine, home-brewed beer, and
other alcoholic drinks, as well as many juices. In certain
foodstuffs, such as some milk products, acetaldehyde is used for
preservation purposes and to add flavour, or the acetaldehyde is
formed in the product as a consequence of microbial activity. For
example, sugary juices or sugar-containing foodstuffs, in general
provide a food substrate for microbes. High concentrations of
acetaldehyde are formed, for example, in fermented milk products,
such as yoghurt. The microbes used to make yoghurt produce
acetaldehyde in the yoghurt. As for alcoholic drinks, sherry and
Calvados contain especially large amounts of acetaldehyde.
[0118] The use of the compositions according to the invention can
be of benefit even, when light alcoholic drinks are enjoyed or
foodstuffs are consumed, which contain small amounts of
alcohol.
[0119] "In connection with consuming alcoholic drinks" herein
refers to the period of time that begins from starting to enjoy
alcohol and ends, when there is no more alcohol in the blood.
[0120] "In connection with smoking" herein refers to the period of
time that begins from starting to smoke and ends, when smoking is
stopped.
[0121] "In connection with eating" herein refers to the period of
time before, during and after eating.
[0122] According to one preferred embodiment of the invention the
composition of the present invention is administered to people
having an increased risk of developing cancer in the stomach. The
acetaldehyde present on these areas can be locally bound by using
the composition according to the invention into a harmless form by
consuming the said compositions during or after eating.
[0123] Furthermore, according to the invention the efficiency of
drug treatment can be improved by using the principles of
theranostics. The key of theranostics (therapy specific
diagnostics) is to improve the efficiency of drug treatment by
helping physicians to identify patients who are the best candidates
for the treatment in question. In addition, the adoption of
theranostics could very well eliminate the unnecessary treatment of
patients for whom therapy is not appropriate, resulting in
significant drug cost savings for these patients.
[0124] According to one preferred embodiment of the invention the
composition of the present invention is administered to people
having atrophic gastritis or achlorhydric stomach.
[0125] In particular, the composition of the present invention is
administered to people having a value outside the reference range
or cut-off values of at least one of the biomarkers of atrophic
gastritis selected from the group comprising pepsinogen I,
pepsinogen II, pepsinogen I/pepsinogen II ratio and gastrin-17 B
(fast) and gastrin-17S (stimulated). Also high HPAB (Helicobacter
pylori antibody) value indicates a risk for developing atrophic
gastritis. A suitable method and kit for examining the biomarkers
is the commercially available GastroPanel.RTM. examination and
software supporting its use (www.biohit.com/gastropanel,
www.biohit.com/gastrosoft). The screening for atrophy of the
corpus, mucosa of the whole stomach and antrum is described in U.S.
Pat. No. 6,696,262.
[0126] The GastroPanel.RTM. examination measures four biomarkers in
blood: Pepsinogen I and II, Gastrin-17 and Helicobacter pylori
antibodies. The GastroPanel.RTM. examination and the GastroSoftg
software interpreting its results have been developed for use as a
primary and follow-up examination in the diagnosis and treatment of
patients with dyspepsia, Helicobacter pylori infection and atrophic
gastritis and related risks (gastric cancer, vitamin B12 deficiency
and peptic ulcer disease). Patients screened for having values
outside the reference range or cut-off values of Pepsinogen I and
II, gastrin-17 values and Helicobacter pylori antibodies and
therefore having or having risk for developing atrophic gastritis
(see Table 1) are treated by administering them the composition
comprising acetaldehyde-binding substances of the present
invention.
[0127] If the GastroPanel.RTM. examination gives a normal result,
the diagnosis is either functional dyspepsia or another disease not
involving the gastric mucosa. The examination diagnoses
Helicobacter pylori infection, atrophic gastritis and its location
(corpus, antrum or both). In addition to these diagnoses,
GastroSoft.RTM. software also alerts to the risks associated with
atrophic gastritis of the corpus of the stomach (gastric cancer and
vitamin B12 deficiency) and to the risks associated with atrophic
gastritis of the antrum (gastric cancer and peptic ulcer disease).
The GastroSoft.RTM. report also indicates the risk of
gastroesophageal reflux disease. If necessary, the report
recommends further examinations, such as gastroscopy and biopsy
specimen examination as well as vitamin B12 and homocysteine
determinations (see Table 2).
[0128] The reference range for pepsinogen I value is between 30-120
.mu.g/l, the reference range for pepsinogen II is 3-10 .mu.g/l, the
reference range for PGI/PGII ratio is 3-20, and the reference range
for Gastrin 17S (stimulated) value is 5-30 pmol/l, the reference
range for Gastrin 17B (fast) is 2-10 pmol/l and the reference range
for HPAB is 0-30 EIU.
