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Description  |
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TECHNICAL FIELD
This invention relates to pharmaceutical compositions and therapeutic
methods for eradication and/or prevention of recurrence of
gastrointestinal disorders associated with infection by Campylobacter
pylori
BACKGROUND ART
C. pylori is a recently described bacterium found to cause chronic
histological gastritis. Its causal role in peptic ulceration is less clear
and even less so in non-ulcer dyspepsia. Its role could be more
effectively studied if effective therapy for its eradication were devised.
Until recent times, C. pylori has been found to be difficult to eradicate
using known chemotherapeutic agents. Although many antibiotics can
suppress C. pylori growth in vitro, in vivo the mucosal concentration
appears to be inadequate and penetration of the usual gastric mucus layer
poor. Hence, development of an adequate in vivo eradication method for
chronic C. pylori infection has been difficult. Moreover, adequate
prediction of in vivo results cannot be predicted from in vitro work.
European Patent Application No. 206,625 and Australian Patent Application
No. 59026/86 describe the use of bismuth together with a single antibiotic
for the treatment of C. pylori. However, bismuth alone achieves low (30 to
70%) initial clearance rates for C. pylori and recurrence of the infection
approaches 100% by twelve months post therapy. Bismuth together with a
single antibiotic, namely amoxicillin, appears to be relatively effective
as a short term means of reducing the symptoms but it is now clear that
the use of bismuth together with a single antibiotic frequently fails to
eradicate the infection and has a high rate of infection recurrence
(Rauws, Erik A. J. et al: Gastro-enterology, 1988; 94: 33-40).
DISCLOSURE OF THE INVENTION
The present inventor has now found that the use of a multi antibiotic
therapy not only results in a high initial clearance rate of C. pylori, of
the order of greater than 90%, but also leads to a high eradication rate
where most patients remain free of infection for more than twelve to
eighteen months. It now seems that therapeutic success measured at eight
weeks biopsy (post treatment) should be termed as clearance only whilst
the term "eradication" should be used in the context of patients who
remain free of C. pylori infection for more than twelve months post
treatment.
The present inventor has also found that C. pylori is not only associated
with gastritis but is also casually associated with peptic ulcer including
duodenal, pre-pyloric, gastric, oesophageal and marginal ulcer and
consequently the novel therapy for eradication of C. pylori described in
the present invention is useful in the treatment of peptic ulcer as well
as non-ulcer dyspepsia. Moreover, the novel therapy of the present
invention is useful in the treatment of oesophageal reflux, reflux
oesophagitis as well as asymptomatic carrier states.
In one broad form the present invention provides a pharmaceutical
composition for the treatment of gastro intestinal disorders associated
with C. pylori infections comprising a pharmaceutically acceptable bismuth
compound, a first antibiotic or antimicrobial agent and a second
antibiotic or antimicrobial agent.
In a further form the invention provides a sequential pack comprising a
first pharmaceutical composition in unit dosage form adapted and presented
in said pack for a first administration period of 3 to 36 days, said first
composition comprising a pharmaceutically acceptable bismuth compound and
a first antibiotic or antimicrobial agent together with a second
pharmaceutical composition comprising a second antibiotic or antimicrobial
agent in unit dosage form adapted and presented in said pack for a second
administration period different from said first administration period.
The invention also provides a sequential pack for the administration of at
least two pharmaceutical compositions comprising a first composition which
comprises a pharmaceutically acceptable bismuth compound, a first
antibiotic or antimicrobial agent and a second antibiotic or antimicrobial
agent, in unit dosage form adapted and presented for a first
administration period of 3 to 36 days, together with a second
pharmaceutical composition which comprises an acid suppressant for ulcer
treatment in unit dosage form adapted and presented for a second
administration period of 3 to 36 days prior to or overlapping with the
initial part of said first administration period.
Preferably, the first antibiotic or antimicrobial agent is selected from
one or more of tetracyclines, penicillins, quinolones, cephalosporins,
furazolidones, lincosamides, nitrofurantoins and/or polypeptides.
Preferably, the second antibiotic or antimicrobial agent is selected from
one or more of quinolones, furazolidones, nitrofurantions, metronidazoles,
and/or cephalosporins.
More preferably the first antibiotic or antimicrobial agent is selected
from tetracyclines and/or penicillins and the second antibiotic is a
metronidazole.
The tetracyclines include tetracycline, oxytetracycline, doxycycline,
demeclocycline, methacycline and minocycline.
The penicillins include penicillin G, penicillin V, oxacillin, nafcillin,
ampicillin, amoxicillin, cloxacillin and carbenicillin.
The metronidazoles include metronidazole and tinidazole.
Rifanpin, trimethoprim and/or nalidixic acid may also be used.
The cephalosporins include cephalexin (Keflex), cefaclor, cephapirin,
cephradine and cefadroxil as well as second and third generation
cephalosporins.
The polypeptide antibiotics include polymyxin B, bacitracin, colisin
sulfate and/or spectinomycin HCl.
Quinolones include ciprofloxacin, norfloxacin and ofloxacin.
Lincosamides include lincomycin and clindamycin.
Whilst it is preferred that the first and second antibiotics or
antimicrobial agents are selected from different classes, they may be
selected from within the one class. Moreover, a third or more antibiotics
may be included in the methodology and compositions of the invention; e.g.
amoxicillin, tetracycline and metronidazole. Keflex is also preferably
used as one of the first or second antibiotics or as a further antibiotic.
Bismuth compounds suitable in the present invention include those selected
from the group consisting of bismuth aluminate, bismuth subcarbonate,
bismuth subcitrate, bismuth citrate, tripotassium dicitrato bismuthate,
bismuth subgalate, bismuth subnitrate, bismuth tartrate, bismuth
salicylate, bismuth subsalicylate, and mixtures thereof. Bismuth citrate,
bismuth subcitrate, tripotassium dicitrato bismuthate, bismuth tartrate,
bismuth subsalicylate, and mixtures thereof are preferred bismuth salts
for use in this invention. The bismuth useful herein may be administered
alone, or in combination with other pharmaceutically-acceptable
components, in a bismuth-containing composition. A variety of such
compositions containing bismuth salts are commercially-available,
including, for example, DeNol, containing tripotassium dicitrato
bismuthate (sold by Gist-Brocades N.V.). Noralac, containing bismuth
aluminate, alginic acid, and magnesium carbonate (manufactured by North
American Pharmaceuticals), Roter bismuth, containing bismuth subnitrate
(sold by Roter Laboratories), Fensobar Polvo, containing bismuth
subcarbonate among other materials (manufactured by USV Pharmaceutical
Corporation), and Pepto-Bismol, containing bismuth subsalicylate (sold by
The Procter & Gamble Company).
In a preferred form of the present invention there is provided a method of
treating gastro intestinal infections associated with C. pylori which
comprises administering an effective amount of a pharmaceutically
acceptable bismuth compound in combination with a tetracycline and/or a
penicillin and a metronidazole.
In a further aspect of the present invention there is provided a capsule
for oral administration to patients suffering from gastro intestinal
infections associated with C. pylori wherein said capsule includes a
pharmaceutically acceptable bismuth compound together with a first
antibiotic and a second antibiotic wherein said capsule is adapted to
release said bismuth within the stomach of the recipient and wherein at
least said first antibiotic and preferably also said second antibiotic is
microencapsulated so that said first and optionally said second antibiotic
is released within the gastro intestinal tract after said stomach.
In a preferred form of this aspect of the invention there is provided a
capsule containing an effective amount of a pharmaceutically acceptable
bismuth compound together with enteric coated micro-spherules of an
antibiotic of the tetracycline class or penicillin class which capsule
also contains an effective amount of a second antibiotic selected from the
metronidazole class which second antibiotic is optionally provided in
enteric coated micro-spherule form.
In a further aspect of the present invention the methodology uses the
treatment regimen comprising the combination of pharmaceutically
acceptable bismuth compound in combination with a first antibiotic and a
second antibiotic for between three to twenty-eight days. Preferably the
treatment is combined with the administration of an acid suppressant such
as an histamine.sub.2 antagonist such as cimetidine, ranitidine or
famotidine to effect symptomatic relief and ulcer epithelialization. This
is followed by the combination of the bismuth and first and second
antibiotic therapy. Preferably the histamine.sub.2 antagonist is
administered for three to twenty-eight days followed by a three to
twenty-eight day therapy of the bismuth/antibiotics combination. Other
acid suppressants may be used instead of an histamine.sub.2 antagonist
such as benzimidazole or prostoglandins. Alternatively, the
histamine.sub.2 blocker or other acid suppressant can be combined with the
pharmaceutical composition of the present invention.
The present invention also provides a sequence presented pack suitable for
therapy for gastro intestinal disorders associated with C. pylori
infection which combines a pharmaceutically acceptable bismuth compound
together with a first antibiotic and a second antibiotic and optionally
further antibiotics so that said treatment regimen can be adapted for
individual patient needs. Optionally the sequence presented pack may also
include an initial therapy comprising an acid suppressant such as a
histamine.sub.2 antagonist or a K/Na ATP-ase inhibitor such as omeprazole
and may be combined with mucus disrupting agents such as carbocysteine,
n-acetylcysteine, corticosteroids or bisolvon. It should be noted that the
pharmaceutical composition comprises at least two antibiotics but further
antibiotics may be selectively added in difficult cases or where resistant
strains and/or multiple strains present a more resistant problem.
In the composition and methodology of the present invention, preferably
from 5 to 5000 mg, more preferably 50 to 250 mg of a pharmaceutically
acceptable bismuth compound is used together with from 5 to 10000 mg, more
preferably 50 to 500 mg of a first antibiotic together with from 5 to
10000 mg, more preferably 50 to 250 mg of a second antibiotic.
Preferably the invention provides a pharmaceutical composition containing
from 50 to 250 mg of a colloidal bismuth in pharmaceutically acceptable
form, 50 to 500 mg of tetracycline or a penicillin (e.g. amoxicillin) type
antibiotic and 50 to 250 mg of a metronidazole type antibiotic such as
metronidazole or tinidazole. Preferably the tetracycline or penicillin is
microencapsulated to prevent bismuth chelation at high pH.
In a further aspect the invention provides a sequential pack comprising an
antimicrobial pharmaceutical composition in unit dosage form adapted for
an administration period of three to thirty-six days, said antimicrobial
composition comprising a pharmaceutically acceptable bismuth compound, at
least a first antibiotic and at least a second antibiotic, together with a
palliative pharmaceutical composition in unit dosage form adapted and
presented for a three to thirty-six day administration period prior to, or
overlapping with the initial part of the administration period of said
antimicrobial pharmaceutical composition wherein said palliative
pharmaceutical composition comprises a therapeutic agent such as an acid
suppressant, adapted for ulcer treatments.
In a further aspect the invention provides a sequential pack comprising a
first pharmaceutical composition in unit dosage form adapted for an
administration period of three to thirty six days, said composition
comprising a pharmaceutically acceptable bismuth compound and at least a
first antibiotic, together with a second pharmaceutical composition in
unit dosage form comprising a second antibiotic adapted for administration
for a period different to said administration period of said first
pharmaceutical composition. Preferably the pack further comprises a
palliative pharmaceutical composition in unit dosage form presented in
said pack in a 3 to 36 day administration period which is prior to or
overlaps with the initial part of the administration period of said first
pharmaceutical composition wherein said palliative pharmaceutical
composition comprises a therapeutic agent, such as an acid suppressant,
adapted for ulcer treatment.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 illustrates results of treatment according to the present invention
in 64 to 100 patients at an average of 19.3 months after treatment; and
FIG. 2 illustrates histologic grading before and after treatment with the
treatment of the present invention.
BEST MODES OF CARRYING OUT THE INVENTION
The methodology and treatment described above is useful in the treatment of
disorders associated with C. pylori which include duodenal ulcer,
pre-pyloric ulcer, gastric ulcer, oesophageal ulceration, reflux
oesophagitis with or without ulceration, bile-reflux "gastritis" non ulcer
dyspepsia associated with C. pylori gastritis and/or asymptomatic carrier
state.
Whilst tablets or capsules of the pharmaceutical composition of the present
invention are preferred, sachets or syrups or other orally ingestible
forms of the compositions are also included within the scope of the
present invention.
The invention will be further described with reference to the following
test procedure of the Example and accompanying Figures.
EXAMPLE
Test Procedure
Patients aged 19 to 79 years (M:F=47:53) with symptoms of dyspepsia lasting
three months or more referred for endoscopy, were entered. Only patients
positive for C. pylori with either duodenal ulcer or non-ulcer dyspepsia
were entered into the study. Patients were deemed to have non-ulcer
dyspepsia if, in the absence of ulcer or other disease, they complained of
food related epigastric discomfort or pain, bloating, belching, nausea, a
feeling of fullness or heartburn. Patients with duodenal ulcer were
entered into the treatment protocol only after ulcer treatment with either
four weeks of ranitidine (300 mg/day) or cimetidine (800 mg/day), known
not to influence C. pylori. Exclusion criteria included coagulopathy,
antibiotic use within two weeks of endoscopy, presence of oesophageal
varices, previous gastrectomy, neoplasm, systemic disease or allergy
preventing use of the medications. Gastric ulcer patients were excluded to
form a separate study. Of 122 patients entered in the study, 112 completed
the triple chemotherapy adequately. Of these, 100 consecutive
re-endoscoped patients became available for analysis of results at eight
weeks after commencement of treatment and constitutes the short term
follow up group. Ten patients did not complete the treatment due to
failure to follow up (4), nausea (2), clostridium difficile-positive
diarrhoea (1), allergy (2), and oral moniliasis (1). At 12 to 37 months
after C. pylori eradication therapy CP-negative patient at eight weeks
from the pilot studies and the abovementioned group were invited for
re-examination by gastroscopy. Of the entire cohort 64 patients returned
for examination and constitute the long term follow up group.
Gastroscopy
All examinations were carried out by the same endoscopist. Two biopsy
specimens were taken from the gastric antrum and one from the body. One
antral specimen was placed in a microtitre tray containing buffered urea
and an indicator to detect rapidly presence of C. pylori urease activity.
The other specimens were placed in 10% buffered formalin for histological
examination. No bacterial cultures were carried out.
Histological Assessment
Paraffin sections of tissues fixed in formalin were stained with
haematoxylin and eosin to grade severity of histological gastritis and
with Warthin-Starry silver stain to grade C. pylori density. Grading was
based on density of lymphocyte/plasma cell (chronic), neutrophil (active)
infiltration, or presence of C. pylori from O to III as previously
described.
Specimens were graded by the same consultant histopathologist without
knowledge of patients' details.
Medication
Except for eight patients allergic to tetracycline, all subjects received a
combination of colloid bismuth subcitrate (108 mg chew-tablets q.i.d.),
tetracycline HCl (500 mg q.i.d.) for four weeks, together with
metronidazole (200 mg q.i.d.) for the first ten days. Amoxicillin (500 mg
q.i.d.) was substituted for tetracycline in the eight allergic patients.
Patients and endoscopist were not blinded to the treatment regimen.
Patients were asked if they had completed the medication as requested but
no tablet count was attempted.
Assessment of Symptoms
For patients with idiopathic non-ulcer dyspepsia (NUD) a questionnaire form
was developed and administered six months following clearance of C.
pylori. Global assessment of percent improvement in these patients is
reported below. In duodenal ulcer patients symptom improvement or
disappearance was recorded.
RESULTS
Clearance of C. pylori at Eight Weeks
Of the 100 consecutive available patients treated for C. pylori, 94 were
negative on urease testing and histology at eight weeks after commencement
of chemotherapy (See Table 1). The six patients remaining positive at
eight weeks claimed to have taken their medication as directed.
Long Term Clearance of C. pylori
Follow up gastroscopic biopsies were obtained in 64 patients (M:F=36:28) at
12 to 37 months after original triple chemotherapy (mean=19.3 months), and
results shown in FIG. 1. These patients were drawn from the 94 who
remained CP negative at eight weeks post therapy and from a small pilot
study carried out some months earlier. Of these 64, paid recalled
volunteers who resubmitted to gastroscopic biopsy, 33 had been originally
diagnosed as having non-ulcer dyspepsia while 28 had endoscopically-proven
duodenal ulcer. At follow up overall 60 or 94% remained free of C. pylori
infection at the 19.3 months. One of the 33 NUD patients was again
positive for the bacteria while three of 31 patients originally with
duodenal ulcer were CP positive. In the latter three patients, two again
had re-ulcerated while the other patient had pronounced duodenitis. All 28
patients who remained free of C. pylori maintained their ulcers
endoscopically healed. They were on no maintenance therapy and were free
of ulcer-like symptoms.
In NUD patients, as a global assessment in the 32 cleared patients, 25/32
(78%) reported a "50% or more improvement" over their initial symptom
scores. On the other hand in four other patients with NUD in spite of CP
eradication and reversal of histologic gastritis no improvement in
dyspeptic symptoms occurred.
An unexpected finding in four of 15 patients who initially had linear
oesophageal ulceration, was total healing and disappearance of the ulcers
after C. pylori eradication. No appreciable weight change had occurred in
these patients and the improvement could not be ascribed to any other
medical therapy.
TABLE 1
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C. pylori at start
C. pylori 8 wks
Patient Age M/F of treatment
past therapy
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1 N.U.D 65 F +ve -ve
2 D.U 59 M +ve -ve
3 N.U.D 62 F +ve -ve
4 N.U.D 63 M +ve -ve
5 N.U.D 35 M +ve -ve
6 P.P.U 74 F +ve -ve
7 G.U 3 40 F +ve +ve*
8 D.U 65 M +ve -ve
9 2 D.U 55 F +ve -ve
10 D.U 60 M +ve +ve*
11 N.U.D 60 M +ve -ve
12 N.U.D 66 M +ve -ve
13 P.P.U 59 M +ve -ve
14 N.U.D 28 F +ve -ve
15 P.P.U 36 M +ve -ve
16 D.U 22 M +ve -ve
17 D.U 42 F +ve -ve
18 N.U.D 65 F +ve -ve
19 D.U 32 M +ve - ve
20 D.U 65 M +ve -ve
21 N.U.D 61 M +ve -ve
22 D.U 29 F +ve +ve*
23 N.U.D 29 M +ve -ve
24 N.U.D 30 M +ve -ve
25 D.U 74 M +ve -ve
26 N.U.D 42 M +ve -ve
27 N.U.D 38 M +ve +ve*
28 P.P.U 51 F +ve -ve
29 N.U.D 26 M +ve -ve
30 D.U 44 F +ve -ve
31 D.U 50 M +ve -ve
32 N.U.D 29 F +ve -ve
33 N.U.D 72 F +ve -ve
34 N.U.D 29 M +ve -ve
35 N.U.D 22 F +ve -ve
36 D.U 28 M +ve -ve
37 D.U 54 M +ve -ve
38 N.U.D 44 F +ve -ve
39 N.U.D 56 F +ve -ve
40 N.U.D 40 M +ve -ve
41 N.U.D M +ve -ve
42 N.U.D 65 F +ve -ve
43 G.U/D.U 53 F +ve -ve
44 N.U.D 43 M + ve -ve
45 N.U.D 73 F +ve -ve
46 N.U.D F +ve -ve
47 N.U.D 46 F +ve -ve
48 N.U.D 41 M +ve -ve
49 N.U.D 46 F +ve -ve
50 N.U.D 34 M +ve -ve
51 N.U.D 58 F +ve -ve
52 N.U.D 51 F +ve -ve
53 N.U.D 23 M +ve -ve
54 N.U.D 54 F +ve -ve
55 D.U 59 F +ve -ve
56 P.P.U 31 M +ve -ve
57 O.U 56 M +ve -ve
58 N.U.D 33 M -ve -ve
59 PREV G.U 78 M +ve -ve
60 N.U.D 63 M +ve -ve
61 N.U.D 27 M +ve -ve
62 N.U.D 45 F +ve -ve
63 N.U.D 38 M +ve -ve
64 N.U.D 36 M +ve -ve
65 N.U.D 66 F +ve -ve
66 N.U.D 70 F +ve -ve
67 P.P.U 66 F +ve -ve
68 D.U 37 F +ve -ve
69 N.U.D 64 M +ve -ve
70 N.U.D 45 M +ve -ve
71 N.U.D 24 F +ve -ve
72 N.U.D 46 M +ve -ve
73 N.U.D 53 F +ve -ve
74 N.U.D 33 M +ve -ve
75 N.U.D 30 M +ve -ve
76 N.U.D 42 F +ve -ve
77 D.U 36 M +ve -ve
78 N.U.D 64 F +ve -ve
79 D.U 34 M +ve -ve
80 N.U.D 65 F +ve -ve
81 N.U.D 56 M +ve +ve*
82 N.U.D 42 M +ve -ve
83 N.U D 43 F +ve -ve
84 N.U.D 75 F +ve -ve
85 N.U.D 62 F +ve -ve
86 N.U.D 64 F +ve -ve
87 N.U.D 51 M +ve -ve
88 N.U.D 39 M +ve -ve
89 N.U.D 39 F +ve -ve
90 N.U.D 40 M +ve -ve
91 N.U.D 34 F +ve -ve
92 N.U.D 60 M +ve -ve
93 N.U.D 59 M +ve -ve
94 N.U.D 67 M +ve -ve
95 N.U.D 60 F +ve -ve
96 N.U.D 38 M +ve -ve
97 N.U.D 53 M +ve +ve*
98 N.U.D 51 M +ve -ve
99 N.U.D 54 M +ve -ve
100 N.U.D 56 M +ve -ve
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*indicates failure to cure infection.
D.U = Duodenal ulcer
O.U = Oesophageal ulcer
P.P.U = Prepyloric ulcer
G.U = Gastric ulcer
N.U.D = Nonulcer dyspepsia
Histological Changes
The effects of therapy on histological grading of C. pylori density as well
as lymphocyte and neutrophil infiltration are summarized in FIG. 2.
Histological scores have been arbitrarily assigned to show graphically the
time-course of inflammation resolution. All patients presented initially
with high scores for both chronic and active gastritis. Neutrophil
infiltration disappeared rapidly parallelling C. pylori clearance.
Lymphocyte infiltration, on the other hand, persisted for a much longer
time.
This study has demonstrated that high (>90%) initial "clearance" of gastric
C. pylori is possible with a combination of available antimicrobial
agents. Such a high level of initial clearance has not been previously
achieved. It is also clear that therapeutic success measure at the eight
week biopsy, should for the present be termed "clearance". The term
"eradication" should be reserved for patients remaining free of CP beyond
six months. In this study most of those patients cleared of CP at eight
weeks remained clear of the infection for more than twelve months.
Although C. pylori is susceptible to numerous antibiotics in vitro, such
agents notoriously fail to eradicate it in vivo. Bismuth appears to be an
important component in the combination chemotherapy. While it is not clear
why several antimicrobials are required to improve eradication of CP,
antibiotic access to the bacteria may be a problem. The bismuth compound
may be required locally within the gastric pits and mucus whereas the
antibiotics could be required to be carried systemically to reach bacteria
deep in gastric pits and within endocytotic vacuoles. Presence of multiple
strains of C. pylori with varying antibiotic susceptibility spectra could
provide another explanation for the need to employ multiple antibiotics.
In view of the multiplicity of strains, it is in fact surprising that such
a high CP clearance rate could be achieved employing only two systemic
antimicrobials and one locally-acting agent (CBS). Perhaps the success can
be further explained by prevention of the development of resistant strains
seen after short courses of single systemic antibiotics.
A clinically useful method for successful long term C. pylori eradication
has not previously been described. Twelve month follow up figures of 51%
and 35% have been reported using bismuth plus a single antibiotic. Such
therapy would clearly be unsatisfactory for patients and may lead to
creation of resistant C. pylori strains. It is also desirable to have an
effective eradication therapy for C. pylori before embarking upon a
double-blind trail designed to demonstrate the relevance of the organism
in a particular disease.
Although it is known that bismuth can decrease tetracycline
bioavailability, the antibiotic combination as used here achieved its
desired effect in spite of presumed chelation. It would appear that
adequate bismuth and tetracycline remained post-chelation to reach the
infected targets. It is known also that chelation is in part pH dependent
and low pH protects against chelation. As some patients with C. pylori
infection will have impaired gastric acid secretion, elevated pH may have
contributed to treatment failures. Other sources of treatment failure
could include reduction in tetracycline bioavailability by ingestion of
milk, antacids, iron or food, or simply non-compliance.
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