GI news May qxd by liaoqinmei


									   n Volume : 4, Issue : 2                                   A compilation of information on gastrointestinal disease and drugs for the medical community.                                                              n June 2006

     Putting immediate-release proton-pump inhibitors into
                                                                                                                                                      Aliment Pharmacol Ther 2005; 22 (Suppl. 3) 31-38
                                                                                                                                                                                                         a GERD patient to specifically address the
                                                                                                                                                                                                         question of nocturnal symptoms, and

            clinical practice -improving nocturnal acid
                                                                                                                                                                                                         develop a treatment programme to con-

       control and avoiding the possible complications of
                                                                                                                                                                                                         trol nocturnal reflux, particularly for
                                                                                                                                                                                                         patients who have complicated disease,

                      excessive acid exposure
                                                                                                                                                                                                         such as Barrett's. The currently available
                                                                                                                                                                                                         delayed-release PPIs [omeprazole
                                                                                                                                                                                                         (OME), lansoprazle, rabeprazole, panto-
                                                                                                                                                                                                         prazole and esomeprazole] effectively
                                                          P.O.KATZ     an increase in nocturnal oesophageal                          the potential of antisecretory therapy to                           inhibit acid secretion with slightly more
                                                                       acid exposure compared to those with                          delay progression to dysplasia in
     division of Gastroenterology, Albert Einstein Medical Center,
                                            Philadelphia, PA, USA
                                                                                                                                                                                                         than 85% of patients experiencing com-
SUMMARY                                                                non-erosive reflux disease. The odds ratio                    Barrett's. Unfortunately, the sample size                           plete relief of night-time heartburn at 4
Nocturnal gastro-oesophageal reflux is an under-appreciated
clinical challenge. This condition may cause symptoms such as
                                                                       (OR) of developing esophageal adeno-                          was too small to demonstrate any effect                             weeks. This persistent night-time heart-
nocturnal heartburn, or it may be asymptomatic. In addition,           carcinoma was increased in patients with                      on the development of adenocarcinoma.                               burn despite daily delayed-release PPI
                                                                       long-standing nocturnal symptoms in                           Normalization of night-time acid expo-
patients may experience sleep disturbances that can potentially
lead to complications such as erosive oesophagitis and Barrett`s                                                                                                                                         therapy may be explained, in part, by the
oesophagus, and may be a risk factor for development of
oesophageal adenocarcinoma. Delayed-release proton-pump                one excellent case-control study.                             sure in patients with Barrett's oesophagus                          pharmacology of delayed-release formu-
inhibitors (PPIs) have traditionally been effective in treating both                                                                 remains challenging. A comparison of                                lations of these agents.
                                                                       NOCTURNAL ACID AND BARRETT'S                                  various PPI regimens in patients with
daytime and night-time reflux symptoms, but are limited in con-
trol of nocturnal acidity by their pharmacodynamic characteris-
This narrative review addresses the prevalence, impact and phar-       OESOPHAGUS                                                    Barrett's oesophagus found that once                   PHARMACODYNAMIC PROFILE OF
macologic approaches used to control nocturnal acidity.                                                                              daily PPI therapy only normalized                      PROTON-PUMP INHIBITORS
                                                                       Assessment of nocturnal acid exposure in
Methods to optimize nocturnal acid control include careful atten-
tion to dosing schedule, using higher doses of PPIs, or adding an                                                                    oesophageal acid exposure about 30% of
histamine H2- receptor antagonist at bedtime to once or twice          patients with Barrett's may be especially                     the time and even higher does of an H2
daily delayed-release PPI, or using immediate-release omepra-
                                                                       important as these patients will often have                                                                          All PPIs are weak bases, acid labile, and
zole (Zegerid powder for oral suspension: Santarus Inc. San
                                                                                                                                     RA at bedtime do normalize all patients.               require protection from gastric acid to
Diego, CA, USA).
                                                                       continued nocturnal oesophageal reflux                        Two prospective studies have reinforced
This new formulation appears to provide sustained control of
                                                                       even when on twice daily proton pump-                                                                                prevent degradation before absorption.
                                                                                                                                     that twice daily dosing with PPIs
intragastric pH at steady state, and when dosed at bedtime and
may be effective in improving control of nocturnal pH and treat-
                                                                       inhibitor (PPI) and when asymptomatic.                                                                               PPIs are absorbed in the duodenum and
ing night-time GERD.
                                                                       This will illustrated by a study in which 30                  (rabeprazole 20 mg or esomeprazole                     transported to gastric parietal cells by
                                                                       patients with Barrett's were treated with                     40mg) will normalize oesophageal acid                  the bloodstream where they are converted
OF NOCTURNAL REFLUX                                                    once daily lansoprazole (15-30 mg/day)                        exposure in about 71-77% of patients.                  to their active form and block active pro-
                                                                       until they were asymptomatic and then                         Thus either higher doses of delayed-                   ton pumps. Delayed-release PPIs have a
                                                                       underwent distal oesophageal pH moni-                         release PPI or alternative approaches will             slow onset of action, usually taking 3-5
The prevalence and importance of noc-                                  toring. Although many were on high-dose
turnal heartburn and nocturnal gastro-                                                                                               be needed in order to normalize acid                   days to achieve a steady-state antisecre-
                                                                       therapy, 40% of subjects continued to                         exposure in these patients.                            tory effect. There is individual variability
oesophageal reflux have been underes-                                  have abnormal oesophageal acid expo-
timated as a clinical problem. Almost                                                                                                Thus, it is crucial for the clinician treating
                                                                       sure, potentially damaging the mucosa,
three quarters of patients with frequent                               despite being asymptomatic. This has
                                                                                                                                                  Comparison of the effects of immediate-release
daytime gastro-oesophageal reflux dis-                                 implications for long-term management,
                                                                                                                                                                                                          Aliment Pharmacol Ther. 2005 Jun 15;21(12):1467-74.

ease (GERD) symptoms also have night                                   as continued acid reflux may be a stimulus
time-symptoms. Close to 27 million                                     for cellular proliferation, a precursor to               omeprazole powder for oral suspension and pantoprazole delayed
Americans suffer from night time heart-                                dysplasia. In fact using the patients from
                                                                       the same study, tissue levels of proliferat-               release tablets on nocturnal acid breakthrough in patients with
                                                                                                                                                  symptomatic gastro-oesophageal reflux disease
burn that may be associated with multiple
sleep-related disorders, and which                                     ing cell nuclear antigen (PCNA; a marker
                                                                       for proliferation) were compared in those
results in nocturnal GERD symptoms hav-                                who had, or did not have, normalized
ing a more negative impact on quality of                               oesophageal acid exposure after 6
                                                                                                                             Castell D, Bagin R, Goldlust B, Major J, Hepburn B.
                                                                                                                             Esophageal Disorders Program, Medical University of South Carolina, Charleston, SC, USA.
life than day time GERD symptoms.                                      months. The patients who normalized
Most patients who have frequent noctur-                                oesophageal acid exposure had a signifi-               BACKGROUND: Many patients treated with a proton-pump inhibitor for gastro-
nal GERD symptoms feel that they do not                                cant drop in PCNA, while those who did                oesophageal reflux disease or erosive oesophagitis still have substantial night-time
sleep well and that their sleep distur-                                not normalized showed no change. This                 gastric acidity. A previous trial of a new immediate-release omeprazole oral suspen-
bances have a major effect on their abili-                             suggests that normalizing intra-                      sion suggested that nocturnal gastric acidity could be more effectively controlled
ty to work the following day. It is interest-                          oesophageal acid                                                                   with a bedtime dose of immediate-release omeprazole than with
ing that the patients also comment that                                exposure may be
                                                                       important in the pre-
                                                                                                                                            Inside        a delayed-release proton-pump inhibitor administered before
                                                                                                                                                          dinner or at bedtime.
their inability to sleep well negatively
affects their partner’s sleep.                                         vention of cellular n Traveler's diarrhea vaccine hope
                                                                       proliferation       and                                                            AIM: To compare the ability of immediate-release omeprazole
There is a lack of agreement between                                   dysplasia, and thus n Diabetes makes ulcers more deadly                            with pantoprazole to control nocturnal gastric acidity, when they
doctors and patients in their assessment                               the role of aggres- n Does gastro-esophageal reflux                                were dosed once daily and twice daily.
of the severity of night-time reflux symp-                             sive suppression in           provoke the myocardial ischemia in
toms, with doctors most often underesti-                               preventing dysplasia          patients with CAD ?                                  METHODS: Thirty-six patients with nocturnal gastro-oesophageal
mating symptom severity. Because it is                                 needs further study. n Advances in Proton Pump Inhibitor                           reflux disease symptoms received immediate-release omepra-
the doctors assessment of the severity of                                                            Therapy : An Immediate Release                       zole and pantoprazole in this open-label, randomized-crossover
                                                                                                     Formulation of Omeprazole
disease that dictates treatment, this may                              The potential for PPI                                                              trial. Median gastric pH, the percentage of time with gastric pH >
explain why many patients with nocturnal                                                                                       therapy prevents 4 and the percentage of patients with nocturnal acid break-
                                                                       therapy to delay or n Omeprazole maintenanceaftersurgery for
symptoms are not effectively treated. In a                             reduce the develop-
                                                                                                     recurrent ulcer bleeding
                                                                                                     duodenal ulcer
                                                                                                                                                          through, were evaluated with 24-h pH monitoring.
recent survey, 71% of 791 adults with                                  ment of dysplasia n Peptic ulcer incidence declining
night-time heartburn reported taking                                                                                                                      RESULTS: Repeated once daily (bedtime) dosing with immedi-
                                                                       was examined in a                                                                  ate-release omeprazole suspension produced significantly better
over-the-counter medication with only                                  retrospective study n Prevention of stress-related inhibitors
                                                                                                                                                          nocturnal gastric acid control than repeated once daily (predin-
                                                                                                     bleeding with proton-pump
29% indicating satisfactory symptom                                    in patients with                                                                   ner) or twice daily (prebreakfast and bedtime) dosing with panto-
relief. In addition, 41% stated they tried a                           Barrett's oesopha- n Asthma and gastroesophageal reflux:                           prazole delayed-release tablets (median pH: 4.7 vs. 2.0 and 1.7;
                                                                                                     acid suppressive therapy improves
prescription medication for their symp-                                gus. The annual               asthma outcome                                       percentage of time pH > 4: 55 vs. 27 and 34; nocturnal acid
toms but only 49% of these adults report-                              incidence of dyspla- n Persistent hiccups indicate                                 breakthrough: 53 vs. 78 and 75). Twice daily dosing (prebreakfast
ed a satisfactory effect. These observa-                               sia was 4.7%, which           esophageal cancer risk                               and bedtime) with immediate-release omeprazole 20 and 40 mg
tions underscore the importance of rec-                                was similar to other n A novel antioxidant and antiapoptotic role achieved the best night-time control of gastric acidity. Repeated
ognizing nocturnal symptoms when                                       studies. However,             of omeprazole to block gastric ulcer                 once daily bedtime dosing with immediate-release omeprazole
patients with GERD. Reflux during sleep                                during the 1170               through scavenging of hydroxyl radical               40 mg and twice daily dosing with pantoprazole 40 mg gave sim-
(supine reflux) tends to produce individ-                              patient-years of fol-                                                              ilar 24-h pH control. No safety issues were associated with either
ual reflux episodes of longer duration,                                                                                                                   drug in this trial.
                                                                       low-up, PPI therapy was associated with a
overall delayed esophageal acid clear-                                 significant reduction in the risk of devel-                      CONCLUSIONS: Dosed once daily at bedtime, immediate-release omeprazole
ance, and is associated with more severe                               oping dysplasia (p<0.0001) compared                              reduced nocturnal gastric acidity to a degree not observed with once daily dosing of
GERD, patients with erosive oesophagitis                               with untreated patient and those taking                          delayed-release proton-pump inhibitors..
(in particular the higher grades), peptic                              only an histamine-2 receptor antagonist
stricture and Barrett's oesophagus have                                (H2RA). This was the first study to show