[0129] Typical cut-off values for the biomarkers are selected from
the group comprising: pepsinogen I 30 .mu.g/l, pepsinogen II 3
.mu.g/l, PGI/PGII ratio 3, Gastrin-17S (stimulated) value 5 pmol/l,
Gastrin-17B (fast) 2 pmol/l and HPAB 30 EIU.
[0130] If pepsinogen I value is low, it is close to the lower limit
or below the reference range 30-120 .mu.g/l. Close to means
typically lower limit +/-5. If pepsinogen II value is low, it is
close to the lower limit or below the reference range 3-10 .mu.g/l.
Close to means typically lower limit +/-1. If PGI/PGII ratio is
low, it is close to the lower limit or below the reference range
3-20. Close to means typically lower limit +/-0.5. If Gastrin 17B
(fast) value is high, it is close to the upper limit or above the
reference range is 2-10 pmol/l. Close to means typically upper
limit +/-0.5. If Gastrin-17S (stimulated) value is low, it is close
to the lower limit or below the reference range is 5-30 pmol/l.
Close to means typically lower limit +/-2. If HFAB is high it is
close to or above the upper limit of the reference value 0-30 EIU.
Close to means typically upper limit +/-3.
[0131] Pepsinogen I and II and their ratio act as biomarkers for
atrophic gastritis in the corpus of the stomach. Five out of the
seven early stages of the enzyme pepsin form the pepsinogen I
group, which is produced only by the main cells in the corpus of
the stomach and the mucus-secreting cells in the neck of the
stomach. The remaining two form the pepsinogen II group, which is
produced in the glands of the entire stomach and to some extent
also in the Brunner glands in the upper duodenum. The lower the
concentration of pepsinogen I detected in the plasma sample
(reference range 30-120 .mu.g/l) and/or the pepsinogen I to II
ratio (the reference value being more than 3.0), the more severe
the atrophic gastritis (Zagari et al. 2002, Sipponen et al. 2001,
2002, Vaananen et al. 2003, Pasechnikov et al. 2005, Nurgalieva et
al. 2005, DiMario et al. 2005). Corpus atrophy increases the risk
of gastric cancer of the corpus (Varis et al. 2000, Uemura et al.
2001, Zagari et al. 2002 and may result in vitamin B12 deficiency
(Sipponen et al. 2003). An asymptomatic, progressive vitamin B12
deficiency of a few years' duration may cause permanent damage to
the central and peripheral nervous system, resulting in e.g.
dementia, depression and polyneuropathies. Vitamin B12 deficiency
may also increase the concentration of homocysteine in the body,
which has been thought to be an independent risk factor for
atherosclerosis, strokes and cardiac attacks.
[0132] One component of gastric juice is hydrochloric acid (HCl),
the secretory product of the parietal, or oxyntic cell of the
corpus of the stomach. It is known that the capacity of the stomach
to secrete HCl is almost linearly related to parietal cell numbers
(Yao et al. 2003, Samuelson et al. 2003). Acid secretion is
dependent on function of the H+/K+ ATPase or proton pump located in
the cannilicular membrane of the parietal cell. Several drugs have
been developed that non-competitively bind and inactivate the
ATPase, resulting in strong inhibition of acid secretion.
Omeprazole (Prilosec) is an acid-activated prodrug that binds
covalently to two cysteines on the ATPase, resulting in its
irreversible inactivation. Other proton pump inhibitors (PPIs),
including lansoprazole (Prevacid), esomeprazole (Nexium),
rabeprazole (Aciphex) and pantoprazole (Protonix) have similar
modes of action (Hellstrom et al. 2004, Sachs et al 1994, Shamburek
et al. 1992, Welag et al. 2003). The presence of gastrin stimulates
parietal cells of the stomach to secrete hydrochloric acid
(HCl)/gastric acid. Gastrin and hydrochloric acid form a known
feed-back controlling mechanism that is an intimate part of the
normal gastric physiology (Schubert 2004; Modlin et al. 1997).
[0133] Amidated gastrin-17, a peptide hormone, is the biomarker for
atrophic gastritis of the antrum of the stomach. Physiologically,
gastrin-17 is one of the most important fragments of gastrin.
Gastrin (peptides consisting of 14, 17 and 34 amino acids) is
formed in the G cells. G cells are found in the glandular
epithelium of the antrum of the stomach and the duodenal mucosa.
The blood concentration of amidated gastrin-17 produced by the G
cells in the antrum continues to decrease as the atrophy of the
antrum becomes more severe (Zagari et al. 2002, Vaananen et al.
2003, Pasechnikov et al. 2005, Sipponen et al. 2001, 2003,
Nurgalieva et al. 2005, DiMario et al. 2005). If the patient has
atrophic gastritis of the antrum of the stomach caused by a
Helicobacter pylori infection, the fasting values of gastrin-17 are
low (less than 2 pmol/l). In this case, the number of
gastrin-17-secreting G cells in the mucosa of the stomach is
decreased or the cells have disappeared completely (severe
atrophy). The fasting value may also decrease if acid secretion in
the stomach is high.
[0134] Gastric acid (HCl) inhibits the secretion of gastrin-17 from
the G cells of the antrum, resulting in a reduced concentration of
gastrin-17 in the plasma. Patients without Helicobacter pylori
infection and with gastrin-17 fasting values of less than 2.0
pmol/1 may be at risk of esophageal reflux disease and its
complication, Barrett's esophagus. This risk is significantly more
likely if the fasting value of gastrin-17 is 1.0 pmol/l or lower
(Sipponen 2005).
[0135] If necessary, possible atrophic gastritis of the antrum can
be confirmed or excluded by determining the concentration of
protein-stimulated gastrin-17 in plasma in addition to fasting
GastroPanel tests. It is thus possible to distinguish patients with
atrophic gastritis in the antrum from patients whose low fasting
concentration of gastrin-17 is entirely due to a high secretion of
acid. If the antrum is not atrophied, protein stimulation (see
www.biohit.fi/Service laboratory/Sampling instructions or
www.biohit.com/Diagnostics/Instructions for the Collection of Blood
Samples for the GastroPanel Examination) increases the production
of gastrin-17 in the antrum G-cells, thus increasing the amount of
gastrin-17 in the blood (over 5.0 pmol/l). If the
protein-stimulated gastrin-17 concentration is less than 5.0 pmol/l
and the patient has a Helicobacter pylori infection, it is very
likely that the patient has atrophy of the antrum mucosa and a
consequent risk of gastric cancer and peptic ulcer disease.
[0136] U.S. Pat. No. 6,696,262 discloses a method for screening
atrophic gastritis based on quantitavely measuring pepsinogen I and
gastrin-17 concentrations. The patent discloses also an immunoassay
for detecting the presence of Helicobacter pylori infection.
[0137] Interpretation of GastroPanel.RTM. paramaters can be carried
out based on the expected range according to the general
information provided by table 1 (for more information
GastroSoft.RTM.).
TABLE-US-00008 TABLE 1 How GastroPanel paramaters tends to behave
in different cases PGI PGII PGI/II G17B G17S HPAB Atrophic
gastritis in low low high corpus Atrophic gastritis in low low high
antrum Atrophic gastritis in low low low low antrum/corpus
Non-atrophic gastritis high Non-atrophic gastritis, high high H.
pylori infection Gastroesophageal low reflux disease (GERD)
[0138] Table 2. Summary of the data provided by the GastroPanel
examination and the .sup.13C-urea breath--or stool antigen test of
the "test-and-treat" strategy to the doctor in charge. The
stochastic GastroSoft program supplies a patient report and in
consecutive examinations the graphs on the probabilities of
different conditions). The reports produced by GastroSoft are based
on clinical studies comparing the results of GastroPanel
examinations with results from gastroscopy and biopsy examinations
(www.biohit.com/gastrosoft).
[0139] The serious medical and ethical problems of the test and
treat strategy can be corrected simply and economically by
replacing its .sup.13C-urea breath--or stool antigen test by the
GastroPanel examination (www.biohit.com/gastropanel).
TABLE-US-00009 The .sup.13C - urea GastroSoft breath test or report
Stool antigen test At an early stage . . . states: report: the
diagnosis for Functional vs. organic dyspepsia. YES NO When
GastroPanel indicates the gastric mucosa is healthy, the dyspepsia
complaints are often caused by functional dyspepsia or another
disease not involving the gastric mucosa H. pylori infection
(gastritis) YES NOT RELIABLE (1) Atrophic gastritis (damaged and
severely YES NO dysfunctional gastric mucosa) and the probabilities
of different conditions affecting the mucosa of the gastric corpus
or antrum or both (normal, gastritis or atrophic gastritis) the
risks (related to atrophic gastritis) of Gastric cancer YES YES/NO
(2) Vitamin B12 deficiency YES NO Peptic ulcer disease YES YES/NO
(3) the risks of Gastroesophageal reflux disease and YES NO
Barrett's esophagus YES NO if necessary, a recommendation for
Gastroscopy and biopsy examination YES NO Treatment of H. pylori
infection YES YES/NO (4) Determination of vitamin B12 and YES NO
homocysteine Follow-up examination to monitor the incidence of
atrophic gastritis YES NO the healing of the H. pylori infection
YES YES the healing of atrophic gastritis YES NO
[0140] (1) The .sup.13C-urea breath--and stool antigen tests give
false negative results if the patient has atrophic gastritis (a
risk of gastric cancer and peptic ulcer disease and vitamin B12
deficiency and related diseases, such as dementia, depression and
polyneuropathia as well as atherosclerosis, strokes and heart
attacks), MALT lymphoma or bleeding peptic ulcer or if the patient
is currently receiving antibiotics or PPIs. [0141] (2) The risk of
gastric cancer is very low without atrophic gastritis in corpus,
antrum or both. But in some cases, a H. pylori infection without
histologically observable atrophic gastritis may be associated with
gastric cancer and peptic ulcer disease. [0142] (3) No peptic ulcer
disease with corpus atrophy (no acid, no ulcer). The risk of peptic
ulcer disease is very low without antrum atrophy. [0143] (4) When
the incidence of H. pylori-related atrophic gastritis is monitored,
the patient can be offered targeted, safe treatment at the right
time. The need for medication and the costs and adverse effects of
medication can thus be reduced. If the patient has been diagnosed
with peptic ulcer disease (gastric or duodenal ulcer), the H.
pylori infection has to be treated (5). It should also be treated
if the patient has atrophic gastritis. The patient and the doctor
may also agree on eradication treatment for other reasons for
example when the patient's close relatives have been diagnosed with
gastric cancer. [0144] (5) Press Release: The 2005 Nobel Prize in
Physiology or Medicine, 3 Oct. 2005 jointly to Barry Marshall and
J. Robin Warren for their discovery of "the bacterium Helicobacter
pylori and its role in gastritis and peptic ulcer disease":--"An
indiscriminate use of antibiotics to eradicate Helicobacter pylori
also from healthy carriers would lead to severe problems with
bacterial resistance against these important drugs. Therefore,
treatment against Helicobacter pylori should be used restrictively
in patients without documented gastric or duodenal ulcer disease."
http://nobelprize.org/medicine/laureates/2005/press.html
[0145] The diagnosis and treatment of atrophic gastritis of the
stomach may be exemplified by the following example:
Diagnosis and Treatment or Theranostics (i.e. Therapy Specific
Diagnostics)
[0146] In atrophic gastritis of corpus the concentration of
Pepsinogen I and the ratio of the concentrations of Pepsinogen I/II
decrease. In addition, since corpus does not secrete acid (HCl) due
to atrophic gastritis because of the feed-back controlling
mechanisms, the concentration of gastrin-17 (G-17) increases.
[0147] When the person has low pepsinogen I value, low pepsinogen
I/pepsinogen II ratio and high gastrin-17 (in particular G-17B
fast) value, compared to the cut-off value or reference range, the
person is diagnosed to have atrophic gastritis in the corpus, most
often due to Helicobacter pylori infection and rarely due to
autoimmune disease, leading to achlorhydric or low acid stomach and
production of acetaldehyde by microbes in the stomach.
Treatment
[0148] The composition comprising an effective amount of
acetaldehyde-binding compound(s) is administered to the person. A
suitable amount may be a composition comprising typically 100-200
mg L-cysteine in connection of eating, preferably two times a day,
before, during or after eating.
[0149] The effect of the treatment may be monitored by testing
later the concentrations of pepsinogen I, pepsinogen I/II, and
Gastrin-17. A suitable time for monitoring may be 4 weeks and 8
weeks after the treatment was started or according to the estimate
of the physician.
[0150] The diagnosis and testing can be made by commercially
available GastroPanel.RTM. test kit.
Achlorhydric Stomach
[0151] Acid inhibitory drugs are widely used in Western societies,
often long periods of time, and continuously in some patients. In
various physiological experiments and small patient samples, acid
inhibitory drugs are shown to influence serum gastrin, output of
pepsin into gastric juice and output of pepsinogens into
circulation (Gillen et al., 1999; Qvigstad & Waldum, 2004;
Festen et al., 1984; Iwao et al., 1995; Brunner et al., 1995;
Schumann & Massarat, 1991; Stoschus et al., 1998; Fraser et
al., 1993; Ohsawa et al., 2002; Lazzaroni et al., 1992; Sanduleanu
et al., 1999). According to our recent study it was examined how
the use of antacids/alginates, H2RA's and PPI's influence the serum
levels of gastrin-17 (G-17) and pepsinogens in everyday clinical
practice.
[0152] PPI's, H2RA's and antacids/alginates affect acid secretion
and intragastric acidity and may thereby influence normal gastric
physiology. We examined the effect of these drugs on serum levels
of gastrin-17 (G-17) and pepsinogens (PGI and PGII) in a large
adult random population sample from Northern Sweden. The sample
(n=1000, mean age 50.4 span 20-80) was endoscoped and biopsies were
taken, and all subjects fulfilled a questionnaire of the use of
acid inhibitory drugs (none; antacids/alginates; H2RA's or PPI's)
during the last week or during the last three months. All subjects
(n=590) with a normal gastric mucosa (no Helicobacter pylori, no
gastritis nor atrophic gastritis) by biomarkers were analyzed for
the influence of the acid inhibitory drugs on the fasting levels of
serum G-17 B and PGI and PGII (and PGI/PGII ratio).
[0153] The serum levels of G-17 or pepsinogens did not differ
between the users of antacids/alginates or H2RA and those who did
not use the drugs. On the other hand, the mean and median levels of
fasting serum G-17, PGI and PGII were significantly (P<0.001;
non-parametric test) higher among the PPI users than among those
without drugs. The mean and median levels of G-17, PGI and PGII
were approximately doubled among the PPI users (both in those who
used PPI during the last (previous) week or last three months) as
compared to the means and medians in those without drugs. The ratio
of PGI/PGII was, on the other hand, similar between the PPI users
and those without drugs, or those with antacids/alginates or
H2RA's. Among subjects with PPI use, the serum levels of
pepsinogens correlated positively with the serum levels of G-17.
The results are presented in Tables 3 and 4.
[0154] The PPI's but not the antacids/alginates or H2RA's raise
markedly the fasting levels of serum G-17 and pepsinogens among
ordinary users of these drugs. The increase in pepsinogens
associates with an increase in G-17 among the PPI users.
[0155] The present findings support particularly the possibility
that the action mechanisms of PPI's to raise serum pepsinogens are
due merely to enhancement of the synthesis and/or release of
pepsinogens from gastric corpus than to trophic influences alone.
The serum levels of pepsinogens were approximately twice as high
among the users of PPI as among the controls. This doubling of the
serum pepsinogens cannot be hardly due to doubling of the mass of
the oxyntic glands or cells in the stomach.
[0156] However, a long-lasting use of PPI's can cause parietal cell
hypertrophy, and hypergastrinaemia of any reason may result in
hyperplasia or hypertrophy of gastric corpus. Some earlier studies
have shown that the Z-E syndrome is characterized by increased
serum levels of both PGI and PGII (Lamers et al 1988, Biemond et al
1994) as was also the case in the present subjects who used
PPI's.
TABLE-US-00010 TABLE 3 Mean and median values of serum fasting
gastrin-17 and pepsinogens in subjects with or without a use of
acid inhibitory drugs during the last (previous) week. No drugs;
Antacid H2RA PPI Controls 1 week 1 week 1 week N = 463 N = 29 N = 9
N = 23 Gastrin-17 pmol/l Mean .+-. S.D. 5.0 .+-. 11.3 3.8 .+-. 3.4
3.0 .+-. 3.3 24.7 .+-. 66.4*** Median 2.4 2.7 1.5 6.1 Pepsinogen I
(PGI) .mu.g/l Mean .+-. S.D. 88.8 .+-. 33.2 91.0 .+-. 42.4 92.3
.+-. 20.0 216 .+-. 90.3*** Median 81.8 75.1 90.6 209 Pepsinogen II
(PGII) .mu.g/l Mean .+-. S.D. 7.2 .+-. 3.6 8.5 .+-. 7.1 6.7 .+-.
1.9 14.5 .+-. 7.5*** Median 6.4 6.6 7.5 12.3 PGI/PGII Ratio Mean
.+-. S.D. 13.4 .+-. 4.0 12.4 .+-. 3.9 14.6 .+-. 4.1 16.1 .+-. 5.0**
Median 13.3 12.5 14.6 16.0 difference significant ***(P <
0.001), **(P < 0.01) if compared with controls. Nonparametric
test (Mann-Whithey U).
TABLE-US-00011 TABLE 4 Mean and median values of serum fasting
gastrin-17 and pepsinogens in subjects with or without a use of
acid inhibitory drugs during the last (previous) three months. No
drugs; Antacid H2RA PPI Controls 3 months 3 months 3 months N = 419
N = 62 N = 16 N = 29 Gastrin-17 pmol/l Mean .+-. S.D. 4.8 .+-. 9.1
6.1 .+-. 19.7 14.2 .+-. 38 19.5 .+-. 59.7** Median 2.4 2.2 2.6 4.1
Pepsinogen I (PGI) .mu.g/l Mean .+-. S.D. 90.3 .+-. 35.6 84.5 .+-.
34.3 82.9 .+-. 22.3 182 .+-. 95.9*** Median 82.9 76.6 79.8 181
Pepsinogen II (PGII) .mu.g/l Mean .+-. S.D. 7.3 .+-. 3.8 7.4 .+-.
5.4 7.5 .+-. 3.2 12.3 .+-. 7.5*** Median 6.5 6.2 6.9 10.5 PGI/PGII
Ratio Mean .+-. S.D. 13.4 .+-. 4.0 13.1 .+-. 4.4 12.5 .+-. 4.7 15.8
.+-. 4.8** Median 13.3 12.6 13.0 15.9 difference significant ***(P
< 0.001), **(P < 0.01) if compared with controls.
Nonparametric test (Mann-Whitney U).
Diagnosis and Treatment of Achlorhydric or Low Acid Stomach
[0157] In connection of PPI (Proton Pump Inhibitor) medication of
gastroesophageal reflux disease or Helicobacter pylori infection
the function of mucous membrane of stomach changes. This results
mainly as increase of gastrin-17, in particular G-17 B (fast)
concentration. The bigger decrease in the secretion of acid caused
by PPI, the higher is the G-17 value. A strong increase in the
concentration of G-17 indicates achlorhydric stomach, which remains
as long as the PPI medication is continued. Also the PGI and PGII
concentrations may increase, since direct PPI stimulus to the cells
secreting PGI and PGII or/and the cells secreting try to cause
corpus to secrete acid to non-acid stomach to compensate the
situation.
[0158] Antacids and H2RA medications are used also for treatment of
oesophageal reflux disease.
[0159] When the person has high gastrin-17 value, high PGI value
and high PGII value as a result of PPI, antacid or H2RA
medicaments, compared to the reference ranges in the population,
the person is diagnosed to have achlorhydric or low acid stomach or
a risk for it.
[0160] Achlorhydric or low acid (HCl) stomach is suitable
environment for the growth of microbes of mouth. The microbes may
produce ethyl alcohol and acetaldehyde from sugar and carbohydrate
containing foodstuffs.
[0161] The composition comprising an effective amount of
acetaldehyde-binding compound(s) is administered to the person. A
suitable amount may be a composition comprising typically 100-200
mg L-cysteine in connection of eating, preferably two times a day,
before, during or after eating.
[0162] The effect of the treatment may be monitored by testing
later the concentrations of PGI, PGII, and Gastrin-17. A suitable
time for monitoring may be 4 and 8 weeks after the treatment was
started.
[0163] The diagnosis and testing can be made by commercially
available GastroPanel.RTM. test kit.
Compositions of the Invention
[0164] By the composition comprising acetaldehyde-binding
compound(s) is here meant also compositions intended for binding
acetaldehyde (or aldehydes in general) in mouth. Such compositions
can contain the acetaldehyde-binding compound(s) as described here
and the compositions can be prepared as described in WO
2006/037848. Such compositions comprise chewable tablets, buccal
tablets, sublingual tablets, candies, pastilles, lozenges, chewing
gums and gels. Such preparations comprise preparations which
release aldehyde-binding substances within less than 30 minutes,
preferably within less than 15 minutes, typically within less than
10 minutes. Such preparations may comprise acetaldehyde (or
aldehyde-binding) substances 1 to 500 mg, preferably 1 to 300 mg,
still more preferably 1 to 250 mg, even more preferably 1 to 150
mg. According to a preferred embodiment the preparation may
comprise 1 to 50 mg, preferably 5 to 30 mg, more preferably 5-10
mg, typically 10 to 20 mg, suitable 1 to 5 mg or 1-20 mg.
[0165] By the composition comprising acetaldehyde-binding
compound(s) is here meant also compositions intended for binding
acetaldehyde (or aldehydes in general) in mouth as a long-acting
preparation. Such preparations can contain the acetaldehyde-binding
compound(s) as described here and the compositions can be prepared
as described in WO 02/36098. Such compositions may comprise for
example tablets or other preparations, which may be placed between
the cheek or the lip and the gum, or preparations that are sucked
or chewed in the mouth. Such preparations may comprise acetaldehyde
(or aldehyde-binding) substances 1 to 500 mg, preferably 50 to 300
mg, more preferably 100 to 200 mg, still more preferably 1 to 250
mg, even more preferably 1 to 150 mg. According to a one preferred
embodiment the preparation may comprise 1 to 50 mg, preferably 5 to
30 mg, more preferably 5-10 mg, typically 10 to 20 mg, suitable 1
to 5 mg or 1-20 mg. Under the oral conditions 15 to 25 mg of the
compound(s) may be released in an hour.
Other Applications of the Invention
[0166] If by the above described method, by using for example
GastroPanel.RTM. test kit, is found Helicobacter pylori infection
or a risk for gastroesophageal reflux disease, and if the patient
has symptoms of it, it is of advantage, if PPI or other treatment
decreasing the acidity of stomach, is combined with
acetaldehyde-binding composition as a suitable preparation (e.g.
capsule, tablet, granule, powder). By using the composition and
method acetaldehyde produced by microbes in achlorhydric or low
acid stomach, is bound into non-harmful acetaldehyde complex.
[0167] By the composition comprising acetaldehyde-binding
compound(s) can be bound or inactivated acetaldehyde formed from
ingested alcohol or from alcohol produced by microbes, and thereby
decrease the disadvantages, such as cancer, risk for cancer and
hangover. The composition and method is of particular advantage for
those who have achlorhydric stomach or low acidity in stomach due
to PPI or other treatment reducing the acidity of stomach or due to
atrophic gastritis of corpus.
[0168] The composition comprising acetaldehyde-binding compound(s)
can be used also in connection with metabolic syndrome. A person
having metabolic syndrome typically has large waistline, high
triglyceride level, high blood pressure, low level of (good) HDL
cholesterol and high blood glucose level. Since the use of chromium
as food supplement may be of benefit for a person having high blood
sugar level, having high cholesterol level and fatness, it has been
presented that one reason for metabolic syndrome may be the
deficiency of chromium. Chromium is needed for the metabolism of
carbohydrates and proteins. Chromium has an effect on the blood
sugar level and reduces the desire for sweet. It is of advantage
therefore to add chromium to the compositions of the present
invention. It would have advantageous effect on metabolic syndrome
and reduce the desire for sweet, which helps to control the weight
and dieting.
[0169] Half of the people with atrophic gastritis of corpus of the
stomach may have an exceptionally low vitamin B12 level and, of
them, at least half have at the same time increased serum
homocysteine. Vitamin B12 deficiency is a strong risk factor for
neurodegenerative disorders, such as dementia, depression and
polyneuropathies. The deficiency of vitamin B12 is one common
reason for hyperhomocysteinemia, an independent risk factor for
atherosclerosis, strokes and heart attacks. Because of corpus
atrophy and poor diet even 15% of individuals over age 50 are
suffering from a preventable epidemic of vitamin B12 deficiency.
With early detection of corpus atrophy by the routine screening for
the biomarkers, for example by GastroPanel.RTM. screening, and
treatment, neurological disability (e.g. dementia, depression and
polyneuropathies) and vascular diseases (e.g. stokes and heart
attacks) can be prevented. The ageing of population is increasing
the need for screening for the biomarkers, for example by the
GastroPanel.RTM. examination and screening, and diagnosis of
atrophic gastritis and related risks and diseases (see Table
2).
[0170] It is of advantage therefore to add vitamin B12 to the
compositions of the present invention. By the compositions of the
present invention can in addition to acetaldehyde-binding prevent
the diseases following atrophic gastritis of corpus and having
vitamin B12 deficiency, such as dementia, depression,
polyneuropathies, arteriosclerosis and heart attacks and
strokes.
[0171] To the compositions of the present invention including
various preparations for gastrointestinal tract and mouth can be
added in addition to chromium, vitamin B12 also other vitamins,
such as A, D, E and C vitamins, niacin, biotin, thiamine, B2, B5,
B6 and folic acid and trace elements, such as chromium, manganese,
selenium, zink and iron. Ferrous compounds are of particular
advantage, since atrophic gastritis is often connected with iron
deficiency anaemia.
EXAMPLES
Example 1
Gel Forming Formulation for Prolonged Binding of Acetaldehyde in
the Stomach
[0172] The locally long-acting preparation that binds acetaldehyde
in the stomach can be prepared and used to decrease the risk of
cancer caused by acetaldehyde as follows:
[0173] The relative composition of the preparation that locally
binds acetaldehyde in the stomach can be as follows, for
example:
TABLE-US-00012 Cysteine 60 parts Chitosan 10-40 parts Calcium
hydrogen phosphate 0-30 parts
[0174] The powder mixture is mixed by conventional mixers (such as
a blender), which are used in the pharmaceutical industry. After
that, the powder mixture is granulated using a 2.5% acetic acid as
a granulation liquid. The granulation liquid can be added to the
same blender. The moist powder mass is pressed through a screen
plate or a perforated plate (the diameter of the aperture being 2
mm). The formed granules are dried and screened. A screen fraction
of 1.2-1.7 mm is recovered, which is dispensed into hard gelatine
capsules so that the dose of cysteine is 100 mg. In the stomach
gastric juice wet cysteine/chitosan granules forming a hydrogel.
Gel starts to release cysteine in a prolonged way and reacts with
acetaldehyde. Chitosan as gel forming component can be replaced by
other well known gel forming pharmaceutical additives (e.g. alginic
acid).
