EDITORIAL Adv Clin Exp Med 2004, 13, 5, 737–747 ISSN 1230−025X

LESZEK PARADOWSKI, WOJCIECH BŁOŃSKI, RADOSŁAW KEMPIŃSKI

20 Years after Introducing Proton Pump Inhibitors. What Have We Achieved in Peptic Ulcer Disease Conventional Treatment? Co osiągnęliśmy w leczeniu zachowawczym choroby wrzodowej po 20 latach od wprowadzenia inhibitorów pompy protonowej? Department of Gastroenterology and Hepatology, Wroclaw Medical University, Poland

Streszczenie Do połowy lat siedemdziesiątych XX w. pacjenci cierpiący na chorobę wrzodową byli skazani na stosowanie re− strykcyjnej diety, częstego odpoczynku i pobytów w szpitalu oraz niejednokrotnie byli operowani z powodu powi− kłań choroby. Wprowadzenie w 1976 r. antagonistów receptorów histaminowych H2 zmniejszyło znacznie liczbę powikłań i hospitalizacji. Obecnie podstawą leczenia antysekrecyjnego są inhibitory pompy protonowej (IPP) wprowadzone na rynek w 1984 r., ale ze względów finansowych leki działające antagonistycznie na receptory H2 są jednak nadal szeroko stosowane. Przełomem w leczeniu zachowawczym owrzodzeń trawiennych było opisanie w 1983 r. przez Warrena i Marschalla wpływu bakterii Helicobacter pylori na błonę śluzową żołądka i dwunastni− cy oraz wprowadzenie leczenia eradykacyjnego (Adv Clin Exp Med 2004, 13, 5, 737–747). Słowa kluczowe: choroba wrzodowa, Helicobacter pylori, antagoniści receptorów histaminowych H2, inhibitory pompy protonowej (IPP).

Abstract Up to middle seventies patients with peptic ulcer were forced to use restrictive diet, long resting, hospitalization and often surgical procedures due to complications of the disease. Introducing of H2−antagonists in 1976 decreased dramatically the number of complications and hospital care of the disease. Nowadays the standard of antisecreto− ry treatment is the use of proton pump inhibitors introduced to the market in 1984 though due to the cost the H2− blokers are still widely prescribed. The breakthrough of peptic ulcer treatment was discovery of Helicobacter pylori influence on gastric and duodenal mucous by Warren and Marschall in 1983 and introduction of eradication treatment (Adv Clin Exp Med 2004, 13, 5, 737–747). Key words: peptic ulcer disease, Helicobacter pylori, H2−receptor antagonists, proton pump inhibitors (PPI).

For the long time patients with peptic ulcer dis− ease had been forced to restrictive lifestyle, fre− quent hospitalizations, often with gastric juice aspi− ration and long resting in bed. Diagnosis and treat− ment of peptic ulcer had been mainly based on the intensity of clinical symptoms. Because of rather vague correlation between clinical symptoms and peptic ulceration there had been no objective way to evaluate the effectiveness of different ways of treatment. No randomized trials had been per− formed and the management of the disease had been based on tradition and personal observations. The introduction of radiological and later endo−

scopic examination of stomach increased the prob− ability of confirming the active ulceration and eval− uation of its healing. From early 60s many ran− domized trials have been performed what com− pletely changed the clinical approach. Gradually the specialist have been withdrawing from restric− tive diet and new drugs have been introduced [1].

History The symptoms that are caused by peptic ulcer were for the first time described by Diokles (350– –325 BC) [2]. Gajus Plinius (23–79 AD) advised