                                                                                                                                                                                 GI news//Vol.4,Issue:2,June 2006                            page 01
  n Volume : 4, Issue : 2                              A compilation of information on gastrointestinal disease and drugs for the medical community.                                      n June 2006

in pH response based on multiple factors                        NOCTURNAL GASTRIC ACID BREAK-                   tions from erosive oesophagitis trails that    30 mg at 8 am daily for 7 days, underwent
such as absorption, cytochrome P450                             THROUGH                                         persistent nocturnal heartburn is seen in      intragastric pH monitoring after the dose
metabolism and genetic polymorphism,                                                                            about 15% of patients with erosive dis-        was given 15-30 min before breakfast or
which may make predicting individual                            Failure of intragastric pH control is fre-      ease treated with once daily delayed-          on an empty stomach with no food until
dose-response difficult. As PPIs require                        quently seen in the sleeping (overnight         release PPIs, Nocturnal oesophageal acid       lunch -time significantly better control of
proton-pump activation for maximal anti-                        monitoring) period (22.00-06.00 hours),         exposure is more likely to be seen during      day time intragastric pH (time intragastric
                                                                even when a patient is on twice daily PPI                                                      pH>4) was found when the PPI was taken
secretory effect, they are best adminis-                                                                        NAB in patients with decreased lower           before breakfast compared with adminis-
                                                                therapy. This drop in pH<4 for at least I
tered before meals, as maximal activation                       continuous hour is a pharmacological            oesophageal sphincter pressure and in          tration on an empty stomach , without a
of the parietal cell occurs in the presence                     phenomenon termed nocturnal gastric             those with ineffective oesophageal body        subsequent meal. Although optimal timing
of food. A comparison study, of several                         acid breakthrough (NAB).This is a class         motility. Symptom frequency during             has not been determined, PPIs should be
delayed-release PPIs, dosed once daily                          effect seen with all delayed - release PPIs.    these nocturnal gastric pH drops has not       given on an empty stomach and followed
in the morning, demonstrated equivalent                         NAB begins about 6-7 h after the evening        been systematically studied. Thus, NAB         by a meal. Many patients, including those
control of intragastric pH and the PPI                          dose of a PPI, so if the dinner meal is eaten   or overnight gastric acid recovery is          with extra-oesophageal symptoms and
were most effective in controlling gastric                      around 6-7 pm and the evening PPI dose          potentially important in some patients         Barretts esophagus are often treated with
pH during the daytime, with universal                           in taken appropriately an hour before the       with severe erosive oesophagitis and in        higher doses of PPI . In these cases , split-
return of some acid secretion during the                        meal. NAB should occur around 1am               patients with Barrett's oesophagus. Up to      ting the dose and giving a PPI , twice daily,
overnight period.                                               When PPIs are given once daily before           50% of patients with Barrett's oesophagi-      before breakfast and dinner, provides
                                                                breakfast, recovery of gastric pH<4                                                            superior intragastric pH control , particu-
                                                                                                                tis will have increased overnight              larly at night ,when compared with a
In a five arm, open-label crossover study                       occurs earlier in the evening, beginning
                                                                around 11pm. Hundreds of normal sub-            oesophageal acid exposure during NAB,          double dose given once daily . This was
of delayed-release PPIs, esomeprazole 40                                                                        despite being asymptomatic.                    first reported in a crossover study in
mg provided significantly better 24-h gas-                      jects and patients have been studied on
                                                                once or twice a day delayed-release OME,                                                       healthy volunteers treated with OME 40
tric pH control compared with OME 20mg                                                                          The NAB is not due to PPI resistance,          mg before breakfast (AM) . 40 mg before
lansoprazole 30 mg, rabeprazole 20 mg                           lansoprazole, rabeprazole, pantoprazole
                                                                and esomeprazole documenting a consis-          which is an extremely rare phenomenon.         dinner (PM), or 20 mg twice daily dose
and pantoprazole 40 mg in patients with                                                                                                                        was significantly better than the other
GERD, although the higher dose of OME                           tent frequency of gastric acid recovery         Patients may appear resistance to PPIs
                                                                regardless of PPI so this is indeed a class     because of the interindividual variability     doses in maintaining 24-h intragastric pH
40 mg was not included in this trial. This                                                                                                                     control. A subsequent crossover study
enhanced gastric pH control with                                effect . Although recent studies suggest        seen with PPIs; however, intragastric pH
                                                                that esomeprazole twice daily is signifi-       control can almost always be improved          assessing the same dosing strategies,
esomeprazole is a possible explanation for                                                                                                                     confirmed these observation and found
the small, but consistent, improvement in                       cantly better than lansoprazole twice daily     by increasing the dose or switching to
                                                                in terms of total hours with intragastric                                                      that while daytime pH control was similar
healing of erosive oesophagitis with                                                                            another PPI. One study found that six of       regardless regimen, nocturnal pH control
esomeprazole compared with other PPIs.                          pH>4 , the phenomenon of NAB is seen in
                                                                45% of healthy volunteers taking                seven patients who appeared resistant to       was significantly better with the twice daily
The higher healing rates with esomepra-                                                                         20mg b. d. of OME (pH<4 for >50% of            regimen.
zole were more clearly demonstrated in the                      esomeprazole twice daily.
                                                                Oesophageal reflux occurs during NAB in         24-h period) had improved intragastric         Interestingly, the OME 40mg dose given
more severe grades of erosive disease, a                                                                        pH control when the dosage was
clinical situation in which night-time reflux                   only 5% of normal subjects and about                                                           before dinner was more efficacious in
                                                                15% of patients with uncomplicated              increased to 40 mg b.d. Because true PPI       controlling nocturnal gastric pH than the
is likely to be more frequent.
                                                                GERD. This is consistent with observa-          resistance is extremely rare, dosing of        same dose given in the morning. The
                                                                                                                PPIs should be individualized in patients      observation was confirmed in a study
                                                                                                                with refractory symptoms. Understanding        comparing rabeprazole 20 mg morning
                                                 22 Dec 2005                                                    these pharmacological concepts, the            and evening dosing , which found that

