Achlorhydric Patients Research Articles

Biorelevant Dissolution Models for a Weak Base To Facilitate Formulation Development and Overcome Reduced Bioavailability Caused by Hypochlordyria or Achlorhydria.

In this study, two dissolution models were developed to achieve in vitro-in vivo relationship for immediate release formulations of Compound-A, a poorly soluble weak base with pH-dependent solubility and low bioavailability in hypochlorhydric and achlorhydric patients. The dissolution models were designed to approximate the hypo-/achlorhydric and normal fasted stomach conditions after a glass of water was ingested with the drug. The dissolution data from the two models were predictive of the relative in vivo bioavailability of various formulations under the same gastric condition, hypo-/achlorhydric or normal. Furthermore, the dissolution data were able to estimate the relative performance under hypo-/achlorhydric and normal fasted conditions for the same formulation. Together, these biorelevant dissolution models facilitated formulation development for Compound-A by identifying the right type and amount of key excipient to enhance bioavailability and mitigate the negative effect of hypo-/achlorhydria due to drug-drug interaction with acid-reducing agents. The dissolution models use readily available USP apparatus 2, and their broader utility can be evaluated on other BCS 2B compounds with reduced bioavailability caused by hypo-/achlorhydria.

Virtual bioequivalence for achlorhydric subjects: The use of PBPK modelling to assess the formulation-dependent effect of achlorhydria

Majority of bioequivalence studies are conducted in healthy volunteers. It has been argued that bioequivalence may not necessarily hold true in relevant patient populations due to a variety of reasons which affect one formulation more than the other for instance in achlorhydric patients where elevated gastric pH may lead to differential effects on formulations which are pH-sensitive with respect to release or dissolution. We therefore examined achlorhydria-related disparity in bioequivalence of levothyroxine and nifedipine formulations using virtual bioequivalence within a physiologically-based pharmacokinetic (PBPK) modelling framework. The in vitro dissolution profiles at neutral pH were incorporated into PBPK models to mimic the achlorhydria with in vitro–in vivo relationship established using bio-relevant pH media. The PBPK models successfully reproduced the outcome of the bioequivalence studies in healthy volunteers under the normal conditions as well as under proton pump inhibitor-induced achlorhydria. The geometric mean test/reference ratios for Cmax and AUC between levothyroxine tablet and capsule in patients receiving proton pump inhibitor were 1.21 (90%CI, 1.13–1.29) and 1.09 (90%CI, 1.02–1.17), respectively. Extension of the virtual bioequivalence study to Japanese elderly, who show high incidence of achlorhydria, indicated bio-inequivalence which Cmax and AUC ratios between nifedipine control-released reference and test formulations were 3.08 (90%CI, 2.81–3.38) and 1.57 (90%CI, 1.43–1.74), respectively. Virtual bioequivalence studies through the PBPK models can highlight the need for conduct of specific studies in elderly Japanese populations where there are discrepancies in pH-sensitivity of dissolution between the test and reference formulations.

Is achlorhydria a cause of iron deficiency anemia?

We re-evaluated the old hypothesis that gastritis-induced achlorhydria is a cause of iron deficiency anemia (IDA) in humans. First, we analyzed the currently available research on the association between achlorhydria and IDA. When gastric acid secretion was measured after maximal stimulation, the frequency of achlorhydria (or severe hypochlorhydria) was 44% in patients with idiopathic IDA and 1.8% in healthy controls. In some patients with pernicious anemia, presumed achlorhydria preceded the development of IDA in time. However, we found no credible evidence that IDA caused gastritis or that IDA preceded the development of achlorhydria. Thus, correlational results favor achlorhydria as the causal factor in the association between achlorhydria and IDA. Second, we sought to determine whether gastritis and achlorhydria cause negative iron balance. When biosynthetic methods were used to isotopically label iron in food, achlorhydric patients were found to have severe malabsorption of nonheme iron, which persisted after the development of IDA. In 1 study, achlorhydria reduced the normal increase in heme-iron absorption from hemoglobin in response to iron deficiency. After an injection of isotopic iron into normal men, the physiologic loss of iron from the body was found to be 1 mg/d. Patients with chronic gastritis had excess fecal loss of isotopically tagged plasma iron. Calculations based on these results indicate that the absorption of iron from a typical Western diet by achlorhydric patients would be less than physiologic iron losses, creating a negative iron balance that could not be overcome by the adaptive increase in duodenal iron absorptive capacity that occurs in response to iron deficiency. The combination of results from these correlational and pathophysiologic studies supports the hypothesis that gastritis-induced achlorhydria can be an independent cause of IDA.