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to the people with abdominal pains the consump− tion of donkey or cow milk. He claimed that if the ulcer grows in stomach, drinking of milk will heal it. Apart from that the knowledge about ulcer dis− ease in ancient times and the Middle Ages was limited. The studies on human anatomy performed in the Renaisance led to better understanding of the structure of upper gastrointestinal tract [3]. The first documented gastric ulcer was described by Donatus in 1586. Donatus performed the post mortal examination of stomach and found the ulcer in distal part of stomach and pylorus. In 1772 John Hunter described the digestive properties of gastric juice. The term “peptic ulcer” was based on the theory that the lesion is caused by digestion. In 1793 Matthew Ballie described the pathomorphol− ogy and clinical features of gastric ulcer. What is worth mentioning that Ballie and his successors in XIX and XX century paid a lot of attention to gas− tric ulcer – duodenal lesions were considered to appear rarely. In XIX century French scientist Cruveilhier for the first time distinguished the gastric ulcer and gastric cancer. The term “oval Cruveilhiera ulcer” describing the benign ulceration had been used in literature till the end of XIX century. Englishman John Abercrombie in his studies of peptic ulcer dis− ease noticed that in patients with duodenal ulcers the symptoms usually appear after 2–4 hours after the meal. In the treatment Cruveilhier and Abercrombie prescribed the increased consump− tion of milk. Abercrombie recommended light diet with small amounts of food per meal consisted gen− erally of milk and its products. In more advanced clinical cases he suggested occasional administra− tion of bismuth oxide and calcium water.

Conventional Treatment of Peptic Ulcer Disease In XIX and XX century the light diet was the only treatment of peptic ulcer disease. In 1876 Leube recommended complete starvation diet. Gradually the recommendations were extended to milk, eggs, milk products and other light and not stimulating food. In 1901 during Internal Medicine Congress in Wiesbaden Lenhartz proposed frequent and small in amount meals for patients suffering from peptic ulcer. Diet had to be composed of food “not irri− tating” the ulceration and not stimulating the secretion of gastric juice. In his own study Lenhartz showed that among 60 patients remain− ing on his diet only 4 experienced the reoccurrence of hemorrhage from upper digestive tract what was far less than in patients on Leube diet (20%).

It is necessary to mention that those days the pep− tic ulcer disease could only be diagnosed when bloody vomiting or tarry stools were reported – no radiological examinations with contrast were introduced into clinical practice and no random− ized trials were performed to evaluate the efficacy of different diet schemes in ulcer disease. Diet treatment was based on the theory that light meals were less stimulating for gastric juice secretion and that patients on long term diet were more often pain free [4, 5]. In 1912 Bertram Sippy described the algo− rithm of management in peptic ulcer disease. Sippy’s recommendations included: resting in bed, complete starvation diet in the first 5 days fol− lowed by every hour feeding with milk and cream shifting with antacid administration and control− ling the gastric juice secretion [6]. Sippy claimed that: “gastric or duodenal ulcer would heal as quickly as any other ulcer if its surface was not exposed to acid digestion”. The aim of Sippy’s therapy was preventing the ulceration from its digestive activity, what could be achieved by com− plete neutralization of all acid when the stomach is filled with food and the gastric juice is excreted [7]. In 1915 Sippy modified his recommendations: the initial complete diet was liquidated and the amounts of milk and cream in the every hour meals were increased. The patient was resting in bed for 3–4 weeks and every hour between 7 am and 7 pm he was receiving the combination of milk and cream. After 2–3 days the boiled eggs and precooked cereal products were introduced [6]. He also advised the consumption of neutralizing mixtures (calcium carbonate, natrium carbonate, magnesium carbonate) between meals and every 30 minutes between 7 and 10 pm. Sippy was also performing gastric juice aspiration with Ewald catheter (3 times a week) to decrease the nocturnal pains. The amount of aspirate was then measured to calculate the “free and total acid volume” [1]. Zankiewicz in 1948 performed the study of xenogenic blood infusions in 11 patients with gas− tric and duodenal ulcers [8]. The initial dose of 5 ml caused the shock, then the 3–5 day interruption in therapy was made depending on the extent of shock. Then the dose of blood was individually modified even up to 20 ml. Each of 3 patients received 5 blood infusions. In compared group patients received: Extractum Belladonnae, Atro− pinum sulfuricum, Calcium bromatum i.v., Solutio natrii hyposulfurosi i.v. and Phenobarbital. After treatment all patients were symptoms free and in 2 cases the healing of ulceration in radiological examination was confirmed. Zankiewicz also men− tioned the similar study by Mejerowicz and Blumin who were treating 48 patients with blood infusions.

