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− scopic examination of stomach increased the prob− ease had been forced to restrictive lifestyle, fre− ability of confirming the active ulceration and eval− quent hospitalizations, often with gastric juice aspi− uation of its healing. From early 60s many ran− ration and long resting in bed. Diagnosis and treat− domized trials have been performed what com− ment of peptic ulcer had been mainly based on the pletely changed the clinical approach. Gradually intensity of clinical symptoms. Because of rather the specialist have been withdrawing from restric− vague correlation between clinical symptoms and tive diet and new drugs have been introduced [1]. peptic ulceration there had been no objective way to evaluate the effectiveness of different ways of History treatment. No randomized trials had been per− formed and the management of the disease had The symptoms that are caused by peptic ulcer been based on tradition and personal observations. were for the first time described by Diokles (350– The introduction of radiological and later endo− –325 BC) [2]. Gajus Plinius (23–79 AD) advised 738 L. PARADOWSKI, W. BŁOŃSKI, R. KEMPIŃSKI to the people with abdominal pains the consump− It is necessary to mention that those days the pep− tion of donkey or cow milk. He claimed that if the tic ulcer disease could only be diagnosed when ulcer grows in stomach, drinking of milk will heal bloody vomiting or tarry stools were reported – no it. Apart from that the knowledge about ulcer dis− radiological examinations with contrast were ease in ancient times and the Middle Ages was introduced into clinical practice and no random− limited. The studies on human anatomy performed ized trials were performed to evaluate the efficacy in the Renaisance led to better understanding of of different diet schemes in ulcer disease. Diet the structure of upper gastrointestinal tract [3]. The treatment was based on the theory that light meals first documented gastric ulcer was described by were less stimulating for gastric juice secretion Donatus in 1586. Donatus performed the post and that patients on long term diet were more often mortal examination of stomach and found the pain free [4, 5]. ulcer in distal part of stomach and pylorus. In 1772 In 1912 Bertram Sippy described the algo− John Hunter described the digestive properties of rithm of management in peptic ulcer disease. gastric juice. The term “peptic ulcer” was based on Sippy’s recommendations included: resting in bed, the theory that the lesion is caused by digestion. In complete starvation diet in the first 5 days fol− 1793 Matthew Ballie described the pathomorphol− lowed by every hour feeding with milk and cream ogy and clinical features of gastric ulcer. What is shifting with antacid administration and control− worth mentioning that Ballie and his successors in ling the gastric juice secretion [6]. Sippy claimed XIX and XX century paid a lot of attention to gas− that: “gastric or duodenal ulcer would heal as tric ulcer – duodenal lesions were considered to quickly as any other ulcer if its surface was not appear rarely. exposed to acid digestion”. The aim of Sippy’s In XIX century French scientist Cruveilhier for therapy was preventing the ulceration from its the first time distinguished the gastric ulcer and digestive activity, what could be achieved by com− gastric cancer. The term “oval Cruveilhiera ulcer” plete neutralization of all acid when the stomach is describing the benign ulceration had been used in filled with food and the gastric juice is excreted literature till the end of XIX century. Englishman [7]. In 1915 Sippy modified his recommendations: John Abercrombie in his studies of peptic ulcer dis− the initial complete diet was liquidated and the ease noticed that in patients with duodenal ulcers amounts of milk and cream in the every hour the symptoms usually appear after 2–4 hours after meals were increased. The patient was resting in the meal. In the treatment Cruveilhier and bed for 3–4 weeks and every hour between 7 am Abercrombie prescribed the increased consump− and 7 pm he was receiving the combination of tion of milk. Abercrombie recommended light diet milk and cream. After 2–3 days the boiled eggs with small amounts of food per meal consisted gen− and precooked cereal products were introduced [6]. erally of milk and its products. In more advanced He also advised the consumption of neutralizing clinical cases he suggested occasional administra− mixtures (calcium carbonate, natrium carbonate, tion of bismuth oxide and calcium water. magnesium carbonate) between