Example 2
Non-Disintegrating Matrix Tablet for Binding Acetaldehyde in the
Stomach
[0175] The relative composition can be as follows:
TABLE-US-00013 Cysteine 25 parts Eudragit RS 20-30 parts
Microcrystalline cellulose 20-50 parts
[0176] From the powder mixture tablets containing 100-200 mg of
cysteine can be compressed with equipments generally used in
pharmaceutical industry. The tablet is a monolitic matrix tablet
which does not disintegrate in the stomach. The active compound
will release and dissolve in gastric fluid in a prolonged way
leading to sustained acetaldehyde binding effect. Eudragit RS as a
water insoluble binder can be replaced with similar pharmaceutical
additives (e.g. ethylcellulose)
Example 3
Film Coated Tablets for Binding Acetaldehyde in the Stomach
[0177] Pharmaceutical formulations releasing acetaldehyde-binding
compound(s) in a sustained manner in the stomach can also be
developed based on tablets coated with a porous film. The
composition of the tablet core can be:
TABLE-US-00014 Cysteine (20-50 parts) 30 parts Lactose 50-80 parts
Magnesium stearate 1-2 parts Talcum 1-2 parts
[0178] From the powder mixture tablets are compressed and
film-coated utilizing techniques commonly used in pharmaceutical
industry. The content of the coating solution can be, e.g.:
TABLE-US-00015 Ethyl cellulose 2-5 parts Hydroxypropyl
methylcellulose (HPMC) 1-2 parts Ethanol 95 parts
[0179] In the gastro-intestinal tract ethyl cellulose does not
dissolve but HPMC dissolves forming pores to the film allowing
cysteine to release from the tablet in a sustained manner.
Example 4
Non-Disintegrating Granules for Sustained Release of
Acetaldehyde-Binding Substances in the Stomach
[0180] The relative composition can be as follows, for example:
TABLE-US-00016 Cysteine 25 parts Eudragit RS or ethylcellulose
20-30 parts Microcrystalline cellulose 40-60 parts Ethanol q.s.
[0181] Powdery substances are mixed and moistened by ethanol in
equipments commonly used in pharmaceutical industry. The moistened
mixture is granulated and dried by well-known methods. If required,
the matrix granules formed can be coated with a low molecular
weight hydroxypropyl methylcellulose film in order mask the taste
of cysteine. Sufficient amounts of granules containing a single
dose (100-200 mg) of cysteine can be dispensed into gelatine
capsules or compressed with microcrystalline cellulose, e.g. to
tablets.
Example 5
Combination Product for Binding Acetaldehyde in the Stomach,
Intestine and Colon
[0182] In practice it is quite often important to bind acetaldehyde
in the stomach, intestine and colon at the same time. If a person
suffers from achlorhydric or low acid stomach he or she most likely
has acetaldehyde in the stomach. At the same time it is most likely
that acetaldehyde can be found also in the intestine. If the person
consumes alcoholic beverages it is obvious that acetaldehyde can be
found also in the colon. For these reasons it is of advantage to
develop a single formulation, which can release
acetaldehyde-binding compound(s) and bind acetaldehyde in the whole
length of the gastro-intestinal tract. For that purpose three
different subformulations are incorporated to the same
pharmaceutical product.
TABLE-US-00017 Fraction 1 Equal to Example 4 Release in the stomach
Fraction 2 Consisting of Example 4 plus Release in the intestine a
film coat dissolving at pH 5-6 Fraction 3 Consisting of Example 4
plus Release in the colon a film coat dissolving at pH 6.5-7.5
[0183] The relative amounts of fractions 1, 2 and 3 can be 2:1:1,
1:1:1, 1:1:2, 1:2:2, 1:2:3 or 1:1:3. Fraction 1 can be prepared as
described in Example 4. Fractions 2 and 3 can be manufactured by
film coating with well-known film-coating techniques. The film
forming polymer for Fraction 2 could be Eudragit L, e.g., and for
Fraction 3 Eudragit S, e.g. The most convenient final product could
be a hard gelatine or HPMC capsule. The total amount of cysteine in
the combination product could be 200 to 500 mg.
Example 6
[0184] A composition comprising acetaldehyde-binding compound(s)
was prepared as described in the earlier examples.
TABLE-US-00018 L-cysteine 25 w-% Metacrylate polymer (Eudragit RS)
25 w-% Microchrystalline cellulose 50 w-%
[0185] The solid substances were mixed carefully in a suitable
device. Ethanol was added in small amounts continuously mixing
until a powder mixture having sufficient moisture was obtained. The
moisture powder mixture was granulated by any in pharmaceutical
industry commonly used method. The formed granules were dried.
[0186] The dissolution experiment was carried out by using an
"artificial stomach". 25 ml of juice and yoghurt contaminated with
mouth bacteria were added to 100 ml bottles, which were incubated
one day at room temperature. A preparation comprising 250 mg of
L-cysteine was added to the bottles and they were slowly shaken at
37.degree. C.
[0187] It was found that within 2 hours the total amount of
acetaldehyde formed from the substrate was bound into harmless
form.
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References