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In 1932 Winkelstein for the first time proposed the treatment of peptic ulcer with constant oral in− fusion of milk. In 1933 he introduced milk with natrium bicarbonate. The infusion rate was 30 drops/ /min (up to 3 liters par day) to the catheter placed in duodenum. In 1942 Cornell et al. compared the effectiveness of different neutralizing mixtures. He found the mixture of milk and calcium bicar− bonate to be the most effective. In 1947 Douthwaite concluded that the most effective in neutralizing the acid is continuous 24−hour infu− sion infusion of 2.5 liters of milk through the catheter placed in stomach. In 1950 Clark in his study proved the efficacy of 9−day intraoe− sophageal milk infusion (3 liters per day) followed by continuous intraoesophageal infusion of mag− nesium bicarbonate (2.5 liters per day). 29 patients were enrolled into the study with ulceration con− firmed radiologically, after the treatment the heal− ing was proved in 19 patients [9]. Lawrence conducted the study to evaluate the effectiveness of Lenharz diet (modification of Sippy’s diet) and naturalizing factors in patients with peptic ulcer disease. Patients were divided into two groups: one on Sippy’s diet, the other on usual diet (also with fried food). Radiological healing was confirmed in 93% in both groups and was 6 days shorter in group receiving usual diet. Lawrence also compared the influence of antacids on pain reduction. The pain was the fastest reliev− ed by magnesium trisilicate, magnesium carbonate and aluminum hydroxide. In the final phase 12 patients received the continuous nocturnal intraoesophageal milk infusion. In 10 out of 12 patients the healing of ulcer was confirmed on radiology (in control group 11 out of 13). Lawrence also proved that resting in bed shortened significantly the healing period (64 days comparing to 86 days in patients with normal activity). No positive influence of smoking quit− ting on healing time was confirmed. Based on his studies Lawrence recommended in patients with peptic ulcer the diet consisted of 3 meals per day without quality and volume limitations. Consumption of 300 ml of milk twice daily and during evening meal was advised. The portion of milk had also to be drunk when patients woke up during the night. Additionally the patient was sup− posed to take antacids every two hours and when wakening up at night. Lawrence emphasize that patient should stay in bed until the complete symp− toms relief and than should be put in vertical posi− tion for one hour per day till radiological confir− mation of ulcer healing. After that the duration of vertical position is prolonged. The strong attention was paid by Lawrence to regularity of meals with intervals not longer than

4 hours. In the first year after healing he advised administration of naturalizing factors such as mag− nesium trisilicate [10]. Doll and Pygott in their study also proved that hospitalization shortened the duration of peptic ulcer healing [11]. In 1956 Doll et al. published the results of the trial comparing the effectiveness of gastric milk infusion in patients with gastric ulcer and in con− trol group. Although the percentage of patients with healed ulcer in both groups was similar, in patients receiving milk the pain withdrawal and weight gain was faster. Doll advised milk con− sumption as additional therapy when the pain was not reduced by resting in bed. This study proved that milk does not cause neutralization of acid in stomach, no influence of milk on ulcer healing was confirmed [12]. It is worth mentioning that the milk contains proteins and calcium what causes increased gastric secretion. The milk causes only transient naturalizing effect, followed by intermit− tent gastric secretion and this is way the treatment with milk is nowadays considered useless [13]. Doll et al. conducted the study to evaluate the value of diet in 64 hospitalized patients with radi− ological recognized gastric ulcer. Patients were divided into two groups: the first group received ulcer diet, the second standard diet with no fried food. After 1 month the ulceration healed in 5 of 32 patients in first group and in 10 of 32 in second group. Doll et al. also evaluate peptic ulcer diet in 80 outpatients with gastric ulcer and 50 outpatients with duodenal ulcer. Patients were divided into groups: ulcer diet and standard diet. After 1 year in 45% on ulcer diet and 51% patients on standard diet ulcer healing was confirmed radiologically. The examination performed by Doll proved that the diet consisted of light food (ulcer diet) does not improve the peptic ulcer healing outcome [14].

Estrogens in Peptic Ulcer Healing Due to higher incidence of peptic ulcer disease in men the studies evaluating the estrogens influ− ence on peptic ulcers were performed. In 1937 Korbsch adapted estrogens injections in 4 men with gastric ulcer and observed faster healing. In 1940 Winkelstein used estrogens injections in 20 postmenopausal women with peptic ulcer. The symptoms resolved quickly but relapses were seen often, improved by estrogen administration. In 1952–1954 Truelove et al. administered Stilboestrol in 40 men with duodenal ulcer. 0.5 mg of Stilboestrol was administered twice daily for 6 months. In 50% of patients on Stilboestrol therapy the radiological healing of ulcer was confirmed after 6 months.

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Because the side effects the estrogen therapy of peptic ulcer is now not used [15].

Liquorice in Peptic Ulcer Extract of liquorice had been used in peptic ulcer treatment since 1946. Liquorice acid is responsible for the activity of the extract. It has anti−inflammatory properties and increases the mucous production in stomach. Doll et al. showed the role of Biogastrone in peptic ulcer treatment. It shortened the time of gastric ulcer healing with no significant influence on duodenal ulcer [16]. In multicenter trial Misiewicz et al. confirmed that Carbenoxolone had no effect on the healing of duo− denal ulcer [17]. In other study the authors proved that Carbenoxolone improved the healing of duo− denal ulcer in initial phase but after 12 weeks there was no significant superiority over placebo [18]. The discussed substances cause many adverse events: edema, hypertension, hypokaliemia because if its aldosterone−like activity.

Irradiation Therapy of Peptic Ulcer In 1917 Bruegel described that irradiation of stomach can temporarily inhibit the gastric secre− tion. In 1957 Levin et al. published the results of treatment of 723 patients with duodenal ulcer treated with irradiation and then followed up for 5 to 18 years. 46% of patients had the relapse of disease. Levin concluded that this type of therapy can be additional to normal management of patients with ulcer disease (resting in bed, contin− uous milk and cream consumption and antacids) [19]. The therapy that destroys the excreting cell and causes atrophy of the gastric mucosa met a lot of resistance and lost its sense [20].

Freezing of the Stomach In 1962 Wangensteen et al. started with “freez− ing of stomach” as the treatment of duodenal ulcer. Despite initial enthusiasm American Gastro− enterology Association during the meeting in San Francisco stated that the broad usage of the method will be only possible after evaluating its safety and efficacy in controlled trials. In 1963 multicenter randomized trial was conducted to describe the effectiveness of stomach freezing in patients with duodenal ulcer. The balloon was introduced into the stomach and then perfused by

cooled alcohol (–10°C). In control group the balloon was perfused with liquid in +37°C temperature. The trial showed no effectiveness of stomach freezing comparing to placebo [21].

Anion Exchange Resin Between 1940 and 1950 the studies on anion exchange resin in peptic ulcer were performed due to its fast acting, complete inhibition of digestive properties of gastric juice by inhibition of pepsin and no constipation during therapy. In 1947 Spears et al. published the results of poliamin resin in 30 patients with peptic ulcer with resolve of symp− toms after treatment [22]. Also Kraemer et al. showed in 1947 the results of anion exchange therapy in 18 patients with radi− ologically confirmed ulcer. The patients were receiving 3500 mg of substance 4–8 times per day for 4 months. In all patients the symptoms of pep− tic ulcer disease resolved during therapy [23]. In 1950 Wirts et al. demonstrated that effective− ness of anion exchange resin was comparable to aluminium hydroxide gel. In 21 of 24 patients tak− ing the resin and in 16 of 20 on aluminium hydrox− ide therapy the healing of ulcer was confirmed [24].

Psychotherapy in Chronic Peptic Ulcer In 1950 Selesnick described the influence of psychotherapy on duodenal ulcer disease. 30 pa− tients with peptic ulcer were treated only with psy− chotherapy: group and individual. In 29 out of 30 patients the symptoms of duodenal ulcer dis− solved [25]. In 1977 the results of several trials evaluating the role of trimipramine in peptic ulcer were pub− lished. Trimipramine was proved to decrease the gastric secretion. Wetterhus et al. showed that 50 mg of trimipramine per day caused faster resolve of dys− peptic symptoms and quicker healing of ulcer com− paring to placebo [26]. Guldahl et al. used 50–75 mg of trimipramine in 4 patients with duodenal ulcer and masked depression. The healing of ulcer was confirmed in 3 patients and the signs of depression improved in all patients [27]. In other multicenter double−blind trial the high effectiveness of 4 week treatment with trimipramine was confirmed [28].