meals and every 30 minutes between 7 and 10 pm. Sippy was also performing gastric juice aspiration with Ewald Conventional Treatment catheter (3 times a week) to decrease the nocturnal of Peptic Ulcer Disease pains. The amount of aspirate was then measured to calculate the “free and total acid volume” [1]. In XIX and XX century the light diet was the Zankiewicz in 1948 performed the study of only treatment of peptic ulcer disease. In 1876 xenogenic blood infusions in 11 patients with gas− Leube recommended complete starvation diet. tric and duodenal ulcers [8]. The initial dose of 5 ml Gradually the recommendations were extended to caused the shock, then the 3–5 day interruption in milk, eggs, milk products and other light and not therapy was made depending on the extent of stimulating food. shock. Then the dose of blood was individually In 1901 during Internal Medicine Congress in modified even up to 20 ml. Each of 3 patients Wiesbaden Lenhartz proposed frequent and small received 5 blood infusions. In compared group in amount meals for patients suffering from peptic patients received: Extractum Belladonnae, Atro− ulcer. Diet had to be composed of food “not irri− pinum sulfuricum, Calcium bromatum i.v., Solutio tating” the ulceration and not stimulating the natrii hyposulfurosi i.v. and Phenobarbital. After secretion of gastric juice. In his own study treatment all patients were symptoms free and in Lenhartz showed that among 60 patients remain− 2 cases the healing of ulceration in radiological ing on his diet only 4 experienced the reoccurrence examination was confirmed. Zankiewicz also men− of hemorrhage from upper digestive tract what tioned the similar study by Mejerowicz and Blumin was far less than in patients on Leube diet (20%). who were treating 48 patients with blood infusions. Achievements in Peptic Ulcer Disease Conventional Treatment 739

In 1932 Winkelstein for the first time proposed 4 hours. In the first year after healing he advised the treatment of peptic ulcer with constant oral in− administration of naturalizing factors such as mag− fusion of milk. In 1933 he introduced milk with nesium trisilicate [10]. Doll and Pygott in their natrium bicarbonate. The infusion rate was 30 drops/ study also proved that hospitalization shortened /min (up to 3 liters par day) to the catheter placed the duration of peptic ulcer healing [11]. in duodenum. In 1942 Cornell et al. compared the In 1956 Doll et al. published the results of the effectiveness of different neutralizing mixtures. trial comparing the effectiveness of gastric milk He found the mixture of milk and calcium bicar− infusion in patients with gastric ulcer and in con− bonate to be the most effective. In 1947 trol group. Although the percentage of patients Douthwaite concluded that the most effective in with healed ulcer in both groups was similar, in neutralizing the acid is continuous 24−hour infu− patients receiving milk the pain withdrawal and sion infusion of 2.5 liters of milk through the weight gain was faster. Doll advised milk con− catheter placed in stomach. In 1950 Clark in his sumption as additional therapy when the pain was study proved the efficacy of 9−day intraoe− not reduced by resting in bed. This study proved sophageal milk infusion (3 liters per day) followed that milk does not cause neutralization of acid in by continuous intraoesophageal infusion of mag− stomach, no influence of milk on ulcer healing was nesium bicarbonate (2.5 liters per day). 29 patients confirmed [12]. It is worth mentioning that the were enrolled into the study with ulceration con− milk contains proteins and calcium what causes firmed radiologically, after the treatment the heal− increased gastric secretion. The milk causes only ing was proved in 19 patients [9]. transient naturalizing effect, followed by intermit− Lawrence conducted the study to evaluate the tent gastric secretion and this is way the treatment effectiveness of Lenharz diet (modification of with milk is nowadays considered useless [13]. Sippy’s diet) and naturalizing factors in patients Doll et al. conducted the study to evaluate the with peptic ulcer disease. Patients were divided value of diet in 64 hospitalized patients with radi− into two groups: one on Sippy’s diet, the other on ological recognized gastric ulcer. Patients were usual diet (also with fried food). Radiological divided into two groups: the first group received healing was confirmed in 93% in both groups and ulcer diet, the second standard diet with no fried was 6 days shorter in group receiving usual diet. food. After 1 month the ulceration healed in 5 of Lawrence