    Traveler's diarrhea vaccine hope
                                                                                                                potential importance of NAB, and their         intragastric pH control was better with the
                                                                                                                effects on efficacy of delayed-release         evening dose .
                                                                                                                PPIs in acid control have important
  45th Annual Interscience Conference on Antimicrobial Agents                                                   implications for the treatment of night-       COMBINATION THERAPY: PPIs
  and Chemotherapy; Washington DC, USA: 16-19 December
  2005.                                                         Of those given the vaccine, 156 devel-          time reflux and offer room for improve-        AND H2RAs
                                                                oped sufficient immunoglobulin                  ment.
  Researchers revealed at the Interscience                      responses to be considered vacci-                                                              The H2 RAs given at bedtime in conjunc-
  Conference on Antimicrobial Agents and                                                                        APPROACH TO TREATMENT:                         tion with a delayed-release PPI can aug-
                                                                nated. The occurrence of traveler's             OPTIMIZING NOCTURNAL
  Chemotherapy in Washington DC, USA,                                                                                                                          ment overnight pH control. The addition
  that they have found an oral vaccine that                     diarrhea in these participants was then         OESOPHAGEAL ACID CONTROL                       of an H2RA (ranitidine 150 mg or
  may offer protection against a major                          compared with that in 195 controls
                                                                                                                                                               300mg)at bedtime to twice daily
  cause of traveler's diarrhea, the                             who received placebo.                           If nocturnal reflux is part of the clinical    delayed-release PPI therapy improved
  Escherichia coli bacterium.                                                                                   presentation a key lifestyle modification      overnight pH control particularly with the
                                                                Among the individuals who showed a              is to recommend that patients do not eat
                                                                response, the vaccine was about 77%                                                            first dose of H2RAs , and although effica-
  Lead scientist Louis Bourgeois, from                                                                          a large evening meal within 2-3 h of bed-
                                                                effective in the prevention of diarrhea.                                                       cy was maintained during the first week of
  the Center for immunization Research                                                                          time. It is intuitive that a full stomach
                                                                In the six individuals who did suffer                                                          therapy, pH control varied over time.
  at the Johns Hopkins Bloomberg                                                                                prior to sleep will predispose the patients
                                                                from traveler's diarrhea despite being                                                         Several studies highlight the important
  School of Public Health in Baltimore,                                                                         to reflux in the overnight period. A 30 -
                                                                vaccinated, symptoms were relatively                                                           issues regarding the long-term efficacy of
  Maryland, USA, told delegates: "The                                                                           min time window after eating, prior to
                                                                mild compared with those of volunteers                                                         adding a bedtime dose of H2RA to a
  further development of this promising                                                                         lying down to sleep, may be all that is
                                                                who were given placebo. Only two stu-                                                          delayed-release PPI regimen. The effect
  enterotoxigenic E. coli vaccine is war-                                                                       necessary; however until that result is
                                                                dents felt that their symptoms were bad                                                        on intragastric pH of OME 20 mg b.d. for
  ranted and should be pursued."                                                                                confirmed, patients should be encour-
                                                                enough to affect their daily lives.                                                            2 weeks, followed by the addition of an
                                                                                                                aged to maintain the 2-3 h window. One         H2RA(2 hours) provided significantly bet-
  The team administered their vaccine,                                                                          study suggested that patients should
  which contains formalin-killed E. coli                        In contrast, 20 participants who                                                               ter acid control on day 1 compared with
                                                                                                                attempt to sleep on the left side, since       the PPI regimen alone but tolerance
  whole cells plus the B-subunit of the                         received placebo developed diarrhea,            reflux frequency in the sleeping period
  cholera enterotoxin, to 700 students                                                                                                                         quickly developed as evidenced by the
                                                                15 of whom experienced moderate-to-             was decreased compared with lying on
  who were traveling to Guatemala and                                                                                                                          fact that benefit of the H2RA was no longer
                                                                severe symptoms, and 16 individuals             the right side, prone, or supine.
  Mexico. A further 700 volunteers visit-                                                                                                                      apparent at the 1 and 4 weeks assess-
                                                                changed their daily plans because of                                                           ments. A small proportion of subjects
  ing these regions were administered a                         their condition.                                The key to optimal nocturnal acid control
  placebo.                                                                                                                                                     (21%) did not develop tolerance, and
                                                                                                                is effective antisecretory therapy.
                                                                "We feel this is a very promising concept       Maintenance of intragastric pH>4 is the        some patients (26%) had a highly vari-
  The vaccine had to be taken in two                            for a vaccine for traveler's diarrhea,"         desire goal, as this will decrease the dam-    able response to the addition to the H2RA
  doses, 7 to 21 days apart.                                    Bourgeois said. "This approach is very          aging nature of the gastric refluxate.         at different time points in the study.
  Unsurprisingly, students who showed                           straightforward and seems to work," he          Delayed release PPI can be optimized in        The role of bedtime H2RA was assessed
  the strongest response to the vaccine                         added.                                          several ways Although food affects the         in a retrospective review of prolonged
  were subsequently better protected                                                                            bioavailability of each moleclue differently   ambulatory pH monitoring studies in
  against the bacterium than those show-                        However, Bourgeois emphasized that              , it is recommended that all PPIs be given     patients on twice daily delayed-release
  ing a weak response. It was assumed                           the vaccine is presently in the early           before a meal . This is based on the con-      PPI, plus a bedtime H2RA and group who
  that the vaccine had "taken" if an individ-                   stages of development and is not ready          cepts of proton-pump activation dis-           had received both treatment strategies.
  ual had immunoglobulin titers to E. coli                                                                      cussed above, and results of an                Among the patients who were taking H2
  of more than 1358 units on arrival in                         for use outside of clinical trials.
                                                                                                                intragastric pH study addressing this issue    RAs at bedtime, intragastric pH>4 was
  Guatemala or Mexico.                                                                                          , in a crossover study, normal subjects
                                                                                                                treated with OME 20 mg or lansoprazole         recorded for the entire recumbent period

 page 02          GI news//Vol.4,Issue:2,June 2006
  n Volume : 4, Issue : 2                  A compilation of information on gastrointestinal disease and drugs for the medical community.                                                                                    n June 2006

in only 27% of patients and for 90% or                32 patients received pantoprazole 40 mg,                   bedtime on an as-needed basis com-                               How might uncontrolled nocturnal acid
more of the time in 36% of patients. The              while 15 received IR-OME 20mg and 17                       pared with delayed-release PPIs IR-OME                           exposure contribute to the extra-
combination therapy of twice daily PPI                received IR-OMR 40 mg .On day 6,the                        offers an alternative method of delivering                       oesophageal manifestations of GERD?
and H2RA was significantly better at                  median percentage of time that gastric pH                  the antiscretory efficacy of a PPI and has
maintaining intragastrice pH>4than                    was>4 for the night-time interval (10.00                   demonstrated efficacy when dosed at                              It is thought that the true asthmatic with
twice daily PPI therapy alone. Among 11               PM to 6.00 AM) was 54.7% for IR-OME 40                     bedtime eliminating the need for a meal                          reflux and patients with night time cough,
                                                      mg once daily and 26.5% for pantorazole                                                                                     are likely to have some night -time acid
patients who received both regimens, the              40mg once daily(P<0.001). On day 7,                        to optimize control of nocturnal gastric                         exposure is resolved by twice daily PPI
median percentage time with intragastric              with twice daily dosing , the median per-                  acidity.                                                         therapy , the acid component is likely not
pH >4 overnight increased from 54.6%                  centage of time that gastric pH was >4                                                                                      nocturnal. There is a strong clinical
without H2RA to 96.5% with H2RA at bed-               was 92.0% for IR-OME 40mg b.d and                          DISCUSSION                                                       impression that night -time acid exposure
time. These two studies come to different             36.5% for pantoprazole 40 mg b.d                                                                                            has a lot do with these symptoms , but
conclusions; finally adding an H2RA at                (P<0.001). Nocturnal gastric acid control                  Is uncontrolled nocturnal acid exposure a                        more data are needed .
bedtime, increasing to twice demonstrate              as also significantly better with IR-OME 40                risk factor for Barretts oesophagus and
any symptom improvement with any of                   mg once daily (day 6) compared with pan-                   oesophageal adenocarcinoma ?                                     What would be the benefits of a PPI with
these regimens over a PPI alone, so it                toprazole 40mg twice daily (day 7; 54.7%                                                                                    fast and sustained control of intragastric
likely would be practical to add an H2RA              and 33.9%, respectively; p<0.001). The                     Nocturnal acid exposure may not be a risk                        pH in treating these disorders ?
at bedtime to once daily PPI therapy on               median night-time gastric pH values were                   factor; but it is seen in a large proportion
                                                      4.7 for IR-OME once and twice daily,                       of people with Barretts whether it is a risk                     In practice, there is confusion regarding
an-needed basis only for reasons of cost.             respectively (p<0.001 for each compari-
                                                                                                                 for the development of adenocarcinoma                            what NAB is. Data has not demonstrated a
                                                      son). The significantly superior nocturnal                                                                                  good correlation between gastric acid
IMMEDIATE-RELEASE OMEPRAZOLE                          gastric acid control with IR-OME suggests                  is unknown. However the OR of develop-
                                                                                                                 ing oesophageal adenocarcinoma was                               events and symptoms, both oesophageal
                                                      that this IR formulation of OME offers a                                                                                    and extra-oesophgeal. NAB is the norm:
Availability of immediate-release omepra-             potential in controlling night-time acidity.               increased in patients with of long-stand-
zole [(IR-OME) Zegerid; santarus Inc., San                                                                                                                                        seen in about 70% of healthy individuals
                                                                                                                 ing nocturnal symptoms in one case-                              and patients with GERD. IR-OME has
Diego, CA, USA] powder for oral suspen-               CONCLUSION                                                 controlled study. There are still many
sion, offers interesting possibilities for the                                                                                                                                    demonstrated superior control of noctur-
                                                                                                                 unanswered questions about acid expo-                            nal pH compared with a delayed -release
management of night-time heartburn. this                                                                         sure in terms of whether continuous may
formulation offers the potential to before            Nocturnal acid reflux is an under-appreci-                                                                                  PPI . The rapid onset of action may make
dinner, and still achieve overnight control           ated problem that negatively effects sleep                 be less harmful than intermittent acid                           IR-OME the PPI formulation of choice for
of gastric pH. By day 7,IR-OME maintained             and may increase the risk of GERD-relat-                   exposure the healing repair cycle and the                        on -demand treatment of GERD, which
intragastric pH>4 for 18.6h with the 40               ed complications. In patients with                         stimulus of that may be of greater con-                          may provide an important advantage for as
mg dose and 12.2h with the 20mg dose,                 Barrett's oesophagus, there exists the                     cern in terms of cancer risk than perhaps                        needed use in patients with nocturnal
with the median intragastric pH being 5.2             potential for acid-induced oesophageal                     continuous exposure or completely effec-                         reflux: however this has not yet been inves-
and 4.2 respectively, when dosed before               damage overnight, even in patients who                     tive treatment . Very little is known about                      tigated clinically. Patients with cough or
breakfast.                                                                                                       the biology of acid exposure and its                             laryngeal symptoms related to GERD who
                                                      are asymptomatic. Optimal control of                                                                                        have swallowing difficulties, might benefit
In a randomized, open-labels, crossover               nocturnal gastric pH is important. In opti-                effects on cell turnover and repair.
trial, IR-OME at bad time offered signifi-                                                                                                                                        from IR-OME.
                                                      mizing treatment for patients with noctur-
cantly better control of nocturnal gastric            nal GERD, clinicians should pay attention
pH compared with once or twice daily
                                                                                                                         Does gastro-esophageal reflux
delayed-release pantoprazole tablets, in              to timing of meals, prescribe a once daily
36 patients with symptomatic nocturnal                delayed-release PPI before dinner rather

                                                                                                                       provoke the myocardial ischemia in
GERD. IR-OME 40 mg and pantoprazole                   than before breakfast, increase the dose
40 mg were administered once daily: at                of a delayed-release PPI to twice daily, or
bedtime on day 1, and at bedtime and
predinner, respectively on days 2-6. On
                                                      administer IR-OME once daily at bedtime.
                                                      As an additional option , clinicians may                               patients with CAD ?
days 7 and 8, twice daily dosing (pre-                augment PPI therapy (either once or twice

                                    Diabetes makes
breakfast and at bedtime )was assessed:               daily) with administration for an H2 RA at

                                                                                                                                                                                                                    International Journal of Cardiology
                                                                                                                                                                                               Volume 104, Issue 1, 15 September 2005, Pages 67-72

                                                                                                                        Slawomir Dobrzyckia, Andrzej Baniukiewiczb, Janusz Koreckic, Hanna Bachórzewska-Gajewskaa, Przemyslaw Prokopczuka,
                                                                                                                                                                             Wlodzimierz J. Musialc, Karol A. Kaminskic and Andrzej Dabrowskib
                                                                                                                              Department of Invasive Cardiology, Medical University in Bialystok, Ul. Sklodowskiej 24a, 15-276 Bialystok, Poland
                                                                                                                                                                           Department of Gastroenterology, Medical University, Bialystok, Poland
                                                                                                                                                                                 Department of Cardiology, Medical University, Bialystok, Poland

                                                     more deadly
                                                                                                                                                               Received 20 April 2004; revised 10 September 2004; accepted 4 October 2004.

                                                                                                                  Gastro-esophageal reflux disease (GERD) may cause chest pain. The aim was to
                                  Reuters Health
                                  Friday, April 14, 2006                                                          determine the correlation between ischemia and gastro-esophageal reflux in
                                                                                                                  patients with CAD and to assess the influence of short-term “anti-reflux” therapy on
         EW YORK (Reuters Health) - Among patients with bleeding or perforated                                    the ischemia in patients with GERD and CAD.
         ulcers, those with diabetes appear to be at substantially increased risk of
         dying, according to a report in the journal Diabetes Care.                                               Methods
                                                                                                                  Fifty patients with angiographically proven CAD underwent simultaneous 24-h con-
Dr. Reimar W. Thomsen, from Aarhus University Hospital in Denmark, and colleagues                                 tinuous ECG and esophageal pH monitoring. We assessed the number of ST-seg-
hypothesized that diabetic patients with complicated ulcer disease may face a higher                              ment depression episodes (ST dep.) and total duration of ischemic episodes,
short-term death risk because of diabetic blood vessel problems, blurring of symp-                                expressed as total ischemic burden (TIB). In pH-metry, we assessed: time percent-
toms, and an increased risk of overwhelming bacterial infection.                                                  age of pH lower than 4, total time of pH lower than 4 and the number of patholog-
                                                                                                                  ical refluxes (PR). Patients fulfilling the GERD criteria received a 7-day therapy with
To investigate, the researchers assessed the outcomes of 7323 patients hospitalized                               omeprazole 20 mg bid. On the 7th day of therapy, simultaneous Holter and
for bleeding ulcers and 2061 patients with perforated ulcers. Roughly, 10 percent of                              esophageal pH monitoring was repeated.
the former group and 7 percent of the latter had diabetes.                                                        Results
                                                                                                                  Total number of 224 PRs in 42 patients (84%) was recorded during esophageal pH-
Among patients with bleeding ulcers, the 30-day death rate was 17 percent in the dia-                             metry. GERD criteria were fulfilled in 23 patients (46%). Out of 218 episodes of ST
betic group versus just 10 percent in the nondiabetic group, the report indicates. This                           dep., 45 (20.6%) correlated with PR. GERD patients had larger TIB and higher num-
translates into a 40 percent increased risk of death for the diabetic group.                                      ber of ST dep. (p<0.015 and p<0.035, respectively). The anti-reflux therapy
                                                                                                                  reduced all analyzed parameters of esophageal pH monitoring (p<0.0022) as well
The mortality difference in the perforated ulcer group was even more pronounced.                                  as the number of ST dep. (p<0.012) and TIB (p<0.05).
Diabetic patients had a 30-day death rate of 43 percent compared with 24 percent for
nondiabetic patients, representing an increased risk of 51 percent.                                               Conclusions
                                                                                                                  Gastro-esophageal reflux disease is common in patients with CAD and may provoke
"Our findings suggest that efforts to improve outcomes from these medical emergen-                                myocardial ischemia. Short-term proton pump inhibitors therapy that restores nor-
cies in diabetic persons should be directed to reducing preventable diabetes compli-                              mal esophageal pH significantly reduces myocardial ischemia, possibly due to
cations," the authors conclude.                                                                                   elimination of acid-derived esophago-cardiac reflex compromising coronary perfu-
                                                                                                                  sion the phenomenon known as “linked angina”.
                                                                            SOURCE: Diabetes Care, April 2006.

                                                                                                                                                          GI news//Vol.4,Issue:2, June 2006                                           page 03
  n Volume : 4, Issue : 2                                  A compilation of information on gastrointestinal disease and drugs for the medical community.                                                              n June 2006

Advances in Proton Pump                                                                                                                                                             al cost of therapy. Lapses in controlling

Inhibitor Therapy : An Immediate-
                                                                                                                                                                                    gastric pH during PPI therapy may impair
                                                                                                                                                                                    the ability of PPIs to adequately protect
                                                                                                                                                                                    against stress related intestinal mucosal
Release Formulation of Omeprazole                                                                                                                                                   disease, a significant clinical problem
                                                                                                                                                                                    that occurs in 70% to 90% of critically ill
                                                                                                                                                                                    patients and portends increased morbidi-
         Ref: Drug Forecast, Vol. 30 No. 12 • December 2005 • P&T
                                                                    ty required the active ingredient in all                         stricture for-                                 ty as well as extended hospital stays.
                                        Ralph E. Small, PharmD
                                                                    delayed-release oral PPI formulations to                         mation, and                                    Among patients who are not given pro-
                                                                    have an enteric coating. The coating pro-                        esophageal                                     phylactic pharmacological therapy, overt
PROTON PUMP INHIBITORS:                                             tects the active ingredient from degrada-                        adenocarci-
AN OVERVIEW                                                                                                                                                                         upper gastrointestinal (GI) bleeding has
                                                                    tion by gastric acid, but it also delays                         n o m a .                                      been documented in 17% of critically ill
                                                                    absorption, so that the peak plasma con-                         Individuals with nocturnal heartburn also      patients. More than a decade ago, inves-
Acid-related disorders encompass a wide                             centration (Cmax) is not typically attained                      report less satisfaction with PPIs and a
variety of diagnoses, including the                                                                                                                                                 tigators found that various degrees of acid
                                                                    for up to five hours after oral administra-                      diminished quality of life in terms of both    suppression produced different physio-
extremely prevalent gastroesophageal                                tion of these formulations. In addition,                         mental and physical components, com-
reflux disease (GERD), which affects an                                                                                                                                             logical effects in the gastric milieu. At a
                                                                    patients must not chew or crush the                              pared with GERD patients, who do not           pH of 4.5 or above, pepsin begins to be
estimated 25 million Americans,1 duo-                               tablets or the entericcoated granules. For                       experience        nocturnal      heartburn.
denal and gastric ulceration, stress relat-                                                                                                                                         inactivated; at a pH of 5 or above, it
                                                                    patients who cannot swallow intact cap-                          Strategies for managing nocturnal gastric      becomes completely inactivated; and at a
ed mucosal disease, and acute upper                                 sules or tablets or who have a nasogastric                       acidity include increasing PPI adminis-
gastrointestinal bleeding, a common                                                                                                                                                 pH of 7 or above, there is a potential for a
                                                                    tube in place, various liquid formulations                       tration from once to twice daily, increas-     decreased incidence of peptic ulcer
medical emergency resulting in approxi-                             have been compounded extemporane-                                ing the dose, switching to another PPI, or
mately 300,000 hospitalizations annually.                                                                                                                                           rebleeding in patients who have already
                                                                    ously from sodium bicarbonate solution,                          adding an H2RA at bedtime. Although this       achieved hemostasis. Some investigators
During the last three decades, the man-                             with omeprazole or lansoprazole gran-                            last strategy may provide short-term effi-
agement of these disorders has been rev-                                                                                                                                            suggest that a gastric pH of 6.5 or higher
                                                                    ules, or crushed pantoprazole tablets.                           cacy, its clinical utility may be limited by   is optimal for preventing stress ulcera-
olutionized by the introduction of hista-                           These formulations have a limited shelf                          the potential for the development of toler-
mine- 2 receptor antagonists (H2RAs)                                                                                                                                                tion; at this value, pepsin is inactivated
                                                                    life and may adhere to the syringe and the                       ance to H2RAs as well as by the addition-      and blood coagulation parameters are
and proton pump inhibitors (PPIs). Five                             tubing used for administration, with the
available delayed-release PPIs include                              result that the tubing has the potential to
omeprazole         (Prilosec®,        Astra-                                                                                           24 Apr 2006
                                                                    become clogged. Limitations to enteric-

                                                                                                                                       Peptic ulcer incidence declining
Zeneca),lansoprazole (Prevacid®, TAP),                              coated PPI formulations also include the

pantoprazole (Protonix®, Wyeth),                                    potential for nocturnal acid breakthrough
esomeprazole magnesium (Nexium®,                                    (NAB), defined as an intragastric pH
Astra- Zeneca), and rabeprazole                                     below 4 for at least one hour during the
(Aciphex®, Eisai/Janssen). These drugs
                                                                                                                                                                                                   Am J Gastroenterol 2006; Early online edition

                                                                    night with PPI therapy. NAB occurs in up
are highly effective, irreversible inhibitors                       to 70% of patients with GERD. Despite                                      esults of a Danish population-based epidemiological study have revealed
of H+/K+ ATPase, the final step in gas-                             adequate therapeutic dosing (including                                     that the incidence of uncomplicated as well as perforated peptic ulcers is
tric acid secretion. Although these agents                          twice-daily administration), patients tak-                                 decreasing, while the incidence of bleeding ulcers is stable.
form the therapeutic cornerstone of man-                            ing enteric coated, delayed-release PPIs
agement for a variety of acid-related dis-                          may experience nocturnal gastric acidity,                          The research findings also indicate that an increasing proportion of patients with
orders, there is still room for improve-                            whether or not the agent is taken before                           incident peptic ulcers are using non-steroidal anti-inflammatory drugs (NSAIDs),
ment in our armamentarium. For exam-                                breakfast, before dinner, or twice daily                           and that mortality and the risk of complicated ulcer is 2.5- to 37-times higher
ple, all PPI compounds are weak bases                               and may have nighttime symptoms of                                 among patients with incident peptic ulcer than among the general population.
that are acid labile and are rapidly                                heartburn. Patients with nocturnal GERD                            The study authors write in the American Journal of Gastroenterology that although
degraded, usually within minutes, in the                            may have a higher potential for severe                             the risk of developing a complicated ulcer is known to be increased among indi-
acidic environment of the stomach. Until                            reflux induced complications such as                               viduals with previously diagnosed peptic ulcer, the magnitude of this risk in daily
the recent introduction of immediate-                               esophagitis, Barrett’s esophagus,                                  clinical practice is unclear.
release omeprazole (IR-OME [Zegerid®,                               esophageal motility disorder, esophageal
Santarus]), this pharmacological proper-                                                                                               Moreover, "while NSAID use is expected to account for an increasing proportion of
 Omeprazole maintenance therapy prevents                                                                                               the peptic ulcers, ecological studies of the relation have shown divergent results,"

 recurrent ulcer bleeding
                                                                                                                                       they add.

 after surgery for duodenal ulcer                                                                                                      Annmarie Lassen, from Odense University Hospital, and colleagues therefore
                                                                                                                                       aimed to describe the incidence and prognosis of uncomplicated and complicat-
                                                                                                                                       ed peptic ulcers in patients from Denmark between 1993 and 2002.
      Konstantinos Demertzis, Dimitrios Polymeros, Theodoros Emmanuel, Konstantinos Triantafyllou,

                                                                                                                                       Over the study period, the incidence of uncomplicated duodenal ulcer decreased
                                                                Pericles Tassios, Spiros D Ladas

      Konstantinos Demertzis, Dimitrios Polymeros, Theodoros Emmanuel, Konstantinos Triantafyllou,
  Pericles Tassios, Spiros D Ladas, Hepatogastroenterology Unit, 2nd Department of Internal Medicine, “Attikon” University General     from 0.55 to 0.37 per 1000 person-years, while uncomplicated gastric ulcer inci-
       Hospital, 11528 Athens, Greece Correspondence to: Professor Spiros D Ladas, MD, PhD, Hepatogastroenterology Unit, 2nd           dence decreased from 0.56 to 0.40 per 1000 person-years, and the incidence of
                                                                                                                                       perforated ulcer fell from 0.14 to 0.08 per 1000 person-years.
                                                                                                            Department of Internal
                                                                  Medicine, “Attikon” University General Hospital, Athens, Greece.
                                                                                                                                       In contrast, the incidence of bleeding ulcer remained stable, at 0.55 and 0.57 per
        o evaluate the omeprazole maintenance therapy in patients with recurrent                                                       1000 person-years in 1993 and 2002, respectively.
        ulcer bleeding after surgery for duodenal ulcer. We studied 15 consecutive
        patients with recurrent ulcer bleeding after surgery for duodenal ulcer.                                                       The proportion of possible NSAID-related incident peptic ulcers increased signif-
        Omeprazole (20 mg/d) maintenance therapy was given after ulcer healing. In                                                     icantly from 39% (320 out of 827 patients) in 1993 to 53% (363 out of 686 indi-
 addition to clinical follow-up, ambulatory 24-h gastric pH assay was performed                                                        viduals) in 2002.
 before and during omeprazole therapy in those patients and controls with previous
 duodenal ulcer surgery but no ulcer recurrence.                                                                                       Finally, the scientists followed-up a cohort of 3233 and 4421 individuals with inci-
                                                                                                                                       dent complicated or incident uncomplicated peptic ulcer, respectively, for up to 10
 All the 15 ulcers were healed after being treated with omeprazole (40 mg/d) for 2                                                     years.
 mo. Eleven patients with two (1-9) episodes of recurrent ulcer bleeding completed
 the follow-up (43, 12-72 mo). None of them had a bleeding episode while on                                                            Results revealed that during the first month after diagnosis of complicated ulcer,
 omeprazole. One patient discontinued the therapy and had recurrent bleeding. The                                                      the standardized mortality rate was 37.1, falling to 5.1 for the remainder of the year
 median 24-h fraction time of gastric pH <4 in patients was 80, 46-95%, and was                                                        and 2.6 per year thereafter. The corresponding rates for uncomplicated ulcer were
 reduced to 32, 13-70% by omeprazole ( P=0.002).                                                                                       11.6, 4.0, and 2.5, respectively.

 Long-term maintenance therapy with omeprazole (20 mg/day) is effective in pre-                                                        "We found that incidence of peptic ulcers decreased by calendar year, that an
 venting recurrent ulcer bleeding.                                                                                                     increasing proportion was related to NSAID use, and that mortality as well as risk
                                                                                                                                       of recurrent complicated peptic ulcer was increased in peptic ulcer patients," the
                                                                                                                                       researchers conclude.

 page 04           GI news//Vol.4,Issue:2, June 2006
  n Volume : 4, Issue : 2              A compilation of information on gastrointestinal disease and drugs for the medical community.                                                             n June 2006

maintained, although other authors con-        omeprazole capsules. During each treat-                          40-mg dose of IR-OME in healthy older                   head studies have compared IR-OME with
sider a pH of 3.5 to 4 or above to be suf-     ment period, healthy subjects received                           subjects was 76%. The extent of metabo-                 delayed-release esomeprazole, lansopra-
ficient. H2RAs can be effective in attaining   seven consecutive single daily doses of                          lite excretion in the urine (70%) was sim-              zole, or rabeprazole, the duration of time
these levels, but tachyphylaxis is a fre-      each dosage strength one hour before                             ilar to that observed in younger subjects.              that IR-OME 40 mg and 20 mg maintain
quent occurrence. More recent studies          they ate a standardized high-fat breakfast.                      The plasma half-life was also similar at                the gastric pH above 4 is slightly longer
support the clinical efficacy of PPI thera-    The Tmax observed with each dosage                               approximately one hour.                                 than the values reported in the product
py in the management of these critically       strength of the IR formulation occurred                                                                                  labeling for these delayed-release com-
ill patients; a recent Cochrane                much sooner (P < .001) (at approxi-                              Hepatic Impairment                                      pounds. In all cases, given the relatively
Collaboration found that the ability of PPI    mately 30 minutes with each dose) than                           In patients with chronic hepatic disease,               short plasma half-lives of these medica-
therapy to raise gastric pH is independent     that of the respective dose of the enteric-                      the bioavailability of IR-OME increases,                tions (about one hour), the extended
of the route of administration; however,       coated formulation (at 1.8 and 1.4 hours,                        reflecting a decrease in firstpass metabo-              durations of antisecretory effects proba-
this effect must be sustainable. Therefore,    respectively) with delayed-release                               lism. The plasma half-life increases to                 bly reflect the irreversible binding to the
although significant progress has been         omeprazole 40 mg and 20 mg.                                      approximately three hours, and plasma                   parietal cell H+/K+ ATPase enzyme by
made in treating acidrelated disorders,        The AUC of IR-OME 40 mg is about three-                          clearance decreases to about 70                         the PPIs.
patients would benefit from advances in        fold higher than that of the 20-mg dose,                         ml/minute.
PPI therapy. Specifically, an acid-sup-        and repeated exposure to the IR form                                                                                     CLINICAL TRIALS
pressing agent that shows more rapid           results in increased bioavailability. The                        Renal Impairment
absorption; that can be administered           observed increase in the AUC is almost                           In patients with chronic renal impairment               Efficacy
orally, even in patients who cannot swal-      doubled from a single dose, compared                             (the creatinine clearance is between 10                 Nocturnal Acid Control
low intact capsules or tablets; that pro-      with the steady state. Because taking IR-                        and 62 ml/minute per 1.73 m2), the                      One trial has confirmed the effectiveness
vides better nocturnal acid control; and       OME one hour after a meal decreases the                          bioavailability of omeprazole is slightly               of a bedtime dose of IR-OME in control-
that sustains gastric pH above a critical      AUC by approximately 26% at steady                               increased and urinary elimination is                    ling nocturnal gastric acidity. Goldlust
threshold would be a welcome addition to       state, optimal pharmacokinetic parame-                           decreased. The reduced elimination is                   and colleagues43 presented data from an
the PPI class.                                 ters are achieved when patients take this                        related to the decrement in creatinine                  open-label study. IR-OME 20 mg – was
                                               drug on an empty stomach. However, the                           clearance.                                              administered once a day one hour before
THE ADVENT OF IMMEDIATERE-                     AUC associated with a postprandial 40-                                                                                   breakfast for seven days to 17 healthy
LEASE OMEPRAZOLE                               mg dose of IR-OME is still substantial                           PHARMACODYNAMICS                                        subjects. On the eighth day, the partici-
                                               (3,862 mg • hour/ml) in the range asso-                                                                                  pants received IR-OME 20 mg twice daily,
Approximately one year ago, the U.S.           ciated with a 70% reduction in baseline                          A gastric pH of greater than 4 has long                 one hour before breakfast and at bedtime
Food and Drug Administration (FDA)             gastric acidity.                                                 been established as the target for effec-               (10 p.m., or 2200 hours). Twenty-four-
approved a unique IR formulation of            Approximately 95% of omeprazole is pro-                          tive mucosal healing. Studies in healthy                hour gastric pH monitoring was per-
omeprazole (Zegerid®) to treat a variety       tein-bound. In healthy subjects, its plas-                       subjects have found that once-daily dos-                formed on days seven and eight. The 24-
of acid-related disorders and to reduce        ma half-life is about one hour (range,                           ing of 40 mg and 20 mg of IR-OME main-                  hour median gastric pH profiles of
the risk of upper gastrointestinal bleeding    0.4–3.2 hours) and the plasma clearance                          tains the gastric pH above 4 for 77% and                patients taking IR-OME at the steady state
in critically ill patients. This compound      averages between 500 and 600 ml/                                 51%, respectively, of a 24-hour period. In              with 40 mg once daily in the morning, 20
was developed by combining a highly            minute. Most of the omeprazole (77%) is                          these two studies, IR-OME maintained a                  mg once daily in the morning, and 20 mg
effective PPI (omeprazole) with an                                                                                                                                      twice daily, in the morning and at bed-
antacid buffer (sodium bicarbonate),                                                                                                                                    time. The bedtime dose of IR-OME rapid-