Antacids Antacids were “always” used in the treatment

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of peptic ulcer disease. By neutralizing the acid they protect the gastric mucosa from its aggressive activity [29]. Patients prefer the antacid treatment because it brings almost instant pain relief [30]. Different antacids were used: natrium bicarbonate is fast and effective due to its good solubility in water, but the effect disappears after several min− utes followed by increased gastric secretion and need for the next dose of the antacid. Calcium car− bonate is not soluble in water and shows slower but more prolonged activity, but causing constipa− tion. Magnesium oxide acts much longer but caus− es diarrhoea. Natrium hydroxide and calcium carbonate are not the treatment of choice anymore but they are often the element of different compounds [31]. The results of first randomized trial with antacids was published by Cayer et al. in 1957. 144 patients were treated with aluminium hydroxide or placebo. Long term (8 months) effect was seen in 74% of patients taking the medication and 24% taking placebo [31]. Until 1990 14 randomized trials based on endoscopic findings and evaluating the antacid therapy in duodenal ulcer disease were per− formed. In 6 trials the antacids were compared to placebo in 8 to H2−receptor antagonists (cimeti− dine, ranitidine). Peterson et al. studied the effec− tiveness of high doses of antacids (1000 mmol/ /day) in duodenal ulcer healing. Patients were receiving magnesium−aluminium hydroxide every 1 and 3 hours after the meal and before sleep. After 4 weeks in 78% of patients taking the med− ication comparing to 45% in placebo group the healing of ulcer was confirmed. The study proved that high doses of antacids accelerate the healing of duodenal ulcer [32]. High doses of antacids were causing diarrhoea and the treatment was not accepted by patients. Therefore trials with lower doses (100–200 mmol/ /day) were performed and they proved the similar effectiveness of lower doses of antacids in healing of peptic ulcer [33]. Furthermore the antacids proved to be more effective than H2−receptor antagonists in preven− tion of peptic ulcer. This indicated that the mecha− nism of antacids activity is not only connected to the neutralizing properties. The antacids also pro− tect the gastric mucosa from aggressive acid by inducing prostaglandin production [34]. Antacid containing aluminium hydroxide bind the bile salts, decrease pepsin production and increase the secretion of mucoproteins [35−36]. Nowadays the antacids are used for fast symp− toms relief and during the diagnosing of peptic ulcer disease or before the proper treatment (for example Helicobacter pylori eradication).

Mucosal Protecting Agents Mucosal protecting agents accelerate the ulcer healing and prevent the relapse of peptic ulcer without inhibition of gastric secretion [37]. Sucralfate and colloidal bismuth had been thoroughly studied starting from early seventies of XX century. Sucralfate generates thick suspension in stomach and duodenum, covering the mucous, particularly the ulcer lesions. Sucralfate stimulates the mucous for prostaglandin releasing and binds with epidermal growth factor, which stimulates cell proliferation and healing of ulcer. Trials described that sucralfate caused duodenal ulcer healing in 79% of patients after 4 weeks and gas− tric ulcer healing in 75% of patients after 8 weeks [38]. Besides sucralfate is as effective as cimeti− dine or ranitidine in treatment of peptic ulcer. Smoking has no influence on ulcer healing during treatment with sucralfate [39–41]. Colloidal bismuth subcitrate acts similarly to sucralfate and in the seventies was basal treatment for peptic ulcer. It significantly accelerates the healing of the ulcer [42]. Clinical trials also showed that colloidal bismuth subcitrate is as effective as cimetidine in gastric and duodenal ulcer healing process. The peptic ulcer relapse rate was lower after colloidal bismuth subcitrate then cimetidine [43–45]. Later it was discovered that bismuth has also the activity against Helicobacter pylori.

