DOCTOR OF MEDICAL SCIENCE
`
`Intraluminal pH of the human
`gastrointestinal tract
`
`Jan Fallingborg
`
`This review has been accepted as a thesis together with five previously pub-
`lished papers, by the University of Aarhus, December 14, 1998, and defended
`on April 23, 1999.
`Department of Medical Gastroenterology, Aalborg Sygehus.
`Correspondence: Jan Fallingborg, Duebrodrevej 23, DK-9000 Aalborg.
`Official opponents: Pel' Brobech AJol'tensen, MD, Peter iVI. Funcil Jensen,
`MD, and Steen Lindk(el' Jensen, professor, MD.
`
`1. INTRODUCTION
`The recent and increasing interest in the pH of the contents of the
`gastrointestinal tract is well founded. One reason is the development
`of several oral preparations which release the drug at a site andlor at
`a rate determined by the pH of the surrounding fluid (1-10). Precise
`knowledge of the pH profile of the gut, including the interindividual
`variability, is a prerequisite for designing optimal delivelY systems
`based on this concept.
`From a theoretical point of view the intraluminal pH ofthe gut pri-
`marily is determined by three factors: the absorption and secretion of
`acid and base by the intestinal epithelium, the bacterial degradation
`of ingested food, and the rate of transport of the intestinal contents
`through the gut.
`Determinations ofthe intraluminal pH ofthe gastrointestinal tract
`have been performed for several decades. Early studies were based
` on aspiration of gastric 01' intestinal fluids, or measurements on fae-
`ces, However, the development of small pH-sensitive, radiotrans-
`mitting capsules has provided a method which allows pH-determina-
`tion under almost physiological conditions,
`The aims of the investigations (11-15) presented in this review
`were as follows: to evaluate a method of determining local intralu-
`minal pH ofthe gut based upon the combined use of pH-capsules and
`fluoroscopy; to use this method in studying the pH-profile ofthe gas-
`trointestinal tract in healthy human subjects and in children; to study
`the effect of various factors on this pH-profile.
`The present review discusses current knowledge of the intralu-
`minal intestinal pH with special reference to data generated with pH-
`capsules.
`
`2. METHODS
`pH ofthe gut is a very sensitive parameter, influenced by many kinds
`of outside impacts. A major problem in measuring gastrointestinal
`pH is, therefore, that it involves the introduction of a tube or a trans-
`ducer into the gut of the subject studied, and the procedure in itself
`might induce changes in the pH it measures. Various methods have
`been developed with the intend to minimize the physical trauma to
`the subject, thereby minimizing the possible effect of the procedure
`on the recorded pH.
`
`2.l INTUBATION TECHNIQUES
`Naso-intestinal intubation techniques are easily performed, but pose
`a number of limitations that can provide less than accurate results.
`For example, hypersalivation caused by the intubation may dilute the
`aspirate and thereby raise the gastric pH due to the alkaline pH of
`saliva. Reflux through the pyloric sphincter due to nausea caused by
`the procedure may also falsely raise the gastric pH. Conversely, gast-
`ric fluid transported along the tube may falsely decrease the pH in
`the small intestine.
`2.1.1 Aspiration technique
`Aspiration of gastric fluids through catheters has been employed for
`decades, and it has the advantage of direct measurement on the fluid.
`Only the proximal gastrointestinal tract is usually studied by this tech-
`
`Danish Medical Bulletin
`
`nique, but Barbero et al (16) studied the entire intestinal tract - from
`the stomach to the rectum - of infants (aged two weeks to three
`months) by an aspiration technique using an infant Miller-Abbott tube
`with a balloon inflated with 5-8 ml air. The balloon was inflated when
`the tube was placed in the duodenum. The tube then passed rapidly to
`the terminal ileum, and more slowly, within 24-36 hours, through the
`colon to the rectum. The ethical aspects of performing this potential-
`ly hazardous procedure in infants are mentioned in their aliicle.
`2.1.2 Dialysis bags
`A method introduced by Mamer (17), later described and utilized by
`Rune and Kastel' (18) involved the use ofa suitable membrane filled
`with distilled water and placed in the stomach via a connecting tube.
`After a time the contents ofthe bag were withdrawn, and the hydro-
`gen-ion content was determined. This method is useful in determin-
`ing an average pH level in the stomach, but does not reflect rapid
`changes in gastric pH.