                                                 Prevention of stress-related mucosal
which neutralizes gastric acid and pro-                                                                                                                                 ly raised the gastric pH and sustained this
tects the PPI from gastric acid degrada-                                                                                                                                effect for approximately eight hours. The
tion. Studies have found that the degrada-
tion half-life of non–enteric-coated             bleeding with proton-pump inhibitors                                                                                   median percentage of nighttime hours
                                                                                                                                                                        during which the gastric pH was above 4
omeprazole is approximately seven hours                                                                                                                                 was 87% with twice-daily dosing of 20

at a pH of 6, compared to less than three                                                                                                                               mg and 39% with once-daily morning
minutes at a pH of 1.2. In an in vitro                                                                          group, but there are some data to sup-                  dosing of 20 mg of IR-OME (P < .001).
model, the sodium bicarbonate buffer in         Digestive Disease Research Institute, Oklahoma City, OK, USA.   port their efficacy in increasing intra-                Twice-daily administration of 20 mg of
IR-OME rapidly increases the pH to    
                                                                                                                gastric pH, and in the case of                          IR-OME also significantly reduced the
greater than 6 within one minute and sus-                                                                       intravenous pantoprazole in preventing                  percentage of patients with NAB, com-
tains this pH environment for approxi-                  tress-related gastric mucosal                           gastrointestinal bleeding. In a large,                  pared with 20 mg administered once
mately 30 minutes. This pharmacological                 bleeding occurs in a substan-                           randomized controlled trial, immedi-                    daily in the morning, namely, 29% (five of
synergy protects omeprazole from gastric                tial number of critically ill                           ate-release omeprazole [(IR-OME)                        17 patients) versus 76% (13 of 17
acid degradation, allows it to be rapidly               patients, with clinically impor-                        Zegerid powder for oral suspension;                     patients) (P = .005).
absorbed, and eliminates the need for an        tant gastrointestinal bleeding prolong-                         Santarus Inc., San Diego, CA, USA]                      Castell and colleagues compared the
enteric coating.                                ing intensive care stay and increasing                          administered via gastric tube, was as                   nighttime gastric pH control of IR-OME
                                                mortality. This paper reviews the role of                       effective as intravenous cimetidine in                  suspension with that of delayed-release
PHARMACOKINETICS                                proton-pump inhibitors in the preven-                           the prevention of clinically significant                pantoprazole tablets. (Pantoprazole is
                                                tion of stress-related mucosal bleed-                           bleeding, and more effective in                         currently the only PPI that is
The pharmacokinetic profile of IROME            ing. Bleeding prophylaxis appears to                                                                                    FDAapproved to treat nighttime symp-
                                                                                                                increasing gastric pH. Effective antise-
differs significantly from that of a            be warranted in patients in intensive                                                                                   toms of GERD.) In the first period of the
delayed-release PPI plus an antacid.                                                                            cretory therapy does not appear to
                                                care units on mechanical ventilation or                                                                                 openlabel, two-period crossover trial,
Specifically, the Cmax of the IR formula-                                                                       increase the risk of nosocomial pneu-
                                                those who have coagulopathy.                                                                                            patients with a history of nocturnal GERD
tion is achieved in 10 to 90 minutes                                                                            monia. In conclusion, immediate-
                                                Intravenous histamine H2 receptor                                                                                       symptoms were randomly assigned to
(mean, 30 minutes) after single or multi-                                                                       release omeprazole provides a safe and                  receive either IR-OME or pantoprazole.
                                                antagonists, particularly cimetidine,                           effective alternative to intravenous
ple oral doses are taken on an empty            have demonstrated efficacy for the pre-                                                                                 IR-OME 40 mg (n = 32) was taken at
stomach. In contrast, several investiga-                                                                        cimetidine for the prevention of stress-                bedtime (10 p.m.) for six days. On day
                                                vention of bleeding in critically ill                           related mucosal bleeding in critically
tors, studying the pharmacokinetics of                                                                                                                                  seven, 15 patients were randomly select-
                                                patients. Standard delayed-release                              ill patients.
delayed-release omeprazole or rabepra-                                                                                                                                  ed to receive IR-OME 20 mg twice daily,
                                                proton-pump inhibitors have not been
zole, coadministered with antacids, found                                                                                                                               one hour before breakfast and at bedtime;
no significant change in the Cmax, the          extensively studied in this patient
                                                                                                                                                                        17 patients received IR-OME 40 mg twice
                                                                                                                                 PMID: 16303037 [PubMed - in process]

mean time to peak plasma concentration                                                                                                                                  daily, also one hour before breakfast and
(Tmax), or the area under the curve                                                                                                                                     at bedtime. Pantoprazole 40 mg was
(AUC). One study of delayed-release lan-       excreted as metabolites in the urine, and                        median gastric pH of 5.2 with the 40-mg                 administered at 10 p.m. on day one and
soprazole, given with an antacid, revealed     the remainder is eliminated in the feces.                        dose and 4.2 with the 20-mg dose. The                   before dinner on days two through six. On
a slight decrease in the AUC and a signif-                                                                      median 24-hour gastric pH exceeded 4                    day seven, this dose was given twice: one
icant decrease in the Cmax with no             Elderly Populations                                              for 18.6 hours with 40 mg and 12.2 hours                hour before breakfast and at bedtime).
change in the Tmax. In an open-label,          Older age produces a slight decrease in                          with 20 mg. The decrease from baseline                  After a 10- to 14-day washout period,
randomized, twoperiod crossover com-           the elimination rate of omeprazole and                           for integrated gastric acidity (or total                patients “crossed over” to the alternate
parator trial with a 10- to 14-day washout     increases its bioavailability. Compared                          accumulated gastric acid) with IR-OME                   treatment in the second period.
period between treatments, IR-OME in           with a bioavailability of 58% in younger                         40 mg was 84%; with 20 mg, the                          Statistically significant differences
strengths of 40 and 20 mg was compared         subjects, the bioavailability of a single                        decrease was 82%. Although no head-to-                  (P<.001) were observed between the
with delayedrelease 40- and 20-mg
                                                                                                                                                    GI news//Vol.4,Issue:2, June 2006                  page 05
  n Volume : 4, Issue : 2            A compilation of information on gastrointestinal disease and drugs for the medical community.                                                                n June 2006

once-daily and twice-daily IR-OME sus-       they had two successive gastric aspi-           the percentage of patients with any evi-                        Safety
pensions and the comparative pantopra-       rates of a pH of 4 or less, whereas the         dence of bleeding and the percentage of                         Adverse Effects
zole regimen in the median percentages       dose of cimetidine was doubled to 100           patients with a gastric pH of 4 or below                        In the U.S. trial of omeprazole, the most
of time that the gastric pH was main-        mg/hour for the duration of the study.          on two consecutive gastric aspirates.                           frequently reported ADEs in 465 patients
tained above 4 during the eight-hour         Patients were permitted enteral feedings        The safety and tolerability of each regi-                       that were considered possibly, probably,
nighttime interval (from 10 p.m. to          after the third day. Feedings were held         men were also assessed. The mean                                or definitely treatment-related were
6 a.m.).                                     for three hours before and for one hour         patient age was 55.7 years (range,                              headache (in 2.4% of patients), diarrhea
The median nighttime gastric pH values       after administration of the IR-OME sus-         16–91 years). These patients, 58.5% of                          (in 1.9%), rash (in 1.1%), nausea (in
were 4.7 with IR-OME 40 mg and 2 with        pension. The primary efficacy endpoint          whom were men and 64% of IR-OME                                 0.9%), constipation (in 0.9%), dizziness
pantoprazole 40 mg on day six (P <           of this non-inferiority study was the           and cimetidine were similar. For                                (in 0.6%), vomiting (in 0.4%), abdominal
.001). The percentage of patients who        occurrence of clinically significant upper      instance,     nosocomial       pneumonia                        pain (in 0.4%), and asthenia (in 0.2%).
experienced NAB was also significantly                                                       occurred at a rate of 11.2% with IR-OME                         Occasional cases of atrophic gastritis
                                             GI bleeding. This was defined as bright-
smaller during IR-OME therapy than with                                                      and at a rate of 9.4% with IV cimetidine                        have been noted in gastric corpus biop-
                                             red blood via a nasogastric or an oro-
pantoprazole on days six and seven (P <                                                      (P=.61). All currently available PPIs,                          sies of patients receiving long-term
.005 for each comparison). On day six,       gastric tube that had not cleared after 5                                                                       omeprazole therapy. A symptomatic
                                             to 10 minutes of lavage or as persistent        including IR-OME, are effective in reliev-
significantly fewer patients treated with                                                    ing GERD symptoms, healing gastroduo-                           response to omeprazole does not pre-
IR-OME 40 mg (53.1%) experienced NAB         Gastroccult®- positive coffee-ground                                                                            clude the presence of gastric malignancy.
                                             material for at least eight consecutive         denal ulcers, providing treatment of
than when they had used pantoprazole 40                                                      erosive esophagitis, and maintaining
mg (78.1%) (P = .005). Twice-daily IR-       hours on days one and two or for two to                                                                         Sodium Bicarbonate
                                             four hours on days 3 through 14 that had        healing of lesions. Unlike the other PPIs,
OME produced a significantly higher                                                          IR-OME may control nocturnal gastric                            Each 40-mg and 20-mg dose packet of
median percentage of time during which       not cleared with 100 ml or more of                                                                              IR-OME contains 460 mg of sodium in
                                             lavage. Because this was a non-inferior-        acidity when it is given at bedtime. IR-
the gastric pH was maintained above 4,                                                       OME is the only PPI that has been sub-                          the form of sodium bicarbonate (1,680
compared with twice-daily pantoprazole       ity study, the primary efficacy analysis                                                                        mg, 20 mEq). This fact should be taken
                                                                                             jected to clinical study and carries an
during the 24-hour interval (10 p.m. to      was conducted on the per-protocol pop-                                                                          into consideration for patients who are
                                                                                             FDA indication for reducing the risk of
10 p.m.). A median gastric pH level          ulation at the one-sided á = 0.025 level                                                                        following sodium-restricted diets. The
                                                                                             upper GI bleeding in critically ill
greater than 4 was maintained for 87.8%      of significance. Secondary endpoints                                                                            use of IR-OME is contraindicated in
of the 24-hour interval with twice-daily     included the percentage of patients with                                                                        patients with metabolic alkalosis and
IR-OME 40 mg, compared with 56.9%            any evidence of bleeding and the per-
(P<.001) observed during twice-daily
                                                                                                                 Asthma and gastroesophageal reflux:
                                             centage of patients with a gastric pH of 4
therapy with pantoprazole 40 mg.             or below on two consecutive gastric
At steady state, the median percentage
of time with the gastric pH above 4
                                                                                                acid suppressive therapy improves asthma outcome
during the 24-hour interval was similar      The safety and tolerability of each regi-
for paired patients taking once-daily IR-
                                                                                                                                                                                        Am J Med. 1996 Apr;100(4):395-405.
                                             men were also assessed. The mean
OME 40 mg and twice-daily pantopra-
                                                                                                                                                  Harding SM, Richter JE, Guzzo MR, Schan CA, Alexander RW, Bradley LA.
                                             patient age was 55.7 years (range,                  Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of Alabama, Birmingham, 35294, USA.
zole 40 mg.                                  16–91 years). These patients, 58.5% of
                                             whom were men and 64% of whom were               PURPOSE: To determine the appropriate omeprazole (Prilosec) dose required for
Reduction in Risk of Upper GI                white, were treated for a mean of 6.8            adequate acid suppression in asthmatics with gastroesophageal reflux, whether
Bleeding in Critically Ill Patients          days. Patient characteristics were similar       aggressive acid suppressive therapy of gastroesophageal reflux improves asthma
                                             between the treatment groups. The rates          outcome in asthmatics with gastroesophageal reflux, the time course of asthma
Conrad and colleagues established the                                                         improvement, and demographic, esophageal, or pulmonary predictors of a positive
efficacy of IR-OME in reducing the risk      of clinically significant bleeding were
                                             4.5% with IR-OME and 6.8% with cime-             asthma response to antireflux therapy.
of upper GI bleeding in critically ill
                                             tidine. These results satisfied the criteria
patients in a multicenter, randomized,                                                        PATIENTS AND METHODS: Thirty nonsmoking adult asthmatics with gastroe-
                                             for the non-inferiority of IR-OME in pre-
doubleblind, double-dummy, parallel-                                                          sophageal reflux (asthma defined by American Thoracic Society criteria and reflux
                                             venting upper GI bleeding in critically ill
group study of 359 patients. These                                                            defined by symptoms and abnormal 24-hour esophageal pH testing) were recruit-
                                             patients compared with IV cimetidine.
patients, who were undergoing mechani-                                                        ed from the outpatient clinics of a 900-bed university hospital. Patients underwent
                                             IR-OME was more effective than IV
cal ventilation in the intensive care unit                                                    baseline studies including a demographic questionnaire, esophageal manometry,
                                             cimetidine in maintaining a median gas-
(ICU) and had Acute Physiology and           tric pH above 4.0 in critically ill patients.    dual-probe 24-hour esophageal pH test, barium esophogram, and pulmonary
Chronic Health Evaluation II (APACHE II)     The effects of IR-OME on gastric pH              spirometry. During the 4-week pretherapy phase, patients recorded reflux and asth-
scores of 11 or higher and one addi-         were consistent regardless of patients’          ma symptom scores and peak expiratory flow rates (PEFs) upon awakening, 1 hour
tional risk factor for upper GI bleeding,    baseline pH values. Median gastric pH            after dinner, and at bedtime. Patients began 20 mg/d omeprazole, and the dose was
were enrolled at 47 sites in the U.S. The    values greater than 6 were observed in           titrated until acid suppression was documented by 24-hour pH test. Patients
patients were assigned to receive either     almost all patients following the first          remained on this acid suppressive dose for 3 months. Responders were identified
IR-OME suspension via nasogastric or                                                          by a priori definitions: asthma symptom reduction by >20% and/or PEF increase
                                             dose of IR-OME. A median gastric pH
orogastric tube at a dose of 40 mg twice                                                      by >20%. Asthma symptom scores, PEF's baseline and posttherapy pulmonary
                                             above 6 was sustained on all days for
daily on day one (six to eight hours                                                          spirometry were analyzed.
                                             patients receiving IR-OME but persisted
apart) and 40 mg once daily thereafter       on only 50% of the days for patients
(and continuous intravenous [IV]                                                              RESULTS: Twenty-two (73%) patients were asthma symptom and /or PEF respon-
                                             receiving cimetidine. After three days of        ders: 20 (67%) were asthma symptom responders, and 6 (20%) were PEF respon-
placebo) or IV cimetidine (Tagamet®,         cimetidine administration, the median
GlaxoSmithKline), given as a 300-mg                                                           ders. Responders reduced their asthma symptoms by 57% (P<0.001), improved
                                             gastric pH began to decline, suggesting          their morning and night PEFs by 8% and 9% (both P <0.005), and had improve-
bolus. This dose was followed by an          the development of tachyphylaxis. After          ment in forced expiratory volume at 1 second (P <0.02), mean forced expiratory
infusion of 50 mg/hour thereafter (and       day eight, at least 25% of the cimetidine        flow during the middle half (25% to 75%) of the forced vital capacity (P <0.04),
placebo oral suspension). Each regimen       patients had a median gastric pH below           and peak expiratory flow (P <0.01) with acid suppressive therapy. Mean acid sup-
was administered for up to 14 days.          4. During the entire trial, failure of pH        pressive dose of omeprazole was 27 mg/d (+/-2.2) with 27% (8) patients requir-
Gastric aspirates were sampled for upper     control (two consecutive gastric aspi-           ing more than 20 mg/d. The presence of regurgitation or excessive proximal
GI bleeding every two hours on the first     rates of pH of 4 or below at least one           esophageal reflux predicted asthma response with 100% sensitivity, 100% negative
and second days, then every six hours        hour apart on the same day) was                  predictive value, specificity of 44% and a positive predictive value of 79%.
for the remaining study days. Gastric        observed in 58% of the cimetidine
aspirates were also used to measure pH       patients but in only 18% of the IROME            CONCLUSIONS: Acid suppressive therapy with omeprazole improves asthma
every two hours on the first and second      patients (P < .001). The incidence and           symptoms and/or PEFs by >20% and improves pulmonary function in 73% of
days and immediately before and one          type of adverse drug events (ADEs)               asthmatics with gastroesophageal reflux after 3 months of acid suppressive thera-
hour after administration of the IR-OME      reported with 3 through 14 that had not          py. Many asthmatics (27%) required >20 mg/d of omeprazole to suppress acid.
suspension on days 3 to 14. The dose of      cleared with 100 ml or more of lavage.           The presence of regurgitation and/or excessive proximal esophageal reflux predicts
IR-OME or cimetidine was doubled for         Because this was a non-inferiority study,        a positive asthma outcome.
patients with two successive gastric         the primary efficacy analysis was con-
aspirates of a pH of 4 or less. A second     ducted on the per-protocol population at                                                                                         PMID: 8610725 [PubMed - indexed for MEDLINE]

daily dose of IR-OME 40 mg was admin-        the one-sided a = 0.025 level of signif-
istered to patients only on the day when     icance. Secondary endpoints included

page 06      GI news//Vol.4,Issue:2, June 2006
  n Volume : 4, Issue : 2                           A compilation of information on gastrointestinal disease and drugs for the medical community.                                                                    n June 2006

hypocalcemia. Sodium bicarbonate                               healthy men, the steadystate plasma                               turnal gastric acidity to an extent that has
should also be used with caution in                            concentrations of omeprazole were                                 not been observed with once-daily
patients with Bartter’s syndrome,                              increased: the Cmax by 30%, the                                   dosing of delayed-release PPIs. Dosage         1 May 2006
hypokalemia, respiratory alkalosis, and                        AUC0–24 by 89%, and the half-life by                              modification is generally not needed in
acid–base imbalances. The long-term                            34%).
                                                                                                                                                                                 Persistent hiccups
                                                                                                                                 elderly patients or in those with mild-to-
administration of sodium bicarbonate                                                                                             moderate renal or hepatic impairment.
                                                                                                                                                                                indicate esophageal
with calcium or milk can induce the milk-                      INDICATIONS                                                       The IR formulation is currently available
alkali syndrome.
                                                                                                                                                                                     cancer risk
                                                                                                                                 as a peach-mint flavored powder for oral
                                                               IR-OME is indicated for the short-term
DRUG INTERACTIONS                                                                                                                suspension in 40- and 20-mg packets.
                                                               treatment (four to eight weeks) of active
                                                                                                                                 Because of this product’s unique phar-
                                                               duodenal ulcer, heartburn, and other

Like the delayed-release, entericcoated,                       symptoms associated with GERD; the                                macokinetic profile, there are no thera-
oral PPI formulations, IR-OME may pro-                         short-term treatment of erosive                                   peutic equivalents, and it is not AB-rated     Royal College of Surgeons in Ireland Research Day 2006: Dublin,
long the elimination of drugs that are                         esophagitis,      as     diagnosed       by                       compared with delayed-release omepra-          Ireland; 19 April

metabolized by oxidation in the liver,                         endoscopy; the maintenance of healing                             zole (Prilosec®, Prilosec® OTC). The
such as diazepam (Valium®, Roche),                             of erosive esophagitis (studies do not                            oral suspension offers an alternative for              ersistent hiccups could be an
warfarin (Coumadin®, Bristol-Myers                             extend beyond 12 months); and the                                 patients (e.g., elderly people and chil-               early sign of esophageal cancer,
Squibb), and phenytoin (Dilantin®,                             short-term treatment of active benign                             dren) who require PPI therapy for acid-                especially when accompanied by
Pfizer).     Increased      International                      gastric ulcer. This is the only PPI to date                       related conditions but who have                        dramatic weight loss and prob-
Normalized Ratios (INRs) and prothrom-                         that is indicated for lowering the risk of                        difficulty swallowing tablets or capsules.     lems swallowing, Irish doctors warn. A
bin times have been reported in patients                       upper GI bleeding in critically ill patients                                                                     prospective study has shown that more
receiving concomitant warfarin and                             and for nasogastric and/or orogastric                             Absorption is optimized when patients          than a quarter of patients with
omeprazole therapy. These increases                            tube administration.                                              take this product on an empty stomach at       esophageal cancer suffered from per-
may lead to abnormal bleeding and pos-                                                                                           least one hour before a meal. For the          sistent hiccupping as one of their symp-
sibly death. Therefore, patients taking                        DOSAGE AND ADMINISTRATION                                         control of nighttime gastric acidity, how-     toms. Difficulty swallowing, weight loss,
warfarin and omeprazole concomitantly                                                                                            ever, the effect is greatest when it is        lethargy, and anorexia were also
should be monitored closely for INRs                           The recommended dose of IR-OME is 40                              taken at bedtime on an empty stomach.          common presenting symptoms among
and prothrombin times. In studies of                           mg or 20 mg, based upon the indica-                               Patients should be instructed to pour a        the 99 patients included in the study.
once-daily omeprazole 40 mg and clar-                          tion, to be taken once daily on an empty                          packet of the powder for oral suspension
ithromycin (e.g., Biaxin®, Abbott) 500                         stomach at least one hour before a meal.                          into a small cup containing one to two         The findings are particularly important
mg every eight hours administered to                           When taken at bedtime, it reduces noc-                            tablespoons (15–30 ml) of water, to stir       given the rising incidence of esophageal
                                                                                                                                 well, and to drink immediately. No other       cancer, which has a poor prognosis, with

       A novel antioxidant and
                                                                                                                                 liquids or foods should be mixed with          just 10% of those diagnosed with the
                                                                                                                                 the powder. The cup should be refilled         disease in Europe surviving for 5 years.

         antiapoptotic role of
                                                                                                                                 with an additional small amount of
                                                                                                                                 water, and this should also be consumed

     omeprazole to block gastric
                                                                                                                                                                                Lead researcher Tom Walsh, from the
                                                                                                                                 right away to ensure that a complete           James Connolly Memorial Hospital in

     ulcer through scavenging of
                                                                                                                                 dose is ingested. For patients with naso-      Dublin, said: "We undertook the study
                                                                                                                                 gastric or orogastric tubes, the powder        because an increasing number of

            hydroxyl radical
                                                                                                                                 should be constituted with approxi-            patients told us that hiccups were the
                                                                                                                                 mately 15 to 30 ml of water (0.5–1.0           first and one of the most dramatic symp-
                                                                                                                                 fluid ounce). Other liquids or foods           toms they had suffered before seeing

                                                                                                                                 should not be used. The suspension             their doctor."
                                               Biswas K, Bandyopadhyay U, Chattopadhyay I, Varadaraj A, Ali E, Banerjee RK.      should be stirred well and administered
           Department of Physiology, Indian Institute of Chemical Biology, 4, Raja S. C. Mullick Road, Kolkata 700 032, India.
                                                                                                                                 immediately, and a syringe of the appro-       Presenting the findings in Dublin at a
                                                                                                                                 priate size should be used to instill the      meeting of the Royal College of
        he mechanism of the antiulcer effect of omeprazole was studied placing                                                   suspension in the tube. The suspension         Surgeons in Ireland, the researchers say
        emphasis on its role to block oxidative damage and apoptosis during                                                      should be washed through the tube with         that of the 99 patients surveyed
        ulceration. Dose-response studies on gastroprotection in stress and                                                      an additional 20 ml of water. The FDA is
                                                                                                                                                                                prospectively, 27% complained of per-
        indomethacin-induced ulcer and inhibition of pylorus ligation-induced                                                    currently reviewing 40-mg and 20-mg
                                                                                                                                                                                sistent hiccupping, lasting 48 hours or
 acid secretion indicate that omeprazole significantly blocks gastric lesions at                                                 IR-OME capsules and IR-OME chewable
                                                                                                                                                                                longer. Six per cent said the persistent
 lower dose (2.5 mg/kg) without inhibiting acid secretion, suggesting an inde-                                                   tablets.
                                                                                                                                                                                hiccups were the initial reason why they
 pendent mechanism for its antiulcer effect. Time course studies on gastroprotec-                                                                                                                 ,
                                                                                                                                                                                consulted their GP and a further 9% said
 tion and acid reduction also indicate that omeprazole almost completely blocks                                                                                                 it was the predominant ongoing symp-
 lesions at 1 h when acid inhibition is partial. The severity of lesions correlates well                                                                                        tom.
                                                                                                                                 The unique “non-enteric” formulation of
 with the increased level of endogenous hydroxyl radical (*OH), which when scav-
 enged by dimethyl sulfoxide causes around 90% reduction of the lesions, indicat-                                                IR-OME provides more rapid absorption
                                                                                                                                 and decreased time to peak plasma con-         The research also showed that 82% of
 ing that *OH plays a major role in gastric damage. Omeprazole blocks                                                                                                           patients reported difficulty swallowing,
 stress-induced increased generation of *OH and associated lipid peroxidation                                                    centrations than do enteric-coated,
                                                                                                                                 delayed-release PPIs. These pharmaco-          68% experienced weight loss, 62%
 and protein oxidation, indicating that its antioxidant role plays a major part in pre-                                                                                         lethargy, and 56% anorexia.
 venting oxidative damage. Omeprazole also prevents stress-induced DNA frag-                                                     kinetic properties may confer advantages
 mentation, suggesting its antiapoptotic role to block cell death during ulceration.                                             for patients with acid-related disorders,
                                                                                                                                 as suggested by emerging data about            Among the patients, who were aged an
 The oxidative damage of DNA by *OH generated in vitro is also protected by                                                                                                     average of 66 years, 50% had tumors in
 omeprazole or its analogue, lansoprazole. Lansoprazole when incubated in a                                                      the product’s effectiveness in controlling
                                                                                                                                                                                the lower esophagus, 18% in the gastric
 *OH-generating system scavenges *OH to produce four oxidation products of                                                       nocturnal gastric pH in symptomatic
                                                                                                                                                                                cardia, 27% in the mid-esophagus, and
 which the major one in mass spectroscopy shows a molecular ion peak at m/z                                                      GERD patients and its ability to control
                                                                                                                                                                                5% in the upper esophagus.
 385, which is 16 mass units higher than that of lansoprazole (m/z 369). The                                                     gastric acidity in critically ill patients.
 product shows no additional aromatic proton signal for aromatic hydroxylation in                                                Oral IR-OME, when taken on an empty            Why esophageal cancer can trigger long
 (1)H NMR. The product absorbing at 278 nm shows no alkaline shift for phenols,                                                  stomach at bedtime, is effective in con-       bouts of hiccups remains unclear. Walsh
 thereby excluding the formation of hydroxylansoprazole. The product is assigned                                                 trolling nocturnal gastric acidity. It is an   and colleagues suggest that esophageal
 to lansoprazole sulfone formed by the addition of one oxygen atom at the sulfur                                                 alternative to the use of IV acidsuppres-      cancer could trigger the phrenic nerve
 center following attack by the *OH. Thus, omeprazole plays a significant role in                                                sant therapy for attaining and sustaining      that controls the motor function of the
 gastroprotection by acting as a potent antioxidant and antiapoptotic molecule.                                                  a gastric pH above 6 and for lowering          diaphragm, in turn causing hiccupping
                                                                                PMID: 12529378 [PubMed - indexed for MEDLINE]    the risk of upper GI bleeding in critically    during spasms of the diaphragm.
                                                                                                                                 ill patients.

                                                                                                                                                               GI news//Vol.4,Issue:2, June 2006                              page 07
n Volume : 4, Issue : 2                 A compilation of information on gastrointestinal disease and drugs for the medical community.                 n June 2006

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