Prostaglandins Misoprostol is the first synthetic analogue of prostaglandin E1. It decreases the secretion of acid and gastric juice, increases the regeneration and healing of mucosa, there is also evidence that it diminishes the lesions caused by such aggressive factors as alcohol and nicotine [46]. Introducing of H2−receptor antagonists and proton pump inhi− bitors decreased the usage of misoprostol though recently the cytoprotective effect in patients taking non−steroidal anti−inflammatory drugs (NSAID’s) has been described. In multicenter randomized trial the effectiveness of misoprostol in prevention of gastric ulceration in patients taking NSAID’s was proved [47]. Cytoprotective mechanism of prostaglandin is not well discovered in humans [48, 49]. The side effects of misoprostol are: nausea, vomiting, diarrhoea and metrorrhagia Misoprostol should not be used during pregnancy. The effectiveness of misoprostol in duodenal ulcer disease was stated in many clinical trials. Brand et al. [50] showed that 200 µg of misopros− tol taken 4 times a day for 4 months caused ulcer

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healing in 77% of patients (dose 50 µg in analogue scheme of treatment was not effective comparing to placebo). Lam et al. [51] administered 200 µg of misoprostol 4 times a day for 4 months and achieved the healing rate of 61%, and with dose 300 µg – 71%. The trials comparing the effective− ness of misoprostol and cimetidine did not show significant difference between these medications [52]. The pain relief is though much stronger after cimatidine comparing to misioprostol. The healing rates in stomach ulcer after 8 weeks were lower than in duodenal ulcer and with 100 µg of misoprostol similar to placebo [53]. 200 µg of misoprostol taken 4 times a day was as effective as 300 mg of cimetidine 4 times a day in gastric ulcer healing [54].

Anticholinergic Drugs Anticholinergic drugs inhibit the vagal stimu− lated gastric secretion and slow down the gastric motility. Usage of this drugs is nowadays limited because of many systemic side effects. First reports on anticholinergic drugs appeared in early fifties of XX century. Avey et al. [55] was admin− istering subcutaneously 1.2 mg of atropine in 12 pa− tients with radiological signs of peptic ulcer and in 10 healthy volunteers. Atropine in interdigestive phase blocked the acid secretion in control group and decreased but not blocked the secretion in patients with peptic ulcer. Authors claimed that gastric secretion in patients with peptic ulcer is mostly regulated via humoral pathways. Then the search for successor of atropine with less systemic side effects began. The best studied drugs were Banthine (methantheline) [56, 57], pro−Banthine (propanthelina bromide) [58, 59] and rarely: antrenyl, bentyl, lergine, merbentyl [60]. These drugs did not meet the expectations because of the side effects (impaired seeing, dryness in mouth), the gastric juice secretion was less pronounced the in classical drugs. Pirenzepine is the best described, selective M1−muscarine receptor antagonist. It inhibits the acid and gastric juice secretion more than mucous production and has weak systemic activity. Pirenzepine was found to be effective in many clinical trials. In duodenal ulcer disease piren− zepine in daily dose of 75 mg for one week and then 50 mg for three weeks caused ulcer healing in 52% of patients, significantly more often then in placebo group [61]. In other study pirenzepine was used in dose of 100 mg daily. After 4 weeks the healing rates of duodenal ulcers were 70% and 32% in placebo group [62]. Increasing the dose to 150 mg/day improved the healing rate to 90% after

4 weeks, the side effects were slightly pronounced (impaired seeing, dryness in mouth) and passed after decreasing the dose to 100 mg for 2–3 days [63]. Similarly in gastric ulcer administration of 150 mg pirenzepine led to lesion healing in 90% of patients after 6 weeks [64], the dose of 75 mg/day caused gastric ulcer healing in 60% of patients after 4 weeks [65]. Until the introduction of H2−receptor antago− nists pirenzepine had been an effective medication in peptic ulcer disease. Initial trial with cimetidine proved its better efficacy in duodenal ulcer disease treatment (healing rate after 4 weeks 82.3% for cimetidine and 71.4% for pirenzepine) [66].

