Bioavailability of aspirin in fasted and fed states of a novel pharmaceutical lipid aspirin complex formulation.

Dyspeptic symptoms are common with aspirin and clinicians frequently recommend that it be taken with food to reduce these side effects. However, food can interfere with absorption, especially with enteric-coated aspirin formulations. We evaluated whether food interferes with the bioavailability of a new, pharmaceutical lipid-aspirin complex (PL-ASA) liquid-filled capsule formulation. In this randomized, open label, crossover study, 20 healthy volunteers fasted for ≥ 10 h and then randomized as either "fasted", receiving 650 mg of PL-ASA, or as "fed", with a standard high-fat meal and 650 mg of PL-ASA 30 min later. After a washout of 7 days, participants crossed over to the other arm. The primary outcome was comparison of PK parameters of the stable aspirin metabolite salicylic acid (SA) between fasted and fed states. Mean age of participants was 36.8 years and 55% were male. The ratios for the fed to fasted states of the primary SA PK parameters of AUC0-t and AUC0-∞ were 88.7% and 88.8% respectively, with 90% confidence intervals between 80 and 125%, which is consistent with FDA bioequivalence guidance. Mean peak SA concentration was about 22% lower and occurred about 1.5 h later in the fed state. Food had a modest effect on peak SA levels and the time required to reach them after PL-ASA administration, but did not impact the extent of exposure (AUC) compared with intake in a fasted state. These data demonstrate that PL-ASA may be co-administered with food without significant impact on aspirin bioavailability.Clinical Trial Registration:http://www.clinicaltrials.gov Unique Identifier: NCT01244100.

Pharmacokinetic/pharmacodynamic assessment of a novel, pharmaceutical lipid-aspirin complex: results of a randomized, crossover, bioequivalence study.

Aspirin (acetylsalicylic acid, ASA) can lead to gastrointestinal mucosal injury through disruption of its protective phospholipid bilayer. A liquid formulation of a novel pharmaceutical lipid-aspirin complex (PL-ASA) was designed to prevent this disruption. We sought to determine the pharmacokinetic (PK)/pharmacodynamic (PD) characteristics of PL-ASA compared with immediate release aspirin (IR-ASA). In this active-control crossover study, 32 healthy volunteers were randomized to receive 1 of 2 dose levels (a single dose of 325 mg or 650 mg) of either PL-ASA or IR-ASA. After a 2-week washout period between treatment assignments, subjects received a single dose of the alternative treatment, at the same dose level. The primary objectives of the study were to assess, for PL-ASA and IR-ASA at 325 mg and 650 mg dose levels, PK and PD bioequivalence, and safety, over a 24-h period after administration of both drugs. PK parameters were similar for PL-ASA and IR-ASA, and met FDA-criteria for bioequivalence. Regarding PD, both drugs also showed Cmin TxB2 values below 3.1 ng/mL (cut-off associated with decreased cardiovascular events) and > 99% inhibition of serum TxB2 ( ≥ 95% inhibition represents the cut-off for aspirin responders) along with similar results in several secondary PK/PD parameters. There were no serious adverse events or changes from baseline in vital signs or laboratory values in either of the 2 treatment groups. PL-ASA's novel liquid formulation has similar PK and PD performance compared with IR-ASA, supporting functional and clinical equivalence. These data coupled with the improved gastric safety of PL-ASA suggest that this novel formulation may exhibit an improved benefit-risk profile, warranting evaluation in future trials.Clinical trial registration: http://www.clinicaltrials.gov . Unique Identifier: NCT04008979.

Endoscopic comparison of gastroduodenal injury with over-the-counter doses of new fast-dissolving ibuprofen and paracetamol formulations: a randomized, placebo-controlled, 4-way crossover clinical trial.

BACKGROUND: While gastrointestinal (GI) effects of standard ibuprofen and N-acetyl-p-aminophenol (APAP) have been reported, upper GI injury following treatment with fast-dissolving (FD) formulations of these analgesics has not been investigