Annex to Chapter 1
Priority Medicines for Europe and the World
"A Public Health Approach to Innovation"
Background Paper for Review
Annex to Chapter 1
Peptic Ulcer Disease
“Pharmaceuticals Closing a Surgical Gap”
By Saloni Tanna, Pharm.D; MPH
20 September 2004
Please send comments to:
Dr Richard Laing
E-mail: laingr@who.int
Annex to Chapter 1-1
Annex to Chapter 1
Table of Contents
Introduction................................................................................................................................................. 3
From Surgery to Effective Pharmacological Therapies ......................................................................... 4
Peptic ulcer disease (PUD) .............................................................................................................. 6
Epidemiology .............................................................................................................................................. 6
Western countries............................................................................................................................. 7
Developing Countries...................................................................................................................... 7
Transmission ............................................................................................................................................... 7
Diagnostic Tests .......................................................................................................................................... 7
Therapy ........................................................................................................................................................ 7
Time Trends in Peptic Ulcer Surgery – Pharmaceuticals Closing the Surgical Gap ......................... 9
Past and Current Research ............................................................................................................ 11
Conclusion ................................................................................................................................................. 12
References .................................................................................................................................................. 13
Annex to Chapter 1-2
Annex to Chapter 1
Introduction
Impressive scientific advances made during the 20th century which include systematization of
medical education, increased research, improved diagnostics, novel and effective medicines and
the growth of medical specialization has collectively transformed the field of gastroenterology
and the management of acid-related diseases including peptic ulcer disease.
Early in the century, access to the digestive tract was limited. Diagnostic and therapeutic
resources were scarce. Clinicians were limited to blood counts, and urine analysis and a few
chemical tests. This has changed dramatically. Today, comprehensive advancements have
helped considerably in the overall and successful management of patients with gastrointestinal
disorders. Some of these favorable advancements include:1
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Diagnostic capabilities, including fiber-optic gastroscopy
knowledge of risk factors,
ability to perform biopsies,
x-ray guided biopsy of the liver and colon,
tests of hepatic and pancreatic functions,
breath tests,
quality x-rays,
ultrasonography,
computerized abdominal tomography,
magnetic resonance imaging,
Assessment of gastrointestinal motility and vascular status
Increased understanding of the inflammatory cascade and gastric protective mechanisms,
along with the discovery of multiple isoforms of the cyclooxygenase (COX) enzyme, have
led to the development of potentially safer non steroidal anti-inflammatory drugs (NSAIDs).
More importantly gastroenterology has experienced tremendous growth in the understanding
and use of therapeutic resources including blood transfusions, nutritional support services,
sulfonamides, antibiotics, adrenocorticosteroids, immune modifiers, H2 blockers, and proton
pump inhibitors. These agents have dramatically altered the management gastroesophageal
reflux disease (GERD), management of peptic ulcer disease (PUD), and the prevention and
treatment of non steroidal anti-inflammatory drug (NSAID)-related gastrointestinal
complications.2
Table 1 highlights some of the significant advances that have had an impact in the field of acidrelated diseases.
Annex to Chapter 1-3
Annex to Chapter 1
Table 1: 20th century advances with significant impact on gastroenterology drug
development and research1, 3
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Gastrointestinal immunology; gut mucosal immune system
Chemistry of digestive acids and bile acids
Radioimmunoassays
Endoscopic technological advances
Nutrition (vitamins, nicotinic acid, folic acid)
Genetic factors in gastrointestinal, liver and pancreatic diseases
Increased support of research
Improved diagnostic tools
Growth of basic biomedical sciences and biotechnology
Improved clinical studies and controlled trials
Rigorous evaluation of medicines
An enlarging body of scientific knowledge
Technological improvements permitting safer and more precise human studies
Increase public and private support of research and training
Entry of young, scientifically trained physicians with a more scientific attitude toward
clinical problems
Controlled clinical studies and growth of evidence based medicine
The establishment of professional and philanthropic organizations
The growth and influence of academic medical research centers
The growth and influence of scientific societies e.g. Helicobacter foundation, the
gastroenterology research group, American society of clinical investigation, The American
gatroenterology foundation
The enlarging scientific communication network (journals, databases, electronic and
computer systems
From Surgery to Effective Pharmacological Therapies
The last 35 years of the 20th century has witnessed a revolution in the treatment of acid-related
diseases. Until then, there had been steady progress in the surgical approach to these ailments,
beginning with Billroth and partial or total gastroectomy, and progressing to highly selective
vagotomy in the 1960’s.4 On the other hand, bland diet and atropine were the only medical
treatment options. Impressive advances in gastroenterology along with the introduction of
effective treatments have changed this. Today, medical therapy is the first step in treating ulcer
disease, with surgery reserved for complications and failure of that therapy. Recent advances in
medical treatment have further reduced the need for operations with gastric surgery perhaps
only being limited to emergent PUD and the treatment of gastric cancer. We are now 100 years
past Billroth’s first successful gastroectomy. The first part of that century led to steadily
increasing numbers of surgical procedures, whereas the second part has been marked by
increasing understanding of physiologic factors, leading to lesser, but better directed
operations.4
Annex to Chapter 1-4
Annex to Chapter 1
Research during the past 35 years into gastric acid related disorders and the development of
agents that effectively suppress gastric acid represents a milestone in the management of these
diseases. Numerous clinical studies have documented the safety and efficacy of these agents in
proving rapid pain relief and improving ulcer healing and erosive GERD without the need for
complicated surgical procedures.
This section reviews some of the critical developments that have occurred over the past
3 decades in the management of acid-related disorders. The time line presented reveals how
improved understanding and new insights have contributed to the evolution of drug therapy
from antacids to histamine 2 receptor antagonists (H2RAs), discovery of H Pylori to the
introduction of proton pump inhibitors onto the market. The history and evolution of
gastroenterology demonstrates the impressive progresses that have been achieved in terms of
basic research, and pharmaceutical developments which has totally changed the management of
PUD. In particular, the introduction of selective histamine receptor antagonists and proton
pump inhibitors has made the medical control of acid secretion, including PUD, an effective
means of therapy with less reliance on costly and complicated surgical procedures. These
impressive advances highlight the successful intervention of effective pharmaceutical therapies
with closure of a therapeutic gap.5, 6, 16
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Based on the discovery of highly selective vagotomy and reduced acid secretion it was
recognized that acid secretion is a regulated process. In 1963, Dr Black and his colleagues
discovered that pharmacological inhibition of gastric acid stimulation would provide an
alternative to surgery.5
Histamine had been discovered as a major stimulant to gastric acid stimulation and although
histamine antagonists were developed for treatment of allergies, there were found to be too
weak to provide any gastric acid inhibition.
With a great deal of focused research during the 1960’s and 1970’s, the first selective
histamine antagonist burimamide was developed and by 1977 cimetidine was launched as a
therapy for peptic ulcer disease. Cimetidine proved to be a breakthrough in the medical
therapy of PUD symptoms and was followed rapidly thereafter by other such H2RAS with
similar efficacy. The discovery of the pharmacological inhibition of acid secretion by
histamine 2 receptor antagonist (H2RAs) provided the first possible alternative to surgery.
Furthermore, until recently GERD was considered a trivial problem with very limited
pharmaceutical interest. However, over the past 10 years, GERD has received significantly
more attention by industry and it is now considered a major market for antisecretory acid
suppression agents.5
Despite effective medical therapy with H2RAs, it was found that although ulcers healed
approximately 70% reoccurred after stopping therapy.
It was not until 1983, when infectious organism Camplobactor Pyloridis (now called
Helicobacter Pylori or H Pylori) was discovered which was thought to be responsible for the
recurrence of peptic ulcer diseases. Rigorous research into this area, established that H Pylori
is a causative agent for most peptic ulcers, with the exception of PUD caused by nonsteroidal anti-inflammatory drugs (NSAIDs). Eradication of H pylori resulted in a cure for
PUD and a sharp reduction in morbidity.1, 7
Annex to Chapter 1-5
Annex to Chapter 1
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In treating acid related disorders it became evident that while acid affliction of the stomach
and duodenum were suppressed by H2RAs gastro-esophageal reflux disease was more
resistant.
A new class of drugs-proton pump inhibitors (PPIs) were launched onto the market which
proved to be more effective in inhibiting acid secretion and targeting acid secretion, the H,K
Atpase or acid pump. The discovery of omeprazole and its unique mechanism of action on
the proton pump inhibitors (PPIs) revolutionized the ability to inhibit acid secretion and
control intragastric pH. All the current PPIs have the same core structure and are pro-drugs.
With the addition of PPIs, approximately 70% of maximal acid secretion were effectively
reduced and its addition to the H Pylori regimen further assisted in the rapid eradication of
the infectious organism.5
Peptic ulcer disease (PUD)
The term PUD generally refers to spectrum of disorders that includes gastric ulcer (GU), pyloric
channel ulcer, duodenal ulcer (DU) and postoperative ulcers at or near the site of surgical
anastomosis.8 Helicobactor pylori has been recognized as the main cause of chronic gastritis,
peptic ulcer disease, gastric adenocarcinoma, and gastric mucosa-associated with lymphoid
tissue (MALT lymphoma). Although H. Pylori is an established cause of several gastric diseases
mentioned above debate continues over whether it has any role in the etiology of disease
outside the stomach.7,8,9
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It is now believed that ulcer results from a complex interplay of acid and chronic
inflammation induced by HP infection although exact mechanism has not been elucidated.
H Pylori is associated with most cases of duodenal ulcer (DU). Other causes of DU are nonsteroidal anti-inflammatory drugs like aspirin, NSAIDs etc. and tumors like Zollinger
Allison syndrome.
Most gastric or stomach ulcers are also associated with H Pylori. However, only a subset of
infected persons develops peptic ulceration. The reasons for this are not known and it may
be due to variation in host factors, bacterial factors or both.
Infected persons have a 2- to 6-fold increased risk of developing gastric cancer and mucosalassociated-lymphoid-type (MALT) lymphoma compared with their uninfected counterparts.
The role of H. pylori in non-ulcer dyspepsia remains unclear.
Epidemiology
Prevalence of H. pylori infection correlates with socio-economic status rather than race, with a
prevalence of 80% in developing countries compared to prevalence of 20-50% in developed
countries.7 In the United States the probability of being infected is greater for older persons, with
prevalence rates greater than 50% in individuals older than 50 years and older. Minorities of
varying age groups have a higher prevalence 40 to 50%, and immigrants from developing
countries such as Latinos have prevalence rates greater than 60%. The infection is less common
in more affluent Caucasians at 20% for individuals less than 40 years of age.10
Although most gastric ulcers are usually caused by H. pylori, reports from the US show that
30% of gastric ulcers can be related to aspirin and other non-steroidal anti-inflammatory drugs
Annex to Chapter 1-6
Annex to Chapter 1
(NSAIDs).10 Most gastric adenocarcinomas and lymphomas occur in persons with current or
past infection with H. pylori. In developing countries, the ulcer groups are smaller and the
gastric cancer group may be larger. For example, in northern Brazil, gastric cancer is the most
common malignancy in men.10
Western countries10
In general, the following statements can be made to summarize prevalence of H Pylori in
Western countries:
 H Pylori affects about 20% of persons below the age of 40 years, and 50% of those above the
age of 60 years.
 H Pylori is uncommon in young children.
 Low socio-economic status predicts H Pylori infection.
 Immigration is responsible for isolated areas of high prevalence in some Western countries.
Developing Countries10
In developing countries, most adults are infected. H Pylori infection which occurs in about 10%
of children annually between the ages of 2 and 8 years so that most are infected by their teens. It
is evident from careful surveys that the majority of persons in the world are infected with H
Pylori.
H pylori can be cultured from the stools in most infected persons This is evidence that spread by
fecal oral contact with infected persons is likely. In addition, polymerase chain reaction (PCR)
can detect H Pylori in dental plaque from 30% of persons with the gastric infection. However,
this may be a less common source of transmission.
Transmission
Transmission is through oral ingestion, documented through vomitus, saliva or feces and
possible through waster sources in developing countries. The exact mode of transmission of H.
pylori stills remains elusive. Although H pylori may be eradicated with antibiotics, infection
may persist unless specific combination of antibiotics and acid suppressing agents are used.
Diagnostic Tests
Infection with H pylori can be diagnosed by endoscopic biopsy (rapid urease testing,
histological examination, culture or polymerase reaction) or by non-invasive methods (serology,
urea breath test, or the detection of H pylori antigens in the stool. The choice of appropriate test
is based on clinical situation.
Therapy
Management of PUD and treatment has changed dramatically. Treatment of PUD has evolved
from dietary modifications and surgery to acid suppression with antacids, H2RAs, proton pump
inhibitors and eradication of H Pylori infection. Prior to the development of H2RAs, patients
were frequently managed as inpatients and surgery was common. Today the use of H2RAs and
Annex to Chapter 1-7
Annex to Chapter 1
later PPIs have dramatically changed the management of PUD from in-hospital to a largely
outpatient setting with reduction in the number of surgical procedures.11
Table 2 shows the currently approved agents for the management of acid –peptide diseases such
as PUD and GERD. Histamine-2 (H2) blockers started coming in 1970s. Proton pump inhibitors
(PPIs) are the new class of drugs that profoundly inhibit acid secretion and have been shown to
be very effective in ulcer healing.
Table 2. Currently approved agents for the management of gastric acid related diseases12, 13, 14
Therapeutic class
Antacids
Prokinetic agents
Mucosal Protective agents
Histamine-2 Receptor antagonists
Proton pump inhibitors
Agents
Calcium carbonate
Magnesium hydroxide
Aluminum hydroxide
Bethanechol
Metoclopramide
Domperidone
Cisapride
Sucralfate
Alginic acid
Cimetidine
Nizatidine
Ranitidine
Famotidine
Omeprazole
Lansoprazole
Pantoprazole
Rabeprazole
Esomeprazole
Therapy for H. Pylori includes 1-2 weeks of a triple therapy of a proton pump inhibitor plus
clarithromicin and either amoxicillin or metronidazole. Quadruple therapy of proton-pump
inhibitor with bismuth subcitrate, tetracycline and metronidazole for more than a week is
equally efficacious. 7 Table 3 shows the currently available therapeutic combinations that can
treat PUD. Table 1 in the annex shows H Pylori regimens with associated cure rates.
Annex to Chapter 1-8
Annex to Chapter 1
Table 3 Suggested regimens for the treatment of H. pylori infection15
Regimen
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PPI (lansoprazole 30 mg OR omeprazole 20 mg) + amoxicillin 1000 mg + clarithromycin 500
mg (each drug given twice daily for 2 wk)
PPI (omeprazole 20 mg OR lansoprazole 30 mg) + metronidazole 500 mg + clarithromycin
500 mg (each drug given twice daily for 2 wk)
RBC 400 mg + clarithromycin 500 mg + amoxicillin 1000 mg OR metronidazole 500 mg OR
tetracycline 500 mg (each drug given twice daily for 2 wk)
Bismuth subsalicylate 525 mg q.i.d. + metronidazole 500 mg t.i.d. + tetracycline 500 mg q.i.d.
+ PPI (omeprazole 20 mg q.day OR lansoprazole 30 mg q.day) (each drug given in the
dosage and frequency indicated daily for 2 wk)
Bismuth subsalicylate 525 mg q.i.d. + metronidazole 250 mg q.i.d. + tetracycline 500 mg q.i.d.
+ H2-receptor antagonist (each drug given in the dosage and frequency indicated daily for 2
wk with the H2-receptor antagonist continued for a further 2 wk)
** Rbc: ranitidine bismuth citrate
A number of studies have documented the dramatic decline in surgery for PUD since 1975. The
studies reviewed below from Europe and the US have demonstrated the widespread impact of
pharmaceutical interventions. Today, operative treatment is limited to a small proportion of
ulcer patients who have complications or those who do not respond to medical treatment. In this
era of very potent anti-secretory agents and increasing knowledge about the role of H pylori,
surgery for routine PUD is of only historic significance. Surgery however may have a greater
role in complicated ulcer disease involving bleeding, perforation and obstruction.
Time Trends in Peptic Ulcer Surgery – Pharmaceuticals Closing the
Surgical Gap
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Time trends in peptic ulcer surgery from 1956 to 1986 based on a nationwide survey in
Sweden report that elective surgical operations steadily declined from 72.1 per 100,000 to
10.7 per 100,000 inhabitants. Also, the operation rate for perforation decreased by 50% from
12.8 to 6.4 per 100,000 inhabitants. Results of the nation wide Swedish survey conclude that
there had been a dramatic decline in elective peptic ulcer surgery with the introduction of
new technologies and effective therapies.16
Results from a report evaluating the incidence of ulcer disease among surgical patients in a
clinic in Germany conclude that the incidence of surgical operations increased after 1949 and
reached a peak from 1964 to 1978, but gradually decreased thereafter.17
A study from Norway assessed the incidence of operations for peptic ulcer disease or related
complications from 1975 to 1989 in people older than 15 years of age in a population of
100,000 inhabitants. Results revealed that the number of elective surgical procedures
decreased significantly by 72% from 1975 to 1989. The greatest reduction in surgery was
Annex to Chapter 1-9
Annex to Chapter 1
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related to duodenal ulcers. The incidence for acute operations also decreased by 35%.
Authors of the study conclude that the dramatic reduction in surgical interventions can be
attributed to the introduction of H2RAs in the 70’s and the more successful pharmacological
management of peptic ulcer disease.18
An evaluation from the department of Surgery from Texas was conducted to determine the
effects of the pharmacological and endoscopic treatment of PUD and the operative
management of PUD over the past 20 years. Results of the study showed that the number of
gastrointestinal operations decreased by 80%, however the number of gastric cancer
operations remains unchanged. Moreover, the evaluations showed that not only were
surgical interventions markedly reduced but the prevalence of bleeding, perforation and
obstruction were also reduced. Authors concluded that the improved pharmacologic and
endoscopic treatments have progressively curtailed the use of operative therapy for PUD.
Elective surgeries were rarely indicated and emergency operations were less common.19
A study from Finland assessed the incidence of surgery, hospital admissions and mortality
of PUD from 1972 to 1999. Results from the study confirmed that the medical therapy of
PUD had improved significantly over the past 20 years with the introduction of effective
agents such as H2RAs and PPIs, as well as the eradication regimens for H Pylori. During the
1990’s, there was a 3-fold increase in the consumption of antisecretory agents as well as an 8fold increase in NSAIDs use. Results of the study showed that there as an 89% reduction in
elective operations (from 1987 to 1997); the number of emergency operation for bleeding
ulcers increased by about 44% during the same time period, and the annual hospital
admissions increased by 79%. This increase was attributed to bleeding ulcers and
complication in elderly women. Mortality rates also increased 74% from ulcer perforations
and hemorrhages. Authors of the report concluded that the increase in emergency surgical
procedures, hospital admissions and mortality reflect the demographic changes and the
increased consumption of NSAIDs among the elderly in particular. Furthermore, regardless
of the increased emergency surgical operations elective operations for PUD had declined
and are not required today.20
A retrospective study was conducted in a community hospital in the United States to
evaluate the impact of H2RAs on the surgical treatment and outcome of patients with PUD
before and after the introduction of H2RAs. Two groups were reviewed: group 1 from 1971
to 1973 and group 2 from 1981 to 1983. Differences between the two groups were noted.