Impaired Drug Absorption Due to High Stomach pH: A Review of Strategies for Mitigation of Such Effect To Enable Pharmaceutical Product Development

Published reports have clearly shown that weakly basic drugs which have low solubility at high pH could have impaired absorption in patients with high gastric pH thus leading to reduced and variable bioavailability. Since such reduction in exposure can lead to significant loss of efficacy, it is imperative to (1) understand the behavior of the compound as a function of stomach pH to inform of any risk of bioavailability loss in clinical studies and (2) develop a robust formulation which can provide adequate exposure in achlorhydric patients. In this review paper, we provide an overview of the factors that can cause high gastric pH in human, discuss clinical and preclinical pharmacokinetic data for weak bases under conditions of normal and high gastric pH, and give examples of formulation strategies to minimize or mitigate the reduced absorption of weakly basic drugs under high gastric pH conditions. It should be noted that the ability to overcome pH sensitivity issues is highly compound dependent and there are no obvious and general solutions to overcome such effect. Further, we discuss, along with several examples, the use of biopharmaceutical tools such as in vitro dissolution, absorption modeling, and gastric pH modified animal models to assess absorption risk of weak bases in high gastric pH and also the use of these tools to enable development of formulations to mitigate such effects.

Using Absorption Simulation and Gastric pH Modulated Dog Model for Formulation Development To Overcome Achlorhydria Effect

Impaired absorption of weakly basic drugs in patients with reduced gastric acidity can lead to loss of efficacy of the therapeutic agent. Hence, a robust formulation which can provide adequate exposure in achlorhydric patients is imperative to achieve the desired efficacy. In this report, formulation development of a weakly basic Merck compound A is described. Compound A shows lower solubility at higher pH and thus is prone to reduced exposure under conditions of achlorhydria, as the compound's solubility increases only in environments of less than pH 2. Several formulations with or without an acidifier were developed and characterized by in vitro dissolution and in gastric pH modified dog model to assess their bioperformance in high gastric pH conditions. To predict the bioperformance of these formulations in humans, a dissolution based absorption model was developed and validated against the observed PPI-interaction data in the clinic and the gastric pH-adjusted dog data. An additional absorption model was developed to allow for incorporation of the dog PK data to provide translation of preclinical to clinical exposure. Based on the in vitro dissolution, in silico absorption modeling and preclinical in vivo data, a citric acid-based formulation (F2) was selected for a human pharmacokinetic study. This study showed that exposures from F2 were not meaningfully different in the presence of proton pump inhibitor (PPI) as compared to non-PPI, thus confirming that the F2 formulation was successful in overcoming the achlorhydria effect. These efforts also highlighted that the complementary use of in vitro/in silico/in vivo (IVISIV) tools may be a helpful strategy in the development of formulations to overcome the achlorhydria effect and achieve adequate exposure in patients with high gastric pH.