`2.1.3 Electrodes
`Intubated glass electrodes or antimony electrodes may be used to de-
`termine the intraluminal pH of the upper gastrointestinal tract.
`Electrodes have the advantage over dialysis bags and aspiration tech-
`niques that they are capable of reflecting pH fluctuations occurring
`in the gut lumen. Furthermore, registrations can be made continu-
`ously on ambulant patients when the electrode is connected to an am-
`bulatory recording system. Savarino et al (19) found an excellent cor-
`relation between values obtained with an intragastric pH monitoring
`equipment (Digitrapper 6000, Synetics, Sweden) and simultaneous
`gastric aspiration.
`2.2 TUBELESS TECHNIQUES
`2.2.1 Chemical methods
`Indirect methods of determining the presence or absence of gastric
`acidity have been suggested. One method involved the use of cationic
`exchange resins to determine the absence or presence of free hydro-
`chloric acid. The procedure depends on the dissociation of the resin
`by the hydrochloric acid in the stomach. The cation is absorbed and
`excreted in the ul'.iw:;in the presence offree acid only (20).
`Another techniqll~ :uWdl:\res:~le u~e\I,$I~Il~(i:~mtaining methy lene
`blue wrapped in an inCffgestible.-&ac tied by a catg\jf.~ut{ll·e. Free acid,
`if present in the stomach, dissolves the suture anct'allows the release
`of the dye. The dye is thtfHlah~or~ed ancl excreted in the urine, Lack
`of free acid prevents the release o'fthe dye. 'This procedure (Desmoid
`pill technique) was first devised by Sahli in 1905 and reintroduced
`by Levere and Palll1el"ill.]1~60'~~~)
`Obviously, these metll'qds,ar<:drldii:ect, nonspecific, time cotlSlllTI-
`ing, and consequently of limited vaiue.
`2.2.2 Radiotelemetry capsules
`In 1957 the first radiotelemetry capsule for measuring pH was in-
`vented by Jacobsen and ]YlacKay (22). A copolymer resin, which
`changed its dimensions with changes in pH, was used as the trans-
`duceI'. The change in dimensions was transferred to an iron core mov-
`ing inside a coil, and this caused a shift in the frequency of the os-
`cillator in the capsule. The very slow response time of the transduc-
`er decreased the clinical value of the capsule, and there are no reports
`of its use for clinical investigations. In 1959 a telemetry capsule using
`an antimony electrode as transducer was developed by Noller (23),
`and this pH-capsule was later referred to as the Heidelberg capsule.
`The pH measuring cell in the Heidelberg capsule is made up of an
`annular external antimony electrode which is in contact with the sur-
`rounding fluid, and an internal AgCl electrode separated by a semi-
`permeable membrane (24). pH changes the potential difference be-
`tween the electrodes, which in tum control the frequency of the ra-
`dio transmitter. The main disadvantages with the early type of this
`capsule were the short life and serious drift problems, caused by an
`oxidation ofthe antimony electrode in the presence ofintestinal fluids
`(25, 26). The limitations of this capsule made it suitable only for
`studies of the stomach and small intestine, although Arullani et al
`(27) used it in a study ofthe entire gastrointestinal tract in human vol-
`
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`unteers and patients. The study subjects initially passed a tube
`throughout the gastrointestinal canal and then the capsule was pulled
`through. Later improvement of the capsule has made it a more l'eli-
`able tool of pH measurement, but the accuracy of the capsule is still
`only about 0.5 pH units (28, 29), and the lifetime is only 22 h (29).
`In 1965-6 two pH capsules using glass electrodes were designed: a
`Japanese capsule (30), which, however, has never later been men-
`tioned in clinical studies, and a capsule manufactured by Remote
`Control Systems Ltd, London, England, referred to in the present pa-
`per as the RCS capsule (31). The main problem with the pH glass
`electrode is the high impedance'. The electrode must also be sealed
`to prevent development of leakage paths, which shunt the potential
`produced by the transducer. The early RCS capsule depended on
`epoxy resins to form the seal, but moisture caused a gradual deteri-
`oration in the pH response and a short lifetime for these capsules.
`Later a covering layer of glass was added which increased the life-
`time of the capsule to more dian one month (32). The Japanese cap-
`sule and the RCS capsules respond to alterations in pH by changing
`the transmission frequency of the transmitter in the capsule. The RCS
`capsule uses a FM Qscillator with a transmission frequency of ap-
`proximately 400 kHz, whereas the transmission frequency of the
`Japanese capsule is 1.9 MHz. The electrical circuits ofthe two cap-
`sules share many aspects. A glass pH-electrode is in contact with the
`surrounding fluid and an Ag/AgCl reference electrode is situated in
`the battery cap of the capsule. Variation in potential difference be-
`tween the pH-electrode and the reference electrode causes a change
`in the capacitance of a reverse biased diode (varicap), with a corres-
`ponding change in output frequency (32, 33). The response in trans-
`mission frequency of the RCS capsule is linear in the interval be-
`tween pH 1 and pH 9 (33, 34).
`A small number of other types of radiotelemetry pH-capsules have
`been developed but the Heidelberg capsule and the RCS capsule (Fig.
`1) are those most frequently used in published clinical studies.
`
`2.2.2.1 Methodological problems using the pH-capsule
`a. Localization of the capsule
`When an untethered capsule isingested, it ,travels freely throughout
`the gastrointestinal canal; lirid a crucial point'is how to determine the
`precise location of the capsule in the gut at the time of pH measure-
`ment. The location which poses most problems is the ileo-caecal re-
`gion. By using a radio directional'anteI1na:to determine the position
`at which the maximum signal strength of transmission is received,
`the regional localization of the capsule can be made with an accur-
`acy of5 cm (35, 36), bur it is not poSsible to determine by this method
`whether it is located in the caecum or in the terminal ileum.
`Fluoroscopy enables a more precise localization, but if the gas con-
`tent ofthe colon is sparse, the distinction between the terminal ileum
`
`Fig. 1. The pH-sensitive, radiotelemet!)! capsule (ReS capsule). Dimensions:
`diameter 7111111, lenght27 111111 (a match is shown/or comparison a/size).
`
`184
`
`and the caecum may be difficult. The use of radiopaque contrast (I5)
`or gamma scintigraphy technique (35) to visualize the region may be
`an advantage. Repeated fluoroscopic investigations with short inter-
`vals in between can be of great help, especially when sudden changes
`in pH occur. It is often observed that a capsule located in the ileocae_
`cal region has dropped 5 to 10 cm downwards (i.e. into the caecum)
`between two fluoroscopic investigations, and usually this is aSSociat_
`ed with a sharp decrease in pH. However, it must be recogniZed that
`even with the use of frequent fluoroscopic determinations ofthe loca-
`tion of the capsule, and even with the assistance of a skilled radiolo_
`gist, a small number of the determinations may be incorrect. The ma-
`jor problem with repeated fluoroscopic investigations is the radiation
`exposure. The length of radiation must be kept as ShOli as possible
`and this may best be achieved with the collaboration of a radiologist:
`An improved method of localisation of the pH-capsule in the
`caecum was used by Sasaki et al (37). A contrast colonogram was ob-
`tained before the investigation. The receiver was connected to a com-
`puter-assisted analysing system, and when pH sharply decreased by
`1 pH unit/min or more (Le. when the capsule entered the caecum) the
`system generated a beeping sound. A plain abdominal x-ray was per-
`formed and superimposed on the previously performed contrast
`colonogram, and the presence ofthe capsule in the caecum could be
`verified. Thereafter, the position ofthe capsule in the colon was de-
`termined at 2-h intervals with a radio directional antenna. In two pa-
`tients a plain x-ray film was taken after a measurement of pH by the
`antenna, and the position of the capsule judged by the antenna method
`was correct. The study demonstrates, that if the configuration of the
`colon is known, the localization of the capsule can be reasonably well
`determined by the use of a radio directional antenna. The method is
`elegant and the computer-assisted analysing system could be of great
`help in monitoring pH in the colon of patients with chronic inflam-
`matory bowel disease, where very low pH values have been report-
`ed (14). However, a contrast colonogrammay not be available in all
`patients, and the topographic position of the colon may be slightly
`influenced by the position (upright or succumb) of the patient.
`
`b. Gastrointestinal transit of the capsule
`When the capsule is ingested, it is freely mobile and its localization
`in the gut will be determined by the propulsion movements of the
`gastrointestinal myometrium. The gastric emptying of large (> 1 mm)
`particles is dependent on the interdigestive migrating myoelectric
`complex (IMMC) (38, 39). When solid food is present in the stOI11-
`ach it contracts 3-4 times per minute, and the pylorus is partially
`opened, allowing liquid and small pmiicles to pass. When the stOI11-
`ach is empty of food, several phases of myoelectric activity occur,
`ending with the phase III, the IMMC, which consists of an opening
`of the pylorus and of3-4 peristaltic-contractions from the stomach to
`the caecum, allowing emptying of the stomach of undigested mate-
`rial ("the housekeeper wave") (40, 41). This cyclic pattern of events
`occurs on average every two hours in fasting humans, but it is inter-
`rupted when food is ingested. The gastric residence time (GRT) of
`the pH-capsule therefore depends on the dietary state of the subject.
`In a fasting subject the average GRT of the capsule is 1.1 to 1.9 hours
`(11-13, 29, 42). A small liquid meal prolongs the mean GRT to 2.6
`hours, and frequent intakes of food increases it to more than 14.5
`hours (42). This important aspect concerning the gastric emptying
`must be taken into account when sustained release tablets with coat-
`ings resistant to acid are prescribed. If such tablets are taken together
`with meals, they will remain in the stomach until it is empty offood,
`and ifthe subject eats frequent meals during the day the stomach will
`not be empty before sometime dllring the night. Consequently, it is
`of no relevance to take such tablets two or more times daily, while
`all or most of the tablets will remain in the stomach the entire day
`and later all are emptied into the duodenum sometime during the fol-
`lowing night (43,44).
`The small intestinal transit time (SITT) of the capsule in adults
`varies from 2.8 to more than 14 hours (11, 45) and average values of
`5.7 to 8 hours are repOlied (11,35). The capsule travels rapidly from
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`the duodenum to the distal part of the small intestine, and about two-
`thirds of the SITT is spent in the part ofthe small intestine that is lo-
`cated in the lower right abdominal quadrant (11). This slow transit
`through the distal small intestine is in accordance with the observa-
`tion of Kerlin & Phillips (46), who found that the IMMC travels
`through the small intestine with a velocity that decreases from 4.7
`cm/min in the jejunum to 0.9 cm/min in the terminal ileum. Ingestion
`oHood also interrupts the IMMC of the small intestine (46). In child-
`ren, the median SITT was almost identical to that of adults (7.5
`hours), and for three quarters ofthat time the capsule is located in the
`distal small intestine (13). The rapid transit tlu'ough the jejunum
`makes it difficult to study the pH ofthis part of the gut with a freely
`moving pH capsule. In a study using capsules tethered with a 2 metres
`long nylon line it was possible to obtain pH measurements from the
`proximal part ofthe jejunum (34). However, the line slowed the tran-
`sit of the capsule considerably, so it was not possible to measure pH
`in the more distal patis of the small intestine in that study.
`The colonic transit time of the capsule is about 17.5 hours (equal
`in adults and children), but it varies widely from less than 10 hours
`to 112 hours, and the capsule is located in the caecum for about half
`ofthis time (11, 13). The colonic transit time, tends to be longerin fe-
`males than in males (11).
`The day-to-day variation of the regional transit times is consider-
`able, and in a study of the day-to-day variation in 13 healthy subjects
`the variation coefficients of the GRT and colonic transit time were
`about one (11). The SITT was more consistent and the variation co-
`efficient was 0.40 (11).
`c. Linearif), ji'equency drift, precision and accuracy
`The response ofthe transmission frequency to alterations in pH was
`tested by MeldrulIl et al (33) and by Fallingborg et al (34) concern-
`ing the RCS capsule, and was found to be linear within the interval
`between pH 1 and pH 9. The response of the Heidelberg capsule has
`also been found to be linear in the interval between pH 2 and 7, but
`above and below this interval the frequency response decreased (47).
`Calibrations ofthe capsules before and after a study will secure their
`accuracy at the calibration levels at the beginning and at the end of
`the study. As previously mentioned, the main problem with the ear-
`ly types of radiotelemetry capsules, and especially the Heidelberg
`capsule, was the frequency drift. This was mainly due to an oxida-
`tion ofthe antimony electrode in the presence ofintestinal fluids. The
`problem was less with capsules using glass electrodes, and in the
`study of Fallingborg at al (11), using the RCS capsule, a maximal
`drift of 0.5 pH units was registered, with the exception of one sub-
`ject in whom the increased drift was due to a defective reference cap.
