U.S. patent application number 09/180305 was filed with the patent office on 2002-12-19 for use of panaverium bromide for preventing cell proliferation and diseases caused thereby in the liver and digestive tract.
Invention is credited to BLENNERHASSET, MICHAEL G., CHRISTEN, MARIE-ODILE, DUC, HUYNH, HUIZINGA, JAN, MAUGARD, JOELLE, SCHERUBL, HANS.
Application Number | 20020193413 09/180305 |
Document ID | / |
Family ID | 9491870 |
Filed Date | 2002-12-19 |
United States Patent
Application |
20020193413 |
Kind Code |
A1 |
CHRISTEN, MARIE-ODILE ; et
al. |
December 19, 2002 |
USE OF PANAVERIUM BROMIDE FOR PREVENTING CELL PROLIFERATION AND
DISEASES CAUSED THEREBY IN THE LIVER AND DIGESTIVE TRACT
Abstract
The use of panaverium bromide for preparing a drug for treating
or preventing diseases of the liver and digestive tract caused by
excessive cell proliferation therem, is disclosed.
Inventors: |
CHRISTEN, MARIE-ODILE;
(PARIS CEDEX, FR) ; MAUGARD, JOELLE; (MARLY LE
ROI, FR) ; DUC, HUYNH; (VILLEJUIF, FR) ;
SCHERUBL, HANS; (BERLIN, DE) ; HUIZINGA, JAN;
(ONTARIO, CA) ; BLENNERHASSET, MICHAEL G.;
(ONTARIO, CA) |
Correspondence
Address: |
YOUNG & THOMPSON
745 SOUTH 23RD STREET 2ND FLOOR
ARLINGTON
VA
22202
|
Family ID: |
9491870 |
Appl. No.: |
09/180305 |
Filed: |
April 26, 1999 |
PCT Filed: |
May 6, 1997 |
PCT NO: |
PCT/FR97/00809 |
Current U.S.
Class: |
514/350 |
Current CPC
Class: |
A61K 31/5375 20130101;
A61P 1/00 20180101; A61P 35/00 20180101 |
Class at
Publication: |
514/350 |
International
Class: |
A61K 031/44; A01N
043/40 |
Foreign Application Data
Date |
Code |
Application Number |
May 6, 1996 |
FR |
96/05640 |
Claims
1. Use of pinaverium bromide for preparing a medicament which is
intended for preventing or treating diseases of the hepatodigestive
tract which are due to excessive proliferation of the cells of the
tract.
2. Use according to claim 1, characterized in that the diseases of
the hepatodigestive tract are intestinal cellular hyperplasia or
hypertrophy of the smooth-muscle-cell wall of the intestinal tract
and motility disturbances which are due to the inflammatory
diseases of the digestive tract (inflammatory bowel disease or IBD,
Crohn's disease or ulcerative colitis) which are characteristic of
the irritable syndromes of the colon (IBS).
3. Use according to claim 1 for preparing a medicament which is
intended for preventing or treating a cancer of the hepatodigestive
tract, comprising cancer of the colon and of the stomach,
hepatocarcinoma and cancer of the pancreas, or else the carcinoid
syndrome or functional diseases which are linked to the carcinoid
tumours.
4. Use according to claim 1 for preparing a medicament which is
intended for preventing and treating cancer of the hepatodigestive
tract in patients who are suffering from irritable syndromes of the
colon (irritable bowel syndrome or IBS), while effecting a
complementary and simultaneous treatment of the symptoms which are
characteristic of the IBS.
5. Use of pinaverium bromide for producing a medicament which is
intended for treating inflammatory digestive diseases, such as
inflammatory intestinal disease (inflammatory bowel disease or
IBD), Crohn's disease or ulcerative colitis, which diseases are
generally associated with thickening of the mucous membrane.
6. Use according to claim 1 in which pinaverium bromide is used in
sufficient quantity to be administered, by the oral route or by the
injectable route, at the rate of from 50 to 450 mg per day using a
solution which is dosed at from 0.2 to 1 mg/ml.
Description
[0001] The present invention relates to a novel use of pinaverium
bromide in gastrointestinal pathologies, inflammatory digestive
diseases (IBD), colites, ulcers, Crohn's disease or functional
colopathies (IBS), during which proliferative phenomena which lead
to pathological complications appear.
[0002] While the constant and rapid renewal of the epithelium of
the digestive tract is an important factor in the maintenance of
the integrity of the mucous membrane, it is also an important
factor in the development of tumours and hypertrophies.
