Masaki Sanaka

Effects of Proton Pump Inhibitors on Gastric Emptying: A Systematic Review

The proton pump inhibitor (PPI) is widely used for the treatment of gastroesophageal reflux disease, peptic ulcer diseases, and functional dyspepsia. The pathogenesis of these acid-related and/or functional upper gastrointestinal disorders is potentially associated with abnormal gastric emptying. To date, variable effects of PPIs on gastric emptying have been reported. Therefore, it is relevant to gather and analyze published information on this topic. A systematic literature search has been performed, showing that the delaying effect of PPIs on gastric emptying of solid meals is consistent, whereas the effect of PPIs on the emptying of liquids is inconsistent. The underlying mechanisms whereby PPIs may affect gastric emptying have been discussed, most of which still remain hypothetic. Gastric emptying of solids involves a process of peptic hydrolysis. PPIs impair the hydrolytic digestion by inhibiting acid-dependent peptic activity, thereby delaying the solid emptying. Gastric emptying of liquids largely depends on volume and energy density of intragastric contents. PPIs variably modify the volume and the energy density by reducing gastric fluid secretion, thereby modifying the liquid emptying in an unpredictable manner. Hypergastrinemia has been considered to delay gastric emptying, but it seems of minor importance in the regulation of gastric emptying during PPI use. The delayed emptying of solids due to PPI therapy may have clinical implications in the management of gastroesophageal reflux disease, functional dyspepsia, as well as diabetes.

Guide for judicious use of the paracetamol absorption technique in a study of gastric emptying rate of liquids

Abstract: The paracetamol absorption technique, a widely used method for evaluating the gastric emptying rate of liquids, appears to be performed inappropriately, resulting from a lack of consideration of pharmacokinetics in paracetamol absorption. This review suggests that appropriate study designs and logical choice of the parameters for the rate of paracetamol absorption are the cornerstone of reliable investigation of gastric emptying using the paracetamol method.

THE WAGNER–NELSON METHOD MAKES THE [13C]-BREATH TEST COMPARABLE TO RADIOSCINTIGRAPHY IN MEASURING GASTRIC EMPTYING OF A SOLID/LIQUID MIXED MEAL IN HUMANS

1 Scintigraphy is the gold standard for measuring gastric emptying, but the use of radioactive isotopes can produce substantial irradiation. The [13C]‐acetate/octanoic acid breath test is widely used as a non‐radioactive alternative. 2 The half [13CO2] excretion time () is closely correlated with the scintigraphic half‐emptying time (). However, is consistently remote from , because the distribution of [13CO2] into the bicarbonate pool delays the respiratory excretion of the [13C] marker, which has already been emptied from the stomach. The time for the distribution process should be adjusted to diminish the discrepancy between the results of the scintigraphic and breath tests. 3 The Wagner–Nelson method provides an accurate profile of drug absorption. We have recently applied the Wagner–Nelson method to breath testing to adjust the time for [13CO2] distribution. In the present study, the [13C]‐breath test with Wagner–Nelson analysis was compared with scintigraphy. 4 Six female volunteers simultaneously underwent scintigraphy and the breath test on two occasions, either to measure gastric emptying of the liquid phase (16 kcal) or for that of the solid phase (214 kcal). Time–percentage gastric retention curves were generated by scintigraphy and the breath test with Wagner–Nelson analysis. The half‐emptying times were determined by interpolation from the scintigraphic curve () and the Wagner–Nelson curve (). was calculated by conventional curve‐fitting techniques. 5 For liquid and solid emptying, the gastric retention curves generated by the Wagner–Nelson method were comparable to the scintigraphic retention curves. For the liquid, was significantly longer than (93.8 ± 7.3 vs 14.2 ± 9.3 min, respectively; P < 0.0001), as was also observed for the solid phase (147.8 ± 34.4 vs 35.3 ± 11.2 min, respectively; P < 0.0001). In contrast, no significant differences were found between and for the liquid (13.5 ± 5.0 vs 14.2 ± 9.3 min, respectively; P = 0.734) and the solid (45.8 ± 10.2 vs 35.3 ± 11.2 min, respectively; P = 0.051) phase. 6 In conclusion, Wagner–Nelson analysis makes the [13C]‐breath test comparable to scintigraphy.