also compared the influence of antacids 32 patients in first group and in 10 of 32 in second on pain reduction. The pain was the fastest reliev− group. Doll et al. also evaluate peptic ulcer diet in ed by magnesium trisilicate, magnesium carbonate 80 outpatients with gastric ulcer and 50 outpatients and aluminum hydroxide. In the final phase with duodenal ulcer. Patients were divided into 12 patients received the continuous nocturnal groups: ulcer diet and standard diet. After 1 year in intraoesophageal milk infusion. In 10 out of 45% on ulcer diet and 51% patients on standard 12 patients the healing of ulcer was confirmed on diet ulcer healing was confirmed radiologically. radiology (in control group 11 out of 13). The examination performed by Doll proved that Lawrence also proved that resting in bed the diet consisted of light food (ulcer diet) does not shortened significantly the healing period (64 days improve the peptic ulcer healing outcome [14]. comparing to 86 days in patients with normal activity). No positive influence of smoking quit− ting on healing time was confirmed. Based on his Estrogens studies Lawrence recommended in patients with in Peptic Ulcer Healing peptic ulcer the diet consisted of 3 meals per day without quality and volume limitations. Due to higher incidence of peptic ulcer disease Consumption of 300 ml of milk twice daily and in men the studies evaluating the estrogens influ− during evening meal was advised. The portion of ence on peptic ulcers were performed. In 1937 milk had also to be drunk when patients woke up Korbsch adapted estrogens injections in 4 men during the night. Additionally the patient was sup− with gastric ulcer and observed faster healing. In posed to take antacids every two hours and when 1940 Winkelstein used estrogens injections in wakening up at night. Lawrence emphasize that 20 postmenopausal women with peptic ulcer. The patient should stay in bed until the complete symp− symptoms resolved quickly but relapses were seen toms relief and than should be put in vertical posi− often, improved by estrogen administration. In tion for one hour per day till radiological confir− 1952–1954 Truelove et al. administered Stilboestrol mation of ulcer healing. After that the duration of in 40 men with duodenal ulcer. 0.5 mg of Stilboestrol vertical position is prolonged. was administered twice daily for 6 months. In 50% The strong attention was paid by Lawrence to of patients on Stilboestrol therapy the radiological regularity of meals with intervals not longer than healing of ulcer was confirmed after 6 months. 740 L. PARADOWSKI, W. BŁOŃSKI, R. KEMPIŃSKI

Because the side effects the estrogen therapy of peptic ulcer is now not used [15]. cooled alcohol (–10°C). In control group the bal- loon was perfused with liquid in +37°C temperature. The trial showed no effectiveness of stomach freez- Liquorice ing comparing to placebo [21]. in Peptic Ulcer Extract of liquorice had been used in peptic Anion Exchange Resin ulcer treatment since 1946. Liquorice acid is responsible for the activity of the extract. It has Between 1940 and 1950 the studies on anion anti−inflammatory properties and increases the exchange resin in peptic ulcer were performed due mucous production in stomach. Doll et al. showed to its fast acting, complete inhibition of digestive the role of Biogastrone in peptic ulcer treatment. It properties of gastric juice by inhibition of pepsin shortened the time of gastric ulcer healing with no and no constipation during therapy. In 1947 Spears significant influence on duodenal ulcer [16]. In et al. published the results of poliamin resin in multicenter trial Misiewicz et al. confirmed that 30 patients with peptic ulcer with resolve of symp− Carbenoxolone had no effect on the healing of duo− toms after treatment [22]. denal ulcer [17]. In other study the authors proved Also Kraemer et al. showed in 1947 the results that Carbenoxolone improved the healing of duo− of anion exchange therapy in 18 patients with radi− denal ulcer in initial phase but after 12 weeks there ologically confirmed ulcer. The patients were was no significant superiority over placebo [18]. receiving 3500 mg of substance 4–8 times per day The discussed substances cause many adverse for 4 months. In all patients the symptoms of pep− events: edema, hypertension, hypokaliemia because tic ulcer disease resolved during therapy [23]. if its aldosterone−like activity. 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− Irradiation Therapy ing the resin and in 16 of 20 on aluminium hydrox− of Peptic Ulcer ide therapy the healing of ulcer was confirmed [24].

In 1917 Bruegel described that irradiation of stomach can temporarily inhibit the gastric secre− Psychotherapy tion. In 1957 Levin et al. published the results of in Chronic Peptic Ulcer treatment of 723 patients with duodenal ulcer treated with irradiation and then followed up for In 1950 Selesnick described the influence of 5 to 18 years. 46% of patients had the relapse of psychotherapy on duodenal ulcer disease. 30 pa− disease. Levin concluded that this type of therapy tients with peptic ulcer were treated only with psy− can be additional to normal management of chotherapy: group and individual. In 29 out of patients with ulcer disease (resting in bed, contin− 30 patients the symptoms of duodenal ulcer dis− uous milk and cream consumption and antacids) solved [25]. [19]. The therapy that destroys the excreting cell In 1977 the results of several trials evaluating and causes atrophy of the gastric mucosa met a lot the role of in peptic ulcer were pub− of resistance and lost its sense [20]. 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− Freezing of the Stomach peptic symptoms and quicker healing of ulcer com− paring to placebo [26]. Guldahl et al. used 50–75 mg In 1962 Wangensteen et al. started with “freez− of trimipramine in 4 patients with duodenal ulcer ing of stomach” as the treatment of duodenal ulcer. and masked depression. The healing of ulcer was Despite initial enthusiasm American Gastro− confirmed in 3 patients and the signs of depression enterology Association during the meeting in San improved in all patients [27]. In other multicenter Francisco stated that the broad usage of the double−blind trial the high effectiveness of 4 week method will be only possible after evaluating its treatment with trimipramine was confirmed [28]. safety and efficacy in controlled trials. In 1963 multicenter randomized trial was conducted to describe the effectiveness of stomach freezing in Antacids patients with duodenal ulcer. The balloon was introduced into the stomach and then perfused by Antacids were “always” used in the treatment Achievements in Peptic Ulcer Disease Conventional Treatment 741 of peptic ulcer disease. By neutralizing the acid Mucosal Protecting Agents they protect the gastric mucosa from its aggressive activity [29]. Patients prefer the antacid treatment Mucosal protecting agents accelerate the ulcer because it brings almost instant pain relief [30]. healing and prevent the relapse of peptic ulcer Different antacids were used: natrium bicarbonate without inhibition of gastric secretion [37]. is fast and effective due to its good solubility in Sucralfate and colloidal bismuth had been water, but the effect disappears after several min− thoroughly studied starting from early seventies of utes followed by increased gastric secretion and XX century. Sucralfate generates thick suspension need for the next dose of the antacid. Calcium car− in stomach and duodenum, covering the mucous, bonate is not soluble in water and shows slower particularly the ulcer lesions. Sucralfate stimulates but more prolonged activity, but causing constipa− the mucous for prostaglandin releasing and binds tion. Magnesium oxide acts much longer but caus− with epidermal growth factor, which stimulates es diarrhoea. cell proliferation and healing of ulcer. Trials Natrium hydroxide and calcium carbonate are described that sucralfate caused duodenal ulcer not the treatment of choice anymore but they are healing in 79% of patients after 4 weeks and gas− often the element of different compounds [31]. The tric ulcer healing in 75% of patients after 8 weeks results of first randomized trial with antacids was [38]. Besides sucralfate is as effective as cimeti− published by Cayer et al. in 1957. 144 patients were dine or in treatment of peptic ulcer. treated with aluminium hydroxide or placebo. Long Smoking has no influence on ulcer healing during term (8 months) effect was seen in 74% of patients treatment with sucralfate [39–41]. taking the medication and 24% taking placebo [31]. Colloidal bismuth subcitrate acts similarly to Until 1990 14 randomized trials based on sucralfate and in the seventies was basal treatment endoscopic findings and evaluating the antacid for peptic ulcer. It significantly accelerates the therapy in duodenal ulcer disease were per− healing of the ulcer [42]. Clinical trials also formed. In 6 trials the antacids were compared to showed that colloidal bismuth subcitrate is as placebo in 8 to H2−receptor antagonists (cimeti− effective as in gastric and duodenal dine, ranitidine). Peterson et al. studied the effec− ulcer healing process. The peptic ulcer relapse rate tiveness of high doses of antacids (1000 mmol/ was lower after colloidal bismuth subcitrate then /day) in duodenal ulcer healing. Patients were cimetidine [43–45]. Later it was discovered that receiving magnesium−aluminium hydroxide every bismuth has also the activity against Helicobacter 1 and 3 hours after the meal and before sleep. pylori. 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 Prostaglandins that high doses of antacids accelerate the healing of duodenal ulcer [32]. Misoprostol is the first synthetic analogue of