PPIs Are Associated with Risk for Bacterial Gastroenteritis

Normal gastric acidity protects against development of bacterial gastroenteritis (GE); achlorhydric patients have higher risk for GE. Limited data

Gastric antisecretory drug-induced achlorhydria causes decreases in serum vitamin B12 levels in patients with zollinger-ellison syndrome (ZES): A prospective study

Markedly decreased acid secretion is known to decrease vitamin B~2 absorption. However, it is controversial whether prolonged treatment with potent gastric antisecretory drugs will caused decreased serum vitamin Btz levels (Bt2 levels). This could be a potentially important problem in conditions such as GERD or ZES, requiring continuous long-term treatment. In a previous study we reported that B~z levels, but not serum folate levels, determined at one time correlated inversely with the length of omeprazole treatment in patients with ZES. In the present study to provide insights into the possible effects of long-term acid suppression on B~2 levels in a given patient, we have analyzed sequential results from 68 patients with ZES who were followed for at least 5 years. Patients had yearly B~ levels and determinations of acid secretory control taken one hour before the next dose of antisecretory drug. The mean age of the patients was 55 ± 1 yrs, there were 22 females and 46 males, and the total duration of gastric antisecretory treatment was 14 _+0.5 yrs. Fifty-two patients were being treated with omeprazole (mean time ± 1SEM=5 ± 1 yrs) and 17 patients with histamine Hz inhibitors. The mean initial B~2 level was 439 ± 21 pg/ml (normal=165-1000 pg/ml) and the last Ba2 level, a mean of 6.3 ± 1.2 yrs later, was 427 ± 21 pg/ml, was not significantly different. The patients had a mean basal acid output of 25 ± 2 mEq/h and M An of 54-+ 4 mEq/h. The patients' acid secretory rate on antisecretory drug for each of the last 5 years was reviewed and 21/68 (30%) had complete achlorhydria defined as no basal acid secretion during each of the last 3 years. The B~ levels over the 6.3 ± 1.1 yrs from the first to the last Bl~ level in the achlorhydric patients showed a highly significant (p=0.001) decrease from 419 _+ 38 to 305 ± 24 pg/ml. In contrast, for the 47 patients without complete achlorhydria over a 6.3 ± 1.2 year period of antisecretory drug treatment, the B~2 levels did not change significantly (447 ± 26 vs 480 ± 35 pg/ml). A significantly higher proportion (p=0.002) [18/21 (86%)] of patients with complete achlorhydria had a decrease in their B~2 levels over this time period compared to the patients without achlorhydria [22/47 (47%)]. These results demonstrate that profound acid inhibition, which occurs in 32% of patients with ZES, lead to a highly significant decrease in serum vitamin levels over a 6-year period. In other studies > 80% of patients with GERD treated long-term with potent antisecretory drugs also have such acid hyposecretion that hypergastrinemia develops. These results suggest that in patients with such conditions as ZES or GERD undergoing prolonged daily treatment with potent gastric acid suppressants such as omeprazole or lansoprazole, routine monitoring of B~2 levels should be considered.

Gastric as well as Duodenal Biopsies May Be Useful in the Investigation of Iron Deficiency Anaemia

Background: Iron absorption is known to be impaired in the setting of gastric achlorhydria, yet gastric atrophy is not usually considered an aetiological factor for iron deficiency anaemia. We aimed to determine the prevalence of achlorhydric gastric atrophy in patients with iron deficiency and no identifiable source of gastrointestinal blood loss, and to assess whether gastric, as well as duodenal, biopsies should be routinely performed in these patients. Patients: Forty-one consecutive patients with iron deficiency anaemia and no specific gastrointestinal symptoms or evidence of a bleeding lesion on faecal occult blood testing or upper gastrointestinal or colonic endoscopy. Methods: As well as routine duodenal biopsies, samples were taken from gastric corpus and antrum for evidence of gastric atrophy. Achlorhydria was considered to be present if plasma gastrin measured on a sample obtained with the patient fasting was over 200 ng/1. Serum was tested for intrinsic factor and gastric parietal cell antibodies. Results: Haemoglobin concentrations ranged from 4.1 to 10.9 g/dl. Eight (20%) of the 41 patients had corpus-predominant or generalized atrophy and high plasma gastrin levels, of whom six had serum intrinsic factor and/or gastric parietal cell antibodies: two also had Giardia lamblia organisms in duodenal biopsies. Four other patients (10%) had villous atrophy of the duodenum. Conclusions: As well as confirming the importance of seeking coeliac disease in patients with iron deficiency anaemia, our results suggest that achlorhydric gastric atrophy is also a common association. Gastric biopsies should be taken in patients with no other explanation for anaemia. The finding of Giardia organisms in two achlorhydric patients, with a possible contributory role, suggests that duodenal biopsies should be obtained even if serum coeliac-related antibodies are absent.