Indications for emergency operations were predominant for group 2 and there was
reduction in elective surgeries from 75% to 55% for group 2. The authors conclude that the
introduction and use of H2RAs have changed the surgical treatment and outcome of patients
with PUD.21
A report from Poland reviewed the indications for surgeries performed on PUD from two
time periods, 1977 to 1981 and 1992 to 1996. What is specific for this evaluation is the
delayed entry and clinical use of antisecretory agents which were available in the late 1980’s.
Results of the study showed a marked reduction in operation for PUD for the second time
period. There were more women of an older age who were operated on for bleeding,
intractable and perforated ulcers in the latter period. Based on the results authors of the
study conclude that the course and management of PUD has changed as the number of
patients undergoing surgery has declined due to the introduction of new effective therapies,
Annex to Chapter 1-10
Annex to Chapter 1
and to a lesser degree it can be attributed to other factors such as lifestyle changes, smoking
and diet.22
Past and Current Research
There has been little advancements in the therapy for H Pylori, however intense research
continues in this area and investigation of H pylori continues to provide new insights into the
pathogenesis of this infectious agent. Clinically, there is considerable debate but little new
information regarding H. pylori and NSAID-induced gastric damage, its role in non-ulcer
dyspepsia and its relationship with esophageal disease. Animal models have been developed
and have been used extensively to study the immune response of H pylori in order to develop
suitable vaccines. Animal models continue to provide important information regarding the
pathogenesis. More importantly the recent knowledge and availability of genomic sequences for
Homo Sapiens and H pylori has stimulated basic research into dissecting the involvement of H
Pylori with gastric malignances at the molecular level. This work is providing new directions for
further research with eventual clinical application. Other areas of study include the following7:
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Prophylactic oral immunization with recombinant H Pylori urease and escherichia coli.
H Pylori and its association with extragastric diseases such as hepatobiliary disease,
pancreatic cancer, and even arthrosclerosis.
H Pylori virulence factors. VacA is a gene of H Pylori. H Pylori stains expressing large
amounts on VacA are associated with a higher incidence of PUD.
Growth and metabolism of H Pylori is also being studies to identify therapies to better target
and eradicate the infection.
PPI and H2Ras are currently the most effective pharmacological treatments for PUD when used
in combination with antibiotics and acid reflux disease. Despite the efficacy of these agents,
there is still a potential for further improvements in pharmacotherapy. Some areas that have
been identified include the following9:
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Faster onset of action for complete acid suppression,
improved duration of efficacy and
combination therapies which can improve compliance.
A number of novel drugs are also under investigation for GERD which may be promising for
PUD. These include transient lower esophageal sphincter relaxation-reducing agents,
serotonergic agents, potassium-competitive acid blockers, mucosal protectants, histamine H3
agonists and anti-gastrin agents. If one or more of these groups prove to effective, additional
options will become available to clinicians to manage acid-related diseases.23, 24
Annex to Chapter 1-11
Annex to Chapter 1
Table 3 New therapeutic agents for acid-peptide diseases23
Potential novel targets
Proton pump inhibitors
Transient lower esophageal
sphincter relaxation reducing agents
(TLESR)
Serotonergic agents/prokinetics
Potassium-competitive blockers
Histamine H3 agonsists
Antigastrin agents
Examples
Ilaprazole
Tentaprazole
Current development
status
Phase II
Phase II
Preclinical
Tegaserod
Phase III
AZD0865
CS-526
Revaprazan
Soraprazan
R-alpha -methylhistamine
Anti gastrin vaccine
Itriglumide
Z-360
Phase II
Phase I
Phase II
Phase II/III
Preclinical
Phase I
Phase I
Phase II
Antacids, which were once considered an old-fashioned acid suppression therapy, may increase
esophageal pH to for up to 90 minutes. There is new interest now in developing combination
over the counter therapies of H2Ras plus antacids. The strategy is aimed at allowing for prompt
treatment of ‘heartburn’ with the prevention of subsequent episodes for several hours. At
present a combination product is not available but given the over the counter market potential
for low dose H2RAS and the competition from PPI going over the counter development and
availability of these agents is not far off.25
Conclusion
Gastric acid related disorders including peptic ulcer disease are common clinical problems.
Important advances have occurred over the past 35 years that have improved our
understanding of these disorders as well medicines that have significantly improved the
management of acid related disorders which have reduced the need for surgery. We now know
that although H Pylori plays a critical role in the pathogenesis and relapse of PUD, effective
gastric acid suppression is required in addition to antibiotic therapy for prompt ulcer healing
and H pylori eradication. Gastric acid also plays a pivotal role in the development of GERD.
Control of gastric acid therefore remains the cornerstone of effective management of these
disorders. Treatment of gastric acid related disorders including PUD has evolved from dietary
modifications and surgery to acid suppression with antacids, H2RAS, proton pump inhibitors
and eradication of H Pylori infection.
Major advances of gastroenterology during the past century has been the application of new
scientific knowledge, market potential, technology, and controlled clinical trials to the study of
Annex to Chapter 1-12
Annex to Chapter 1
gastrointestinal problems. Pharmaceutical commitment to research and development of novel
effective therapies complimented with an array of dosage forms IV, tables, capsules,
suspensions, sustained release compounds have also contributed to the progress in this field. As
we proceed biology, biotechnology, and genomic information will challenge the field of
gatroenterology to utilize this information, strengthen its research efforts and apply the
knowledge towards more effective therapies for gastrointestinal and digestive diseases.
Furthermore, the dramatic decline in surgery for PUD demonstrates that pharmaceutical
progress can significantly change the practice of medicine. It is reasonable to hope that similar
pharmaceutical advances could reduce the need for other costly surgical procedures such as
coronary artery or joint replacement surgery.
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http://www.medscape.com/viewarticle/424446_1 Feb 2000 - Philip Schoenfeld, MD, MSEd, MSc,
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http://www.medlina.com/gastroenterology_organizations.htm. List of gastroenerology organizations.
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Weil P, Buchberger MD. From Billroth to PCV: A century of Gastric Surgery. World J Surg. 1999; 23:736742.
4
Sachs G, Shin JM, Vagin O et al. Current trends in the treatment of upper gastrointestinal disease. Best
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Smooth DT, Go MF, Cryer B. Peptic Ulcer Disease. Primary Care. 2001; 28(3): 487-499.
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Webb D. New Therapeutic Options in The Treatment of GERD and other acid-peptic Disorders. The
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Annex to Chapter 1-13
Annex to Chapter 1
Colin W. Howden, CW, Hunt R. Guidelines for the Management of Helicobacter pylori
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15
Gustavsson S, Nyren O. Time Trends in Peptic Ulcer Surgery, 1956 to 1986. A Nation Wide Survery in
Sweden. Ann Surg. 1989; 210 (6): 704-9.
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Braun L. Incidence of Ulcer Disease Among Patients of the Detmold Surgical Clinic 1949-1989. Zentralbl
Chir. 1991; 116(9):551-8.
17
Haaverstad R, Moen OO, Kannelonnings KS et al. Ulcer surgery and anti-ulcer agents. Changes in
surgical activities and sale of anti-ulcer agents in Nord-Trodelag 1975-1989. Tidsskr Nor Laegeforen.
1994; 20 (11): 904-7
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Schwesinger WH, Page CP, Sirinek KR et al. J Gastrointestin Surg. 2001; 5(4)438-43.
Paimela L, Paimela I, Myllykangas-Luosujarvi R, Kivilaakso E. Current Features of Peptic Ulcer Disease
in Finland: Incidence of Surgery, Hospital Admissions and Mortality for the Disease During the Past
Twenty-Five Years. Scand J Gastroenterol. 2002; 37 (4): 399-403.
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Scheeres DE, DeKryger LL Dean. Surgical Treatment of Peptic Ulcer Disease Before and After
Introduction of H2 Blockers. 1987; 53 (7): 392-7.
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Janik J, Chwirot P. Peptic Ulcer Disease Before and After Introduction of New Drugs –A Comparison
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24
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25
Annex to Chapter 1-14