`The fi'equency drift may affect both the accuracy (zero-point drift)
`and the precision (change of the slope of the response-curve) of the
`pH capsule, but, assuming that the drift develops with a constant rate
`during the study, a correction of the frequency drift can be performed
`after recalibration of the recovered capsule (14):
`
`-
`-
`Tx-To
`-
`-
`OTx-OpHl(To)- Tend-To X(OpHl(To)-OpHl(Tend)
`pHT,~1-8x-----===-",==--------------
`-
`-
`-
`-
`-
`-
`Tx-To
`OpHl(To)-OpH9(To)- Tend-To X(OpHl(To)-OpHl(Tend)-OpH9(To)-OpH9(Tend)
`
`OT':
`OpHl(TO):
`
`Corrected pH value, measured at T,
`Time of pre-calibration
`Time of post-calibration
`Time of pH measurement
`Transmission frequency measured at time Tx
`Transmission frequency of the capsule at pHI, 37°C, measured
`at pre-calibration
`(\H1 (Telld): Transmission frequency of the capsule at pHI, 37°C, measured
`at post-calibration
`OpH9(TO): Transmission frequency of the capsule at pH9, 37°C, measured
`at pre-calibration
`0pH9(Telld): Transmission frequency of the capsule at pH9, 37°C, measured
`at post-calibration
`
`Danish Medical Bulletin
`
`The accuracy pfthe RCS capsule has been evaluated by Meldrum et
`al (33) and by Fallingborg et al (12) by comparing pH in faeces and
`ileostomy output, measured by the RCS capsules and with a pH-meter
`(Radiometer, Copenhagen), respectively. The maximal difference be-
`tween pH values measured with the two methods was 0.2 and 0.3 pH
`units, respectively, in the two studies.
`
`d. Frequency a/measurements
`In some studies pH was automatically registered 6 or 60 times per
`minute and stored in a recording system, whereas in other studies in-
`cluding those made by the author of this thesis the measurements
`were performed manually with intervals of 10 minutes or more. The
`frequent, automatic recording method has several advantages: it can
`be used in outpatients; it is able to demonstrate pH-changes of short
`duration, and measurements can also be performed while the person
`sleep. The major disadvantages ofthis system are that only one sub-
`ject can be studied at a time for each recording system, and that meas-
`urements obtained during periods with low signal or signal loss may
`be incorrect. The importance ofa high signal quality was emphazised
`by Press et al (48) who observed that atiificiallow pH values could
`be registered when the recorder indicated poor signal quality. The
`main advantage with manual recording is that an optimal signal qual-
`ity can be secured at each recording, and that more than one subject
`can be studied at the same time. The disadvantages are that pH-
`changes that occur between measurements will not be discovered,
`and that the method cannot be used in outpatients.
`
`3. GASTROINTESTINAL pH IN NORMAL
`HUMAN SUBJECTS
`Since 1964 a number of studies on human gastrointestinal pH using
`pH-sensitive capsules have been published. The majority of these
`studies deal with measurements of gastric residence time or meas-
`urements of the acid secretory capacity of the stomach, and, there-
`fore, only contain pH measurements from the stomach and the duo-
`denum (Table 1). However, a number of studies also report pH meas-
`urements from more distal parts of the gut (Table 2). Many papers
`contain data obtained from normal human subjects, but in several of
`
`pH
`8
`
`7
`
`6
`
`5
`
`4
`
`3
`
`2
`
`0+--,---.--.--.--,,--.--.---.--.--.--.
`
`Fig. 2. Median (broken line) and interquartile range of gastrointestinal pH
`measured in 33 healthy, adult volunteers (11).
`
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`Table 1. Published studies onllie use o/pH-sensitive, radiolransmitting capsules. In vitro studies and human studies confined to measurements in the stom_
`ach and/or in the duodenum.
`References
`
`Type of capsule
`
`Subjecls
`
`Jacobson & MacKay, 1957 (22) .......................... , prototype, 400 kHz
`Nollel; 1959 (23). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. prototype, 1.9 MHz
`(Heidelberg)
`Connel & Waters, 1964 (25) ............................. , Heidelberg
`Steinberg et aI, 1965 (47) ............................... , Heidelberg
`Watson & Patton, 1965 (49) ............................. , Heidelberg
`RG1?!t & NOllel; 1965 (50) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. Heidelberg
`Watson & Kay, 1965 (31) ....... ' ................... , . . . .. prototype, 400 kHz
`(RCS)
`Stavney et aI, 1966 (51) .................................. Heidelberg
`Kuhn et aI, 1966 (52) .................................. , Heidelberg
`Nollel; 1967 (53) ................................ , . . . . .. Heidelberg
`Stilligel; 1967 (54) ..................................... , Heidelberg
`Maiwald et aI, 1967 (55) ................................ , Heidelberg
`Kiittel; 1967 (56) ...................................... , Heidelberg
`Aynaciyan & Bingham, 1969 (26) ......................... , Heidelberg
`Yarbrough et aI, 1969 (24) .............................. , Heidelberg
`Deyhle et aI, 1969 (57) ................................. , Heidelberg
`Williamson et aI, 1969 (58) ............................... \ Heidelberg
`Stack, 1969 (59). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. Heidelberg
`Russell & Goldberg, 1970 (60) ........................... , Heidelberg
`Goldstein & Packman, 1970 (61) ......................... , Heidelberg
`Andres & Bingham, 1970 (62) ............................ Heidelberg
`Kuntz et aI, 1971 (63) ..... :. . . . . . . . . . . . . . . . . . . . . ... . . . .. prototype, 1.9 MHz
`J6hannesson et aI, 1973, (64). . . . . . . . . . . .. . .. . . . . . . . . . . . .. Heidelberg
`Sadchikova, 1973 (65). . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . .. Heidelberg
`Madee & Miiller-Wieland, 1975 (66) . . . . . . . . .. . . . . .. . . . .. .. Heidelberg
`Kotter et aI, 1975 (67) .................................. , Heidelberg
`T1'lIchaud et aI, 1975 (68) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. Heidelberg
`Ekenved & Walan, 1975 (69) . . . . . . . . . . . . . . . . . . . . . . . . . . . .. Heidelberg
`Stacher & Starkel; 1975 (70) ........................ , .... , Heidelberg
`Misaki & Kawai, 1976 (71) .............................. , 2 prototypes
`Ritschel & Erni, 1977 (72) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. Heidelberg
`Heinkel, 1980 (73) ................. , . . . . . . . . . .. . .. . . . . .. Heidelberg
`McGraw et aI, 1981 (74) ................................. Heidelberg
`Uusilalo & Keyrilainen, 1983 (75) ..................... , . " Heidelberg
`Puch et aI, 1984 (76), , .. , , .... , , , .. , , , . , . , , , , , . , , , .. , , ,. Heidelberg
`Mojaverian etal, 1985 (42) ,." .... " .. "',.,,', .... ,, .. , Heidelberg
`Faegenburgelal, 1985 (77)", .. ", ... " , .. "".,." .. ", Heidelberg
`Reynolds et aI, 1986 (78) ", .. ", .. ", .. "" .. ""."".. RCS
`Rocci et aI, 1987 (79) , , , . , , , , , , .. , , .... , , . , , , , ... , , .. , " Heidelberg
`Mojaverian el aI, 1987 (80) , .. "" .. ", , .. , , , ... , , .. , , , .. Heidelberg
`Mojaverian et aI, 1988 (81) ."" . , , , , .. , , , , .. , , , ... , , ... , Heidelberg
`Ewe et aI, 1989 (82) , , ... , , .... , , .... , , ... , , ... , , ... , , ,. Heidelberg
`Mojaverian et aI, 1990 (83) ."" .. , . , ... , , , , . , , , , ... , , .. , Heidelberg
`Chanetal, 1990(84) " .. ,', ... ,', ... , ..... " ... ,', .. ," Heidelberg
`Mojaverianetal, 1991 (29) .. ,."., .. ", .. " ... ",.,." .. Heidelberg
`Piscitelli et aI, 1991 (85), .. , , , ... , , , , ... , , .. , , , ... , , , .. " Heidelberg
`Knapp et aI, 1991 (86) ... " ... ,",.,",.,"', .. ,', .. ,',. Heidelberg
`Betlach et aI, 1991 (87). , , , ... , , ... , . , ... , , , .. , , , ... , , . .. Heidelberg
`Lebsach et aI, 1992 (88) , ... , , ... , , , .... , .... , , ... , , .. , " Heidelberg
`Russell et aI, 1993 (89) ... , , .. , . , ... , , , , .. , , , .. , , , , . , . , .. Heidelberg
`Meyer et aI, 1993 (90)"., .. "" .. ,." .. " ... ", .. ""." Heidelberg
`Alioth etal, 1993 (91)" ... " ... " .... ,., ... , ... ,"',.". Heidelberg
`Zimmermann et aI, 1994 (92, 93) , .... , , ... , , , ... , , .. , , , .. , Heidelberg
`Russell et aI, 1994 (94) , , .. , , , , .. , , , .. , . , , .. , , , . , , , , , . , ,. Heidelberg
`Zimmermann et aI, 1994 (95) ... , , , .. , . , , . , , , . , . , , .. , , , . " Heidelberg
`Henderson et aI, 1995 (96) ... , , , .. , , , , .. , , .. , , , .. , , , , . , " Heidelberg
`Groning & Berntgen, 1996 (97) ... , , ... , , .. , . , , ... , ... , , .. Heidelberg
`Lewis & Heaton, 1997 (98), .. , , , , .. , , , .. , . , , . , , , , .. , , , . ,. ?
`
`30 duodenal ulcer patients
`
`30 normal subjects and patients
`50 normal subjects (+ antacids)
`
`20 duodenal ulcer patients
`18 patients with dystrophia myotonica
`46 dyspectic patients (+ Spasmo-Nervogastrol®)
`12 patients (+ metoclopramide)
`Cases
`Cases
`24 normal subjects, 22 duodenal ulcer patients
`26 patients
`29 patients
`45 patients with anaemia (21 with pernicious anaemia)
`1 normal subject and 29 patients
`23 dyspeptic patients (+ acetysalicylic acid)
`13 normal subjects (+ antacids)
`27 dyspeptic patients
`Cases
`10 duodenal ulcer patients
`37 healthy children
`16 normal subjects (+ antacids)
`23 normal subjects (transcranial electrotherapy)
`118 normal subjects (+ antacids)
`10 normal subjects (+ antacids)
`5 normal subjects (+ insulin ± bromazepam)
`4 normal subjects + 19 peptic ulcer patients
`12 normal subjects
`147 patients
`1 I normal subjects (+ sucralfate I + antacids)
`24 normal subjects, 31 duodenal ulcer patients,
`10 normal subjects (+ antacids)
`16 normal subjects
`1 patient with Crohn's disease
`4 duodenal ulcer patients
`8 normal men (+ procainamide)
`8 normal subjects (+ aspirin)
`45 normal subjects
`10 normal subjects
`12 normal men (± ranitidine)
`8 healthy men (+ diclofenac sodium)
`4 normal subjects
`6 normal males (+ ketoconazole ± cimetidine ± sLlcralfate)
`6 normal subjects (+ glutamic acid ± ranitidine)
`12 normal subjects (+ theophylline ± ranitidine)
`12 normal subjects (+ enoxacin ± ranitidine/pentagastrin)
`79 healthy elderly subjects
`8 normal subjects, 7 achlorhydric subjects. (+ theophylline)
`18 normal subjects (+ diclofenac ± ranitidine)
`24 normal subjects (+ fluconazole or itraconazole)
`11 healthy subjects (> 64 years, + dipyridamole ± famotidine)
`12 normal subjects (+ fluconazole ± omeprazole)
`10 normal subjects (+ zinc acetate or zinc oxide ± famotidine)
`5 normal sLlbjetcs
`13 normal subjects
`
`these articles the results from the healthy subjects and those obtained
`from patients are not separated, Therefore, only a limited number of
`these study results can be used to describe the pH-profile of normal
`humans (Table 3), On the basis of these selected studies, supple-
`mented with results from studies using other methods, a picture of
`the pH profile ofthe normal gastrointestinal tract can be made,
`However, it should be kept in mind that a normal colonic pH-profile
`may vary in different ethnic and cultural groups and in different parts
`of the world, because dietary habits may affect the intraluminal pH
`(see Chapter 7, I),
`The pH-profile of the normal gastrointestinal tract, based on
`measurements obtained with the RCS capsule, is shown in Fig, 2
`(11),
`
`3,} STOMACH
`The acid environment in the lumen ofthe stomach is attained by pro-
`ton secretion from the parietal cells in the corporal mucosa, In a fast-
`ing subject, the pH of the gastric fluid ranges fi'om 1 to 3.5 (11, 27,
`30, 89), but ingestion offood, milk, or antacids may shortly increase
`pH to about 7 (24, 33, 89, 110),
`
`3.2 DUODENUM
`Due to the rapid transit ofthe untethered pH capsule through the duo-
`denum, only a few recordings can be performed in this region using
`this method, Thus, results obtained with tubes, glass electrodes, or
`tethered capsules must be regarded as the most reliable, In the duo-
`denum, the pH ofthe intestinal fluid is changed from acid to neutral
`
`186
`
`Vol 46 No, 3/June 1999
`
`Patent Owner Ex. 2006
`IPR2015-01241
`Page 4 of 14
`
`

`
`Table 2. Clinical studies 011 human gastrointestinal pH measured with pH-sensitive, radiotransmitting capsules. Studies containing pH measurements in the
`small intestine and lor in the colon
`
`References
`
`Type of capsule
`
`Region
`
`Subjects
`
`Watson & Paton, 1965 (49)
`Kitagawa et ai, 1966 (30)
`Arullani et ai, 1967 (27)
`Maxwell et ai, 1971 (99)
`JV!eldrum et ai, 1972 (33)
`Paiva et ai, 1972 (100)
`Bown etal, 1974 (101)
`Colson et ai, 1981 (32)
`Evans et ai, 1986 (102)
`Patil et ai, 1987 (103)
`Hardy et ai, 1987 (6)
`pye et ai, 1987 (104)
`Youngberg et ai, 1987 (28)
`Evans et ai, 1988 (35)
`Gilbert et ai, 1988 (105)
`Mojaverian et ai, 1989 (45)
`Fallingborg et ai, 1989 (11)
`pye et ai, 1990 (36)
`Fallingborg et ai, 1990 (12)
`Fal!ingborg etal, 1990 (13)
`Hardy et ai, 1991 (8)
`Railllundo et ai, 1992 (106)
`Wyeth et ai, 1992 (107)
`Fa/lingborg et ai, 1992 (108)
`Zimmerman & Leitold, 1992 (109)
`Fa/lingborg et ai, 1993 (14)
`Fal!ingborg et ai, 1994 (34)
`Press et ai, 1996 (48)
`Sasaki Yet ai, 1997 (37)
`Fallingborg et ai, 1998 (IS)
`
`Heidelberg
`prototype, 1.9 MHz
`Heidelberg
`Heidelberg
`RCS
`Heidelberg
`RCS
`RCS
`RCS
`RCS
`RCS
`RCS
`Heidelberg
`RCS
`RCS
`Heidelberg
`RCS
`RCS
`RCS
`RCS
`RCS
`RCS
`RCS (7)
`RCS
`Heidelberg+Flexilog 1010
`RCS
`RCS
`RCS
`RSC
`RSC
`
`jejunum
`Total GI -tract
`Total OJ -tract
`jejunum
`Total GI-tract
`Ileum
`Total OJ-tract
`Upper GI-tract
`Colon
`Term. ileum, colon
`Stomach, sr, caecum, c. asc.
`Colon
`Stomach and SJ
`Total OJ-tract
`Stomach and sr
`Stomach and Sl
`TotalOl-tract
`Total GI-tract
`Stomach and Sl
`Total GI-tract
`Stomach + SJ
`Total Or-tract
`Colon
`Total GI-tract
`Stomach and Sl
`Total Ol-tract
`Duodenum, jejunum
`Total Or-tract
`Total GI-tract
`Stomach, sr, proximal colon
`
`1 normal subject and 16 patients (secretin)
`20 normal subjects and patients
`9 normal subjects, 10 patients
`10 normal subjects, 21 patients
`2 normal subjects, 7 patients
`21 patients receiving potassium
`11 normal subjects (±cathartics)
`cases
`23 normal subjects, 21 colonic neoplasia patients
`6 normal