[0003] In these latter cases, an abnormal proliferation of the
epithelial cells and an increased number of proliferative zones are
always observed; this is also found in patients who are at familial
risk of cancer of the colon or in patients who are suffering from
diseases which predispose to cancer of the digestive tract (chronic
gastrites, inflammatory digestive diseases, Crohn's disease,
ulcerative colites, colonic polyps, etc.). Furthermore, it has been
shown that inflammation of the intestine can give rise to
hypertrophy and hyperplasia of the smooth muscle cells at one and
the same time. This results in a thickening of the muscle wall, and
therefore in a change in its motility, resulting in the appearance
of complications which require surgical treatments.
[0004] In addition, inhibition of the proliferation of neoplastic
cells is a determining factor in the prevention and treatment of
cancers and metastases of the digestive tract.
[0005] Pinaverium bromide is the only calcium antagonist which is
selective for the intestinal tract and which has spasmolytic
activity and which is prescribed for the chronic treatment of
functional digestive disorders (irritable bowel syndrome or IBS).
This compound has been described, in particular, in French patent 2
097 032.
[0006] The authors of the present invention have now surprisingly
demonstrated, by means of studies carried out in vitro, that
pinaverium bromide is able to inhibit the proliferation of
neoplastic and hyperplastic cells of the digestive tract, with this
inhibition being greater than that brought about by another calcium
antagonist, i.e. verapamil. Furthermore, a study carried out in
vivo also demonstrated the efficacy of pinaverium bromide in
decreasing tumours induced in animals.
[0007] Pinaverium bromide can therefore be used as a medicament for
preventing cancer of the digestive tract both in the healthy
individual and the individual suffering from a digestive pathology
such as IBS. In the latter individual, it will then exert a
prophylactic or therapeutic effect which complements its effect on
the IBS.
[0008] This compound may also be used for the therapeutic treatment
of hepatocarcinoma or of cancer of the pancreas and, more
generally, of any cancer of the hepatodigestive tract.
[0009] The present invention therefore relates to the use of
pinaverium bromide for preparing a medicament which is intended for
preventing or treating diseases of the hepatodigestive tract which
are due to excessive proliferation of the cells of the tract.
[0010] More especially, the invention relates to the use of
pinaverium bromide for preparing a medicament which is intended for
preventing or treating intestinal cellular hyperplasias which are
linked to inflammatory digestive diseases, or for preventing
hypertrophies of the smooth-muscle-cell wall of the intestinal
tract and motor disturbances which are due to the inflammatory
diseases of the digestive tract (inflammatory bowel disease or IBD,
Crohn's disease or ulcerative colitis) which are characteristic of
the IBS.
[0011] The invention is also directed towards using pinaverium
bromide for preparing a medicament which is intended for preventing
or treating a cancer of the hepatodigestive tract, comprising
cancer of the colon and of the stomach, hepatocarcinoma and cancer
of the pancreas, or else the carcinoid syndrome or functional
diseases which are linked to the carcinoid tumours.
[0012] It also relates to the use of pinaverium bromide for
preparing a medicament which is intended for preventing and
treating cancer of the hepatodigestive tract in patients who are
suffering from irritable syndromes of the colon (irritable bowel
syndrome or IBS), while effecting a complementary and simultaneous
treatment of the symptoms which are characteristic of the IBS.
[0013] The invention also comprises a method for the prophylactic
or therapeutic treatment of diseases of the hepatodigestive tract
which are due to excessive proliferation of the cells of the tract,
which method consists in administering a medicament containing
pinaverium bromide, as the active principle, to a patient.
[0014] Finally, the method is directed towards using pinaverium
bromide for producing a medicament which is intended for treating
inflammatory digestive diseases such as IBD (inflammatory
intestinal disease or inflammatory bowel disease), Crohn's disease
or ulcerative colitis, which diseases are generally associated with
the thickening of the mucous membrane.
[0015] Preferably, within the context of the present invention, the
pinaverium bromide is used by being administered in a daily
quantity of between 50 mg and 450 mg. Administration is by the oral
route or by the injectable route, using a solution which is dosed
at from 0.2 to 1 mg/ml.
[0016] The advantages of the invention emerge in more detail in the
tests which are described below.
[0017] In addition, the following figure shows the effect of
pinaverium bromide (.box-solid.) on inhibition of the growth of
pancreatic carcinoid cells as compared with the effect of verapamil
(.diamond.).
[0018] Test 1:
[0019] Inhibition of the proliferation of colon cancer cells by
pinaverium bromide as compared with the inhibition induced by
another calcium inhibitor (verapamil)
[0020] The HT29 colon cancer cell line employed (originally
isolated from an adenocarcinoma of the human colon) was obtained
from the ATCC (American Type Culture Collection).
[0021] The cells are cultured at the rate of 10.sup.4 or
5.times.10.sup.4 cells in a well containing 200 .mu.l of culture
medium composed of RPMI 1460 supplemented with 10% fetal calf
serum, 2 mM of L-glutamine and 25 .mu.M gentamicin. Pinaverium
bromide (or verapamil), dissolved in 50% ethanol or DMSO, is added
to the cell culture at various concentrations, and the percentage
inhibition of cell proliferation is assessed by measuring the
incorporation of tritiated thymidine (.sup.3HThdR), with the latter
being added to each well at the rate of 37 KBq (1 .mu.Ci); the
contents of the wells are withdrawn and counted 15 hours later
using a "Filter Mate.TM. Cell Harvester and Matrix 9600.TM. Direct
Beta Counter" (Packard).
[0022] The results are as follows:
1 Concentration of % Inhibition the product tested pinaverium %
Inhibition (% by weight) bromide verapamil .sup.3HThdR 0.025 78 17
0.05 82 17 0.1 86 27
[0023] The inhibitory effect of the pinaverium bromide is from 3 to
5 times greater than that of the verapamil.
[0024] Test 2:
[0025] Effect of pinaverium bromide on hepatocarcinoma cells.
[0026] LFC rat hepatocarcinoma cells (VPR42, Villejuif) are
cultured at the rate of 10.sup.4 or 5.times.10.sup.4 cells in a
well containing 200 .mu.l of culture medium. The products to be
tested (pinaverium bromide and verapamil) are dissolved in 50%
ethanol and used at concentrations of 0.1% and 1% by weight.
[0027] Inhibition of cell proliferation is assessed using tritiated
thymidine as described in Test 1. The assessment is made in
comparison with the reference product, which is verapamil. The
results show a percentage inhibition of proliferation of from 85 to
88% in the case of pinaverium bromide and of 72% in the case of
verapamil.
[0028] Test 3:
[0029] Effect of Pinaverium Bromide on the Growth of STC-1
Carcinoid Intestinal Cells
[0030] The STC-1 mouse intestinal cancer cell lines are cultured in
a DMEM medium which contains 15% horse serum and 2.5% FCS. The
products to be studied are added to the culture and cell growth is
assessed by counting cells or, more frequently, by a fluorescence
technique which is based on the cellular enzymic hydrolysis of the
fluorogenic substrate 4-methylumbelliferyl heptanoate (MUH); thus,
viable cells which are incubated with MUH generate a fluorescent
signal which is proportional to their number and which is
determined using a "Titentec Fluoroscan II" (Flow Laboratory), with
the value being given in arbitrary fluorescence units.
[0031] Pinaverium bromide was found to be twice as active as
verapamil in the test.
(ED.sub.50 PINAVERIUM=7 .mu.M ; ED.sub.50 VERAPAMIL=13 .mu.M)
[0032] Test 4:
[0033] Study of the Inhibition by Pinaverium Bromide of the Growth
of BON Pancreatic Carcinoid Cells
[0034] The BON human pancreatic carcinoid cell lines are cultured
in a DMEM/F12K (1/1) medium to which 10% FCS is added. The
verapamil and the pinaverium bromide are added to the culture and
cell growth is determined after 8 days by means of a fluorescence
technique such as that described in Test 3.
[0035] The results reported in the figure demonstrate the efficacy
of pinaverium bromide in inhibiting the growth of the BON
pancreatic carcinoid cells, and its superiority to verapamil
(ED.sub.50 PINAVERIUM=7.2 .mu.M ; ED.sub.50 VERAPAMIL=43.6
.mu.M).
[0036] Test 5:
[0037] Inhibition by Pinaverium Bromide of the Hyperplasia of Rat
Intestinal Smooth Muscle Cells Which is Induced by PDGF
(Platelet-derived Growth Factor)
[0038] The intestinal smooth muscle cells are cultured in a culture
medium containing 10% fetal bovine serum and then exposed to PDGF
(growth factor found during inflammations) for 20 hours. Cell
growth is assessed by the incorporation of tritiated thymidine.
[0039] Pinaverium bromide (10.sup.-5 M) totally inhibits the growth
of the intestinal smooth muscle cells which is induced by the
inflammation factor PDGF. It therefore has a beneficial effect on
inflammation phenomena of the digestive tract.
[0040] Test 6:
[0041] Effect of Pinaverium Bromide on the Diameters of the Tumours
which are Induced in Nude Mice.
[0042] The tumours are induced by subcutaneously injecting HT29
colon cancer cells into nude mice.
[0043] Pinaverium bromide is injected intraperitoneally a few hours
before injecting the HT29 cells.
[0044] Tumour development is assessed by measuring the diameter of
the induced local tumour in relation to the duration of the
experiment, which is 44 days.
[0045] A 30% reduction in the diameter of the tumours is observed
from the 25th day of the experiment onwards.
* * * * *