High doses of antacids were causing diarrhoea prostaglandin E1. It decreases the secretion of acid and the treatment was not accepted by patients. and gastric juice, increases the regeneration and Therefore trials with lower doses (100–200 mmol/ healing of mucosa, there is also evidence that it /day) were performed and they proved the similar diminishes the lesions caused by such aggressive effectiveness of lower doses of antacids in healing factors as alcohol and nicotine [46]. Introducing of of peptic ulcer [33]. H2−receptor antagonists and proton pump inhi− Furthermore the antacids proved to be more bitors decreased the usage of misoprostol though effective than H2−receptor antagonists in preven− recently the cytoprotective effect in patients taking tion of peptic ulcer. This indicated that the mecha− non−steroidal anti−inflammatory drugs (NSAID’s) nism of antacids activity is not only connected to has been described. In multicenter randomized the neutralizing properties. The antacids also pro− trial the effectiveness of misoprostol in prevention tect the gastric mucosa from aggressive acid by of gastric ulceration in patients taking NSAID’s inducing prostaglandin production [34]. Antacid was proved [47]. Cytoprotective mechanism of containing aluminium hydroxide bind the bile prostaglandin is not well discovered in humans salts, decrease pepsin production and increase the [48, 49]. The side effects of misoprostol are: secretion of mucoproteins [35−36]. nausea, vomiting, diarrhoea and metrorrhagia Nowadays the antacids are used for fast symp− Misoprostol should not be used during pregnancy. toms relief and during the diagnosing of peptic The effectiveness of misoprostol in duodenal ulcer disease or before the proper treatment (for ulcer disease was stated in many clinical trials. example Helicobacter pylori eradication). Brand et al. [50] showed that 200 µg of misopros− tol taken 4 times a day for 4 months caused ulcer 742 L. PARADOWSKI, W. BŁOŃSKI, R. KEMPIŃSKI healing in 77% of patients (dose 50 µg in analogue 4 weeks, the side effects were slightly pronounced scheme of treatment was not effective comparing (impaired seeing, dryness in mouth) and passed to placebo). Lam et al. [51] administered 200 µg of after decreasing the dose to 100 mg for 2–3 days misoprostol 4 times a day for 4 months and [63]. Similarly in gastric ulcer administration of achieved the healing rate of 61%, and with dose 150 mg pirenzepine led to lesion healing in 90% of 300 µg – 71%. The trials comparing the effective− patients after 6 weeks [64], the dose of 75 mg/day ness of misoprostol and cimetidine did not show caused gastric ulcer healing in 60% of patients significant difference between these medications after 4 weeks [65].

[52]. The pain relief is though much stronger after Until the introduction of H2−receptor antago− cimatidine comparing to misioprostol. nists pirenzepine had been an effective medication The healing rates in stomach ulcer after in peptic ulcer disease. Initial trial with cimetidine 8 weeks were lower than in duodenal ulcer and proved its better efficacy in duodenal ulcer disease with 100 µg of misoprostol similar to placebo [53]. treatment (healing rate after 4 weeks 82.3% for 200 µg of misoprostol taken 4 times a day was as cimetidine and 71.4% for pirenzepine) [66]. effective as 300 mg of cimetidine 4 times a day in gastric ulcer healing [54]. H2−Receptor Antagonists

Anticholinergic Drugs H2−receptor antagonists were a complete breakthrough in peptic ulcer disease treatment. Anticholinergic drugs inhibit the vagal stimu− The search for the agent that would selectively lated gastric secretion and slow down the gastric block receptors H2 started in 1964 [67] motility. Usage of this drugs is nowadays limited and finally in 1972 the first H2−receptor antagonist because of many systemic side effects. First burimamide was described [68–70]. The following reports on anticholinergic drugs appeared in early analogue was metiamid and in 1976 cimetidine fifties of XX century. Avey et al. [55] was admin− had its premiere in Great Britain [71, 72]. istering subcutaneously 1.2 mg of atropine in 12 pa− Cimetidine was the first widely used H2−receptor tients with radiological signs of peptic ulcer and in antagonist, a new era in the treatment of peptic 10 healthy volunteers. Atropine in interdigestive ulcer. As the precursor it had side effects (inhibi− phase blocked the acid secretion in control group tion of microsomal enzymes in the liver followed and decreased but not blocked the secretion in by impaired metabolism of some drugs, gyneco− patients with peptic ulcer. Authors claimed that masty in men) and soon new successors were gastric secretion in patients with peptic ulcer is brought into the market: ranitidine, , mostly regulated via humoral pathways. Then the and others. search for successor of atropine with less systemic H2−receptor antagonists are very effective in side effects began. The best studied drugs were the treatment of duodenal ulcer. Cimetidine started

Banthine (methantheline) [56, 57], pro−Banthine the whole “dynasty” of H2−receptor antagonists. (propanthelina bromide) [58, 59] and rarely: From the time it was discovered the number of antrenyl, bentyl, lergine, merbentyl [60]. These patients operated because of peptic ulcer disease drugs did not meet the expectations because of the has dropped dramatically. side effects (impaired seeing, dryness in mouth), H2−receptor antagonists had been widely used the gastric juice secretion was less pronounced the until the introduction of proton pump inhibitors in classical drugs. and description of Helicobacter pylori influence Pirenzepine is the best described, selective on gastric and duodenal mucous. Due to financial

M1−muscarine receptor antagonist. It inhibits the reasons they are still used in the clinical practice. acid and gastric juice secretion more than mucous production and has weak systemic activity. Pirenzepine was found to be effective in many Helicobacter pylori clinical trials. In duodenal ulcer disease piren− Eradication zepine in daily dose of 75 mg for one week and then 50 mg for three weeks caused ulcer healing in In 1983 Warren and Marshall [73] suggested 52% of patients, significantly more often then in the role of Helicobacter pylori in pathogenesis of placebo group [61]. In other study pirenzepine was mucosal lesions in stomach and duodenum. They used in dose of 100 mg daily. After 4 weeks the described bacilli in stomach mucous, causing healing rates of duodenal ulcers were 70% and chronic inflammation. After this discovery the 32% in placebo group [62]. Increasing the dose to revolution in Helicobacter pylori dependent upper 150 mg/day improved the healing rate to 90% after digestive tract diseases has started. The organism Achievements in Peptic Ulcer Disease Conventional Treatment 743 has been blamed for many diseases outside the – proton pump inhibitor (PPI) (standard dose digestive tract, now we know that it is responsible twice daily) + amoxycillin 1000 mg twice daily + for acute and chronic gastritis, duodenal and stom− metronidazole 500 mg twice daily, ach ulcer and for gastric cancer [74]. The preva− – proton pump inhibitor (PPI) (standard dose lence of Helicobacter pylori infection in develop− twice daily) + clarithromycin 500 mg twice daily ing countries is estimated to 80–100% in devel− + metronidazole 500 mg twice daily. oped ones 20–40%. Current consensus concerning management of Helicobacter pylori infection was achieved by Working Group of Polish Association Proton Pump Inhibitors of Gastroenterology in 2004 [75]. Comparing to consensus settled in 2001 the indication for the The discovery of the final element of gastric therapy were widened to eradication in patients acid secretion – H+/K+−ATP−ase (proton pump) in taking non−steroidal anti−inflammatory drugs and 1973 fastened the research on the drugs complete− when the patient asks for therapy. Current indica− ly blocking the acid secretion [76]. H2−receptor tions for Helicobacter pylori treatment are shown antagonists did not provide controlled acid sup− in Table 1. pression particularly in specific situation where it The satisfying eradication rate is 85%. This was essentially needed (Zollinger−Ellison syn− could only be achieved by combined therapy (anti− drome). The decreased effectiveness during long secretory drug + at least two antibiotics). 7−day term therapy with H2−receptor antagonists is also therapy is advised, longer therapy increases the observed causing the relapses of disease. In the eradication rate only in few percent but side effects end of seventies of XX century a lot of attention appear more frequently. The schemes with H2− had been paid to the new group of drugs – ben− receptor antagonists are not recommended because zoimidazoles which blocked the terminal element they seem to be less effective. Due to high of gastric acid secretion – proton pump. The mech− Helicobacter pylori resistance to metronidazole anisms support inhibition of all kind of stimula− (49−69%) and increasing resistance to clar− tion: histamine, cAMP, carbachol and others. In ithromycin these two agents are not recommended 1981 Fellenius et al. [77] described in “Nature” the together in the first attempt of eradication. influence of benzoimidazole analogs on ATP−ase Currently recommended schemes are: inhibition in stomach. Lind et al. [78] proved that – proton pump inhibitor (PPI) (standard dose a single dose of 20 mg of omeprazole highly inhi− twice daily) + amoxycillin 1000 mg twice daily + bits acid secretion and the effect last for 24 hours; clarithromycin 500 mg twice daily, single dose of 80 mg of omeprazole blocked the secretion for 3 days. Howden et al. [79] showed Table 1. Current indications for Helicobacter pylori treat− that after 7−day therapy with either 30 or 60 mg of ment – year 2004 omeprazole almost 100% inhibition of basic acid Tabela 1. Wspólczesne wskazania do leczenia secretion and the secretion stimulated by penta− Helicobacter pylori – 2004 rok gastrin was observed. In 1983 Gustavsson et al. [80] described 1. Duodenal ulcer omeprazole effectiveness in 32 duodenal ulcer 2. Gastric ulcer patients. Patients were given 20 or 60 mg of 3. History of gastric and duodenal ulcer disease omeprazole daily. After 2 weeks the healing rates 4. Previous surgery in peptic ulcer disease were: 100% in 60 mg of omeprazole group and 5. Gastritis (pronounced or aphtous lesions) 63% in patients treated with 20 mg of omeprazole 6. Stomach resection because of early gastric cancer* daily. After following 4 weeks the healing rate 7. Gastric cancer in the family (up to second degree relatives) increased to 93%. In other study the healing of 8. Precancerous lesions (multifocal atrophic gastritis, duodenal ulcer was confirmed in 41 out of 43 meteplasia, dysplasia)* patients after 4 weeks of omeprazole therapy [81]. 9. Adenomas and hyperplastic polyps in stomach * Prichard et al. [82] achieved healing of duodenal 10. MALT−lymphoma in stomach* ulcer after 4 weeks in 83% of patients treated with 11. Ménétrier disease* 10 mg of omeprazole daily and in 94% treated 12. Functional dyspepsia (no effect or relapse after with 30 mg of omeprazole daily. In conclusion, standard treatment) proton pump inhibitors are very effective in duo− 13. Chronic therapy with NSAID’s denal ulcer disease and cause ulcer healing in over 14. Patient’s wish 90% of patients. *indication for hospitalization in gastroenterology depart− Interesting results were shown in randomized ments (also after second failure in eradication treatment trial, conducted in 1999 in 928 patients with duo− and in questionable cases) denal ulcer. 12−month therapy with 10 and 20 mg 744 L. PARADOWSKI, W. BŁOŃSKI, R. KEMPIŃSKI of omeprazole was compared to ranitidine 150 mg Conclusions in maintaining remission of duodenal ulcer disease [83]. After 12−months no ulceration was found Introduction of cimetidine in 1976 was with− respectively in 71%, 87% and 63% of patients and out any doubt the breakthrough in antisecretory there was significant difference between omepra− therapy. The application of proton pump inhibitors zole and ranitidine taking patients. Smoking of in clinical practice gave the possibility for practi− cigarettes, long ulcer history and young age was cally complete inhibition of gastric secretion with risk factor for disease relapse. simple administration regiments. The drugs can be There are few new proton pump inhibitors used in long term therapies without loss of effica− apart from omeprazole: pantoprazole, lansopra− cy. In 1983 Warren and Marshall described the zole, rabeprazole or the first optic isomer role of Helicobacter pylori in pathogenesis of esomeprazole, which is said to have more mucosal lesions in stomach and duodenum. bioavailability (decreased effect of first pass in Introduction of effective Helicobacter pylori erad− liver) and stronger gastric acid inhibition than ication therapies made possible the elimination of omeprazole [84]. The drugs differ in pharmacoki− the factor responsible for ulcer formation. That netic or pharmacodynamic properties and interac− caused enormous decrease in the number of hospi− tion with other drugs what is adapted for promo− talization, complications and relapses of peptic tional targets as proton pump inhibitors are part of ulcer disease. Patients with peptic ulcer are now a great financial market. treated on outpatient basis by family doctors. The Recently the clinical significance of proton number of surgical procedures that include only pump inhibitor has increased even more because complications of disease also dropped dramatical− the drugs became the treatment of choice in gas− ly. In addition indirect costs (number of medical tro−oesophageal reflux disease. This was due to visits, duration of job absence) were reduced. side effects of prokinetic drugs – the indications Introduction of proton pump inhibitors and for this kind of therapy are nowadays limited. Helicobecter pylori eradication did not decrease Although the scientists are still searching for the prevalence of peptic ulcer disease but provided drugs acting in lower oesophageal region, the a huge arm against the disease and its complica− position of proton pump inhibitors seems to be tions. For the first time the possibility for constant safe and sound. healing of peptic ulcer has been achieved.

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Address for correspondence: Leszek Paradowski Department of Gastroenterology and Hepatology Wrocław Medical University Poniatowskiego 2 50−326 Wrocław e−mail: [email protected]