Absorption of the oral iron preparation ferrous acetyl transferrin in achlorhydric patients: a pilot study

Gastric acid secretion is an important factor in iron absorption in humans. Chronic corporal atrophic gastritis (CAG) is a pathologic condition characterized by oxyntic mucosal atrophy and hypochlorhydria that may cause unexplained iron-deficiency states that are difficult to treat with standard oral iron therapy. The molecule ferrous acetyl transferrin (FAT) displays a high degree of homology with human transferrin and may thus use the same transferrin receptor-mediated iron absorption system on ileal and duodenal crypts. We tested this oral iron preparation in nine achlorhydric CAG patients to evaluate its absorption in the total absence of gastric acid secretion. FAT 40 mg was administered twice daily by mouth for 7 days. Blood samples for determination of serum iron, ferritin, and transferrin levels were collected and calculation of the transferrin saturation index was performed before drug administration at 8 am on the first day of the study (when patients had been fasting), on day 8 (13 hours after the last dose of FAT), and on day 15 (7.5 days after the last dose of FAT). Serum iron levels on day 15 (median, 65 μg/dL) were significantly increased over pretreatment levels (median, 32.5 μg/dL) and over the levels observed on day 8 (median, 47.0 μg/dL). A similar increase in median transferrin saturation index was observed (17.52% on day 15 vs 7.33% before treatment and 11.53% on day 8). Serum transferrin levels decreased significantly from day 8 (median, 281.5 mg/dL) to day 15 (median, 264.5 mg/dL). The study shows that in CAG patients with achlorhydria, iron in the form of FAT administered by mouth can be absorbed, resulting in increases in serum iron level and transferrin saturation index, during short-term treatment.

Effect of omeprazole and feeding on plasma gastrin in patients with achlorhydria.

The mechanism of hypergastrinaemia during omeprazole therapy is unclear, but is generally assumed to be entirely a consequence of acid suppression. However, direct stimulation of G cells by omeprazole could also be a factor. In order to further investigate the mechanism of omeprazole-induced hypergastrinaemia, we have studied the effects of the drug on plasma gastrin in patients with achlorhydria, in whom altered acid secretion cannot play a role. We estimated fasting and peptone meal stimulated plasma gastrin in nine patients (seven female) with pernicious anaemia and achlorhydria, before and on the final day of 4 weeks' dosing with omeprazole 40 mg daily. Despite the high fasting gastrin concentrations, the peptone meal produced a further elevation in plasma gastrin concentrations, median gastrin concentrations rising from 1500 ng/L (range 225-10,875 ng/L) to 3750 ng/L (range 585-15,600 ng/L) post-prandially (P = 0.004). The median post-prandial rise in plasma gastrin at this initial visit was 44% (3-260%), and the median time interval until plasma gastrin concentrations returned to fasting levels was 120 min (range 10- > 150 min). There was a significant negative correlation between fasting plasma gastrin concentrations and the percentage increase in plasma gastrin levels in response to meal stimulation (Spearman correlation coefficient -0.79, P = 0.01). Fasting plasma gastrin concentrations were similar pre-omeprazole (median 1950 ng/L, range 240-16,500 ng/L) and post-omeprazole (median 1500 ng/L, range 315-7650 ng/L). Likewise, peak plasma gastrin concentrations were also similar pre-omeprazole (median 2700 ng/L, range 585-16,500 ng/L) and post omeprazole (median 3420 ng/L, range 720-11,250 ng/L). (i) The hyperplastic G cell mass in patients with pernicious anaemia can be further stimulated by a peptone meal, which causes a prolonged rise in plasma gastrin concentrations. (ii) There is a negative correlation between fasting plasma gastrin concentrations and the percentage increase in plasma gastrin levels in response to meal stimulation. (iii) Omeprazole has no effect on plasma gastrin in achlorhydric patients, which is consistent with its hypergastrinaemic effect being entirely secondary to acid inhibition.