EFFECTS OF AGAR AND PECTIN ON GASTRIC EMPTYING AND POST‐PRANDIAL GLYCAEMIC PROFILES IN HEALTHY HUMAN VOLUNTEERS

1 Dietary fibre, such as pectin, delays gastric emptying and may enhance post‐prandial glucose tolerance. Agar, which is high in fibre content, is widely used in the traditional Japanese diet. Although long‐term diet therapy with agar decreases fasting plasma glucose levels in diabetes, knowledge is lacking about the acute effects of agar on gastric emptying and the post‐prandial glycaemic profiles. The present study was designed to investigate the acute effects of agar. 2 Ten healthy male volunteers were studied on three occasions with three different test meals (450 kcal/500 mL): (i) a fibre‐free meal; (ii) a meal with 2.0 g agar; or (iii) a meal with 5.2 g pectin. On each occasion, participants underwent a [13C]‐acetate breath test along with serial blood sampling. To quantify gastric emptying, the half [13CO2] excretion time () and the time for maximal [13CO2] excretion rate (tlag) were determined. The post‐prandial glycaemic response was expressed as an incremental change from the fasting value at each sampling time. Data were analysed using repeated‐measures analysis of variance (anova), followed by a post hoc paired Students t‐test with Bonferroni adjustment. 3 The time‐course for respiratory [13CO2] excretion differed significantly among the three test meals (P = 0.0004, anova). Compared with the control meal, [13CO2] excretion was significantly lower following consumption of the agar meal (between 40 and 105 min post‐prandially; P < 0.025, Students t‐test) and the pectin meal (between 40 and 180 min post‐prandially; P < 0.025, Students t‐test). Among the three meals, significant differences were found in (P = 0.002, anova) and tlag (P = 0.011, anova). Compared with the control meal, the agar and pectin meals exhibited a significantly prolonged (P = 0.007 and P < 0.0001, respectively, Students t‐test) and tlag (P = 0.006 and P = 0.002, respectively, Students t‐test). Neither the agar nor pectin meal affected the post‐prandial glucose profile. 4 In healthy adults, agar and pectin delay gastric emptying but have no impact on the post‐prandial glucose response.

Comparison between gastric scintigraphy and the [13C]-acetate breath test with Wagner-Nelson analysis in humans.

1 The [13C]‐acetate breath test (ABT) quantifies gastric emptying as the half [13CO2]‐excretion time (T1/2b), but T1/2b differs from the scintigraphic half‐emptying time (T1/2s). The aims of the present study were to accurately determine the half‐emptying time by ABT with Wagner–Nelson analysis (T1/2WN), to compare T1/2WN with T1/2s and to validate the Wagner–Nelson strategy in ABT. 2 For a comparative study, eight volunteers simultaneously underwent ABT and scintigraphy. Anterior images were acquired and breath samples were collected every 15 min for 4.0 h after ingestion of a 200 kcal liquid meal labelled with 37 MBq [99mTc]‐colloidal sulphur and 100 mg [13C]‐acetate. For the validation experiment, another six volunteers underwent ABT, on two randomized occasions, using the 200 kcal liquid meal with 100 mg [13C]‐acetate. On either of the two occasions, a gel‐forming agent was stirred into the meal to intentionally delay gastric emptying by increasing meal viscosity. Breath samples were collected at regular 15 min intervals for 4 h post ingestion. 3 The Wagner–Nelson equation for ABT is F(t) = (Abreath(t) + C(t)/0.65)/Abreath(∞), where F(t) is a fractional dose of the [13C] label emptied, C(t) is the [13CO2] excretion (% dose/h), Abreath(t) is the area under the C(t) curve (% dose) and Abreath(∞) is the ultimate [13CO2] recovery in breath (% dose). The percentage gastric retention was estimated as 100 × (1 − F(t)). The time plots of scintigraphic activity and 100 × (1 − F(t)) were fitted to y(t) = 100 × e−K×t, K values were estimated mathematically for each plot by regression analysis and T1/2s and T1/2WN were calculated as (ln2)/K. The time versus pulmonary [13CO2] excretion plots were fitted to z(t) = m × k × β × e−kt(1 − e−k×t)β−1, where m, k and β are constants; T1/2b was calculated as –(ln(1 − 2−1/β)]/k. 4 Values of T1/2WN were closer to T1/2s than T1/2b, although T1/2WN and T1/2b yielded significant under‐ and overestimation of T1/2s, respectively. The high viscosity meal significantly prolonged T1/2WN and T1/2b; T1/2WN could detect the delayed transit of the viscous meal more sensitively than T1/2b. 5 The Wagner–Nelson method improves the accuracy of the ABT.

The Wagner-Nelson Method Can Generate an Accurate Gastric Emptying Flow Curve from 13CO2 Data Obtained by a 13C-Labeled Substrate Breath Test

Background: In pharmacokinetics, the Wagner-Nelson (W-N) method can accurately estimate the rate of drug absorption from its urinary elimination rate. A stable isotope (¹³C) breath test attempts to estimate the rate of absorption of ¹³C, as an index of gastric emptying rate, from the rate of pulmonary elimination of ¹³CO₂. The time-gastric emptying curve determined by the breath test is quite different from that determined by scintigraphy or ultrasonography. In this report, we have shown that the W-N method can adjust the difference. Methods: The W-N equation to estimate gastric emptying from breath data is as follows: the fractional cumulative amount of gastric contents emptied by time t = A_breath(t)/A_breath(∞) + (1/0.65)·d[A_breath(t)/A_breath(∞)]/dt, where A_breath(t) = the cumulative recovery of ¹³CO₂ in breath by time t and A_breath(∞) = the ultimate cumulative ¹³CO₂ recovery. The emptying flow curve generated by ultrasonography was compared with that generated by the W-N method-adjusted breath test in 6 volunteers. Results: The emptying curves by the W-N method were almost identical to those by ultrasound. Conclusions: The W-N method can generate an accurate emptying flow curve from ¹³CO₂ data, and it can adjust the difference between ultrasonography and the breath test.

Follow-Up of Exocrine Pancreatic Function in Type-1 Diabetes mellitus

In a previous study, mild to moderate exocrine pancreatic insufficiency, as measured by the secretin-pancreozymin test, was found in 23 (43%) of 53 patients with type-1 diabetes mellitus. Of these 53 patients, 20 (7 of whom initially had an abnormal secretin-pancreozymin test) were available for a follow-up examination 11 years later. Of the 7 patients with abnormal exocrine pancreatic function at the first test, 5 remained abnormal and 2 became normal, whereas of the 13 patients with initially normal pancreatic function the test result remained normal in 11 patients and became abnormal in 2. In these 2 groups the test result did not differ significantly between both tests. However, exocrine pancreatic function had returned to normal or had become abnormal in 2 patients, respectively, at the second test. In the 3 patients with exocrine pancreatic insufficiency at the first and second tests, the lipase level had not fallen below 10% or less than the normal level at which steatorrhea occurs and therapy is required. There was no significant correlation between the duration of the diabetes and the test results for both time points of investigation. The data suggest that mild to moderate exocrine pancreatic insufficiency found in type-1 diabetes is due to an early event in the course of the diabetes and does not progress. Therefore, this finding is of minor clinical importance and expensive pancreatic enzyme substitution will not be required.

Retention, fixation, and loss of the [13C] label: a review for the understanding of gastric emptying breath tests.

A [13C]-breath test is a promising method for measuring gastric emptying. The methodological relevance is based on a close correspondence between gastric emptying of [13C]-acetate/octanoate (input) and pulmonary excretion of [13CO2] (output). Despite the close input-output correspondence, the pulmonary output is quite remote from the gastric input: the pulmonary output is delayed compared to the gastric input, and the total recovery of [13CO2] in the breath is incomplete. This review focuses on the kinetics of [13C]-acetate/octanoate in the body and suggests that (1) the delayed pulmonary output results from temporal retention of [13CO2] in the well-perfused tissues (heart, brain, etc.), (2) the incomplete recovery results from incorporation of the label into metabolic products (ketone bodies, amino acids, etc.) or from fixation of [13CO2] in the low-perfused tissues (bone, skeletal muscle, etc.), and (3) knowledge on the retention is the key to appropriate interpretations of breath test results. Recognition of these kinetic aspects is essential for appropriate interpretations of these breath test results.

A Case of Solid Pseudopapillary Neoplasm of the Pancreas and Tumor Doubling Time

Background: Solid pseudopapillary neoplasm of the pancreas is a rare tumor with unique clinicopathological features. Although it is considered to grow slowly, little is known about its doubling time. Method: We encountered a young Japanese woman with a solid pseudopapillary neoplasm of the pancreas that had been detected at another hospital 5 years previously but was resected at our hospital. The tumor showed only a solid component without any cysts. Computed tomographic scans taken 5 years apart were compared to determine the tumor doubling time. Result: The tumor doubling time according to the formula of Schwartz and co-workers was determined to be 765 days. Conclusion: These findings confirm that this tumor grows quite slowly and also support long disease-free periods even in patients who have recurrence or metastases.

Effect of cigarette smoking on gastric emptying of solids in Japanese smokers: a crossover study using the 13C-octanoic acid breath test

BackgroundCigarette smoking is associated with an increased risk of peptic ulcer and gastroesophageal reflux disease. Gastric emptying disorders may play a role in the development of these upper gastrointestinal diseases. Thus, studies examining a link between smoking and gastric emptying disorders have clinical relevance. This study was conducted to investigate the effect of smoking on gastric emptying of solids in Japanese smokers.MethodsThe 13C-octanoic acid breath test was performed in eight male habitual smokers on two randomized occasions (either sham smoking or actively smoking). The time vs 13CO2 excretion rate curve was mathematically fitted to a conventional formula of y (t) = m*k*β*e−k*t*(1 − e−k*t)β−1, and the parameters of k and β were determined: under the crossover protocol, a larger (smaller) β indicates slower (faster) emptying in the early phase, and a larger (smaller) k indicates faster (slower) emptying in the later phase. The half 13CO2 excretion time (t1/2b = −[ln(1 − 2−1/β)]/k) and the time of maximal 13CO2 excretion rate (tmax = [lnβ]/k) were also calculated. Between the two occasions, k, β, t1/2b, and tmax were compared by the Wilcoxon signed-rank test.ResultsAfter smoking, k was significantly increased. No significant differences were found in β, t1/2, and tmax between the two occasions.ConclusionsThe increase in k suggests the acceleration of gastric emptying in the later phase. For the first time, this study has revealed that acute smoking speeds the gastric emptying of solids in Japanese habitual smokers.