H2−Receptor Antagonists H2−receptor antagonists were a complete breakthrough in peptic ulcer disease treatment. The search for the agent that would selectively block histamine receptors H2 started in 1964 [67] and finally in 1972 the first H2−receptor antagonist burimamide was described [68–70]. The following analogue was metiamid and in 1976 cimetidine had its premiere in Great Britain [71, 72]. Cimetidine was the first widely used H2−receptor antagonist, a new era in the treatment of peptic ulcer. As the precursor it had side effects (inhibi− tion of microsomal enzymes in the liver followed by impaired metabolism of some drugs, gyneco− masty in men) and soon new successors were brought into the market: ranitidine, famotidine, nizatidine and others. H2−receptor antagonists are very effective in the treatment of duodenal ulcer. Cimetidine started the whole “dynasty” of H2−receptor antagonists. From the time it was discovered the number of patients operated because of peptic ulcer disease has dropped dramatically. H2−receptor antagonists had been widely used until the introduction of proton pump inhibitors and description of Helicobacter pylori influence on gastric and duodenal mucous. Due to financial reasons they are still used in the clinical practice.

Helicobacter pylori Eradication In 1983 Warren and Marshall [73] suggested the role of Helicobacter pylori in pathogenesis of mucosal lesions in stomach and duodenum. They described bacilli in stomach mucous, causing chronic inflammation. After this discovery the revolution in Helicobacter pylori dependent upper digestive tract diseases has started. The organism

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has been blamed for many diseases outside the digestive tract, now we know that it is responsible for acute and chronic gastritis, duodenal and stom− ach ulcer and for gastric cancer [74]. The preva− lence of Helicobacter pylori infection in develop− ing countries is estimated to 80–100% in devel− oped ones 20–40%. Current consensus concerning management of Helicobacter pylori infection was achieved by Working Group of Polish Association of Gastroenterology in 2004 [75]. Comparing to consensus settled in 2001 the indication for the therapy were widened to eradication in patients taking non−steroidal anti−inflammatory drugs and when the patient asks for therapy. Current indica− tions for Helicobacter pylori treatment are shown in Table 1. The satisfying eradication rate is 85%. This could only be achieved by combined therapy (anti− secretory drug + at least two antibiotics). 7−day therapy is advised, longer therapy increases the eradication rate only in few percent but side effects appear more frequently. The schemes with H2− receptor antagonists are not recommended because they seem to be less effective. Due to high Helicobacter pylori resistance to metronidazole (49−69%) and increasing resistance to clar− ithromycin these two agents are not recommended together in the first attempt of eradication. Currently recommended schemes are: – proton pump inhibitor (PPI) (standard dose twice daily) + amoxycillin 1000 mg twice daily + clarithromycin 500 mg twice daily, Table 1. Current indications for Helicobacter pylori treat− ment – year 2004 Tabela 1. Wspólczesne wskazania do leczenia Helicobacter pylori – 2004 rok 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. *

Duodenal ulcer Gastric ulcer History of gastric and duodenal ulcer disease Previous surgery in peptic ulcer disease Gastritis (pronounced or aphtous lesions) Stomach resection because of early gastric cancer* Gastric cancer in the family (up to second degree relatives) Precancerous lesions (multifocal atrophic gastritis, meteplasia, dysplasia)* Adenomas and hyperplastic polyps in stomach * MALT−lymphoma in stomach* Ménétrier disease* Functional dyspepsia (no effect or relapse after standard treatment) Chronic therapy with NSAID’s Patient’s wish

indication for hospitalization in gastroenterology depart− ments (also after second failure in eradication treatment and in questionable cases)

– proton pump inhibitor (PPI) (standard dose twice daily) + amoxycillin 1000 mg twice daily + metronidazole 500 mg twice daily, – proton pump inhibitor (PPI) (standard dose twice daily) + clarithromycin 500 mg twice daily + metronidazole 500 mg twice daily.

Proton Pump Inhibitors The discovery of the final element of gastric acid secretion – H+/K+−ATP−ase (proton pump) in 1973 fastened the research on the drugs complete− ly blocking the acid secretion [76]. H2−receptor antagonists did not provide controlled acid sup− pression particularly in specific situation where it was essentially needed (Zollinger−Ellison syn− drome). The decreased effectiveness during long term therapy with H2−receptor antagonists is also observed causing the relapses of disease. In the end of seventies of XX century a lot of attention had been paid to the new group of drugs – ben− zoimidazoles which blocked the terminal element of gastric acid secretion – proton pump. The mech− anisms support inhibition of all kind of stimula− tion: histamine, cAMP, carbachol and others. In 1981 Fellenius et al. [77] described in “Nature” the influence of benzoimidazole analogs on ATP−ase inhibition in stomach. Lind et al. [78] proved that a single dose of 20 mg of omeprazole highly inhi− bits acid secretion and the effect last for 24 hours; single dose of 80 mg of omeprazole blocked the secretion for 3 days. Howden et al. [79] showed that after 7−day therapy with either 30 or 60 mg of omeprazole almost 100% inhibition of basic acid secretion and the secretion stimulated by penta− gastrin was observed. In 1983 Gustavsson et al. [80] described omeprazole effectiveness in 32 duodenal ulcer patients. Patients were given 20 or 60 mg of omeprazole daily. After 2 weeks the healing rates were: 100% in 60 mg of omeprazole group and 63% in patients treated with 20 mg of omeprazole daily. After following 4 weeks the healing rate increased to 93%. In other study the healing of duodenal ulcer was confirmed in 41 out of 43 patients after 4 weeks of omeprazole therapy [81]. Prichard et al. [82] achieved healing of duodenal ulcer after 4 weeks in 83% of patients treated with 10 mg of omeprazole daily and in 94% treated with 30 mg of omeprazole daily. In conclusion, proton pump inhibitors are very effective in duo− denal ulcer disease and cause ulcer healing in over 90% of patients. Interesting results were shown in randomized trial, conducted in 1999 in 928 patients with duo− denal ulcer. 12−month therapy with 10 and 20 mg

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of omeprazole was compared to ranitidine 150 mg in maintaining remission of duodenal ulcer disease [83]. After 12−months no ulceration was found respectively in 71%, 87% and 63% of patients and there was significant difference between omepra− zole and ranitidine taking patients. Smoking of cigarettes, long ulcer history and young age was risk factor for disease relapse. There are few new proton pump inhibitors apart from omeprazole: pantoprazole, lansopra− zole, rabeprazole or the first optic isomer esomeprazole, which is said to have more bioavailability (decreased effect of first pass in liver) and stronger gastric acid inhibition than omeprazole [84]. The drugs differ in pharmacoki− netic or pharmacodynamic properties and interac− tion with other drugs what is adapted for promo− tional targets as proton pump inhibitors are part of a great financial market. Recently the clinical significance of proton pump inhibitor has increased even more because the drugs became the treatment of choice in gas− tro−oesophageal reflux disease. This was due to side effects of prokinetic drugs – the indications for this kind of therapy are nowadays limited. Although the scientists are still searching for drugs acting in lower oesophageal region, the position of proton pump inhibitors seems to be safe and sound.

Conclusions Introduction of cimetidine in 1976 was with− out any doubt the breakthrough in antisecretory therapy. The application of proton pump inhibitors in clinical practice gave the possibility for practi− cally complete inhibition of gastric secretion with simple administration regiments. The drugs can be used in long term therapies without loss of effica− cy. In 1983 Warren and Marshall described the role of Helicobacter pylori in pathogenesis of mucosal lesions in stomach and duodenum. Introduction of effective Helicobacter pylori erad− ication therapies made possible the elimination of the factor responsible for ulcer formation. That caused enormous decrease in the number of hospi− talization, complications and relapses of peptic ulcer disease. Patients with peptic ulcer are now treated on outpatient basis by family doctors. The number of surgical procedures that include only complications of disease also dropped dramatical− ly. In addition indirect costs (number of medical visits, duration of job absence) were reduced. Introduction of proton pump inhibitors and Helicobecter pylori eradication did not decrease the prevalence of peptic ulcer disease but provided a huge arm against the disease and its complica− tions. For the first time the possibility for constant healing of peptic ulcer has been achieved.

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