24-Hour intragastric acidity and plasma gastrin after omeprazole treatment and after proximal gastric vagotomy in duodenal ulcer patients

The relationship between suppressed gastric acidity and the increase in plasma gastrin levels after pharmacological and surgical treatment of peptic ulcer disease were compared in this study. Eight patients with chronic duodenal ulcer and referred for proximal gastric vagotomy were studied. 24-hour intragastric acidity and plasma gastrin levels were investigated in the same patients on three consecutive occasions: preentry without any treatment; after 4 weeks of administration of 20 mg of omeprazole daily, and 4–6 months after proximal gastric vagotomy. Intragastric acidity was slightly more reduced by omeprazole (94%) than after proximal gastric vagotomy (78%), with no difference found during the day or night with either. Plasma gastrin levels increased slightly more after proximal gastric vagotomy [284% (median, 2120 pmol · h/L; range, 733–2831 pmol · h/L)] than after omeprazole administration [186% (median, 1586 pmol · h/L; range, 495–2573 pmol · h/L)]. There is strong evidence that the increased plasma gastrin concentration following omeprazole treatment is caused by the reduced intragastric acidity. The slight increase in plasma gastrin concentration following proximal gastric vagotomy despite a lesser reduction in intragastric acidity may be the result of additional effects on gastrin release by the vagotomy. Both treatments resulted in a modest increase in plasma levels of gastrin that were far below the gastrin levels observed in achlorhydric patients, e.g., patients with pernicious anemia.

Is the gastrin response to secretin provocation a function of antral G-cell mass? Results in the hypergastrinemia of acid hyposecretion.

Some patients with hypergastrinemic achlorhydria may have false-positive secretin provocation as an exaggeration of the normal gastrin response to secretin, presumably related to an increased, or more responsive, antral G-cell mass. To test this hypothesis, we reviewed our experience with secretin provocation in normogastrinemic subjects with presumed normal antral G-cell mass (normal--17, duodenal ulcer--13) and in patients with hypergastrinemia related to changes in antral G-cells (vagotomy--5, hypochlorhydria--7, achlorhydria--10). Basal serum gastrin (mean +/- SEM) was progressively higher for each group; normal (42 +/- 3 pg/ml), duodenal ulcer (53 +/- 4 pg/ml), vagotomy (226 +/- 54 pg/ml), hypochlorhydria (346 +/- 92 pg/ml), achlorhydria (844 +/- 100 pg/ml). On selective analysis of only those with gastrin rises, significant differences (p less than 0.05) in peak gastrin change were found between achlorhydria (93 +/- 21 pg/ml) compared with all other groups and between hypochlorhydria (40 +/- 12 pg/ml) versus normal (6 +/- 1 pg/ml). Linear regression in these responders showed a significant correlation (p less than 0.001) between basal gastrin and peak gastrin change after secretin. There were no false-positive secretin provocation tests, but four achlorhydric patients had gastrin rises greater than 100 pg/ml, whereas no patient in the other categories had rises above 90 pg/ml. Our results support the concept that patients with hypergastrinemic achlorhydria tend to have greater G-cell responsiveness to secretin provocation, which may account for the false-positive results in some such patients.

Nitrate- and nitrite-reducing bacteria in the achlorhydric stomach.

The microbial composition of samples of gastric juice from eight achlorhydric patients was determined by aerobic and rigorously anaerobic culture techniques. Bacteria from 16 genera were commonly isolated, but representatives of only three genera, (streptococci, neisseriae and haemophili) were isolated from every patient. Nitrate and nitrite were both reduced by veillonellae, haemophili, staphylococci, corynebacteria, lactobacilli, flavobacteria and fusobacteria, but the potential rate of nitrate reduction by suspensions of veillonellae, Haemophilus parainfluenzae and members of the Enterobacteriaceae were up to ten times more rapid than the rate of nitrite reduction. Conversely, although all Neisseria spp. reduced nitrite only some strains reduced nitrate. Streptococci did not reduce nitrate. Streptococcus sanguis reduced nitrite when grown with haematin; other streptococci did not reduce nitrite. Bacterial nitrate and nitrite reduction were active over the pH range 6-8, similar to the pH range of the achlorhydric stomach. From a knowledge of the composition of the bacterial flora and their potential rates of nitrate and nitrite reduction under prevailing conditions, predictions were made about the tendency of nitrite to accumulate during nitrate reduction. Studies of the transient accumulation of nitrite by mixed cultures of H. parainfluenzae and N. subflava were consistent with these predictions. Haemophili and veillonellae could be responsible for the accumulation of nitrite in the gastric juice of some patients, whereas streptococci and neisseriae would tend to remove nitrite from the stomach as rapidly as it formed.

Nitrite accumulation during anaerobic nitrate reduction by binary suspensions of bacteria isolated from the achlorhydric stomach.

Binary suspensions of bacteria isolated from the gastric juice of achlorhydric patients were used to determine conditions which favour nitrite accumulation during nitrate reduction. Suspensions of Veillonella parvula and Haemophilus parainfluenzae accumulated nitrite during nitrate reduction in the absence of nitrite-reducing Neisseria subflava or Streptococcus sanguis. The maximum concentration of nitrite that transiently accumulated decreased predictably as the ratio of nitrite-removing bacteria to nitrite-accumulating bacteria increased. This ratio, but more importantly the bacterial density, determined the duration of nitrite accumulation. These results are correlated with the previously reported tendency of nitrite to accumulate in the gastric juice of hypogammaglobulinaemic and pernicious anaemic patients, and with the extremely high incidence of gastric cancer in the two groups.

Gastric cancer risk in achlorhydric patients. A long-term follow-up study.

Achlorhydria, determined by the augmented histamine test, is the functional expression of the most severe atrophic gastritis and is followed by a 4- to 6-fold increased risk of gastric cancer, as we found 5 cancers in 114 patients after a mean observation period of 8.4 years. The cancers developed from 1 to 17 years after achlorhydria diagnosis--three cases after more than 9 years. The study showed no difference in gastric cancer risk between patients with and without pernicious anaemia. Spontaneous achlorhydria is the late result of atrophic gastritis, which should be regarded the premalignant condition. The development of gastric cancer from pharmacologically reduced acid secretion must be regarded as highly hypothetical, since this is not followed by atrophic gastritis.

Bacterial Colonization and Nitrite Concentration in the Achlorhydric Stomachs of Patients with Primary Hypogammaglobulinaemia or Classical Pernicious Anaemia

The degree and type of bacterial colonization was similar in achlorhydric patients with either severe primary hypogammaglobulinaemia or classical pernicious anaemia. This suggests that antibodies do not play a significant part in controlling the gastric flora in achlorhydric patients. The nitrite concentration in gastric juice was higher in the hypogammaglobulinaemia patients, raising the possibility that these patients may have very high levels of nitrite-derived mutagenic compounds in their gastric juice. This may account for the high incidence of gastric cancer in these patients.

Effect of meal on serum parathyroid hormone and calcitonin: possible role of secretin.

Purified secretin infused in an estimated physiological dose caused an increase in serum immunoreactive PTH (iPTH) and calcitonin (iCT) in man. Ingestion of a gastric acid-stimulating test meal, a procedure known to increase endogenous secretin, caused increases in serum iPTH and plasma iCT in normal subjects. Ingestion of antacid with the test meal blunted the increase in both iPTH and iCT. Ingestion of the test meal by pernicious anemia patients with achlorhydria caused no stimulation of either serum iPTH or plasma iCT. Therefore, based on the observations that 1) exogenous secretin stimulated iPTH and iCT, 2) an acid-stimulating test meal is known to stimulate endogenous secretin release (4), 3) the test meal increased both serum iPTH and iCT in normal man, an effect nullified by simultaneous antacid ingestion, and 4) the test meal caused no increase in either iPTH or iCT in achlorhydric patients, we conclude that endogenous secretin possibly mediates this effect of test meal and, therefore, may play a physiological role in modulating the secretion of PTH and CT.

Release of Plasma Pancreatic Polypeptide in Achlorhydric Patients after Intravenous Infusion of Gastric Inhibitory Polypeptide

In order to evaluate whether gastric inhibitory polypeptide (GIP) could be responsible for the postprandial fall in serum gastrin previously observed in patients with achlorhydria, 7 achlorhydric patients were given 100 ml Lipomul (66 g triglycerides) on one occasion, and 5 of these patients were later given a 30-min intravenous infusion of porcine GIP in a dose of 1 microgram/kg. Following the Lipomul ingestion, serum gastrin fell significantly, whereas no effect on serum gastrin was seen during the intravenous GIP infusion. A small, but significant release of serum insulin was seen shortly after starting the GIP infusion, together with a significant and more sustained release of plasma pancreatic polypeptide (PP). It is concluded that GIP does not lower the serum gastrin levels in achlorhydric patients, but that GIP might participate in the intestinal phase of the PP release.

Duodenal acid is without importance for the postprandial PP release.

In six healthy subjects duodenal infusion of 30 ml 100 mmol/1 HCl caused a slight, but significant, release of plasma pancreatic polypeptide (PP), whereas infusion of 3 g dried cattle bile dissolved in 30 ml distilled water did not affect basal plasma PP levels. In another group of six healthy subjects the postprandial plasma PP release was not affected by inhibition of the gastric H+ secretion by the H2-receptor antagonist ranitidine. Finally, the meal-induced plasma PP release in a group of 19 achlorhydric patients did not differ significantly from that seen in 11 normal controls. We therefore conclude that, although duodenal acidification may elicit release of plasma PP, gastric H+ secretion seems to be without importance for the postprandial plasma PP release.

Effect of gastrin on fasting and postprandial plasma GIP release in man.

In order to evaluate the mechanism behind the augmented postprandial gastric inhibitory polypeptide (GIP) release seen in patients with achlorhydria and hypergastrinemia, 8 healthy subjects were given a liquid test meal on three different days. On 1 day the meal was preceded by ranitidine (H2 receptor antagonist) to block the gastric H+ secretion. On another day the meal was also preceded by ranitidine, but on this occasion gastrin was infused intravenously during the first hour in order to induce hypergastrinemia. On a third day the meal was given along to serve as a control. Finally, 6 healthy fasting subjects were given a 1-hour intravenous infusion of gastrin after pretreatment with ranitidine. Plasma GIP responses after the meal on the days with ranitidine alone or together with the gastrin infusion did not differ significantly from that found on the control day. When gastrin was infused in the fasting state, no effect was seen on the basal GIP levels. Thus, neither exogenous gastrin nor achlorhydria seems to affect the plasma GIP release, and it appears more likely that a rapid gastric emptying rate can account for the augmented GIP response found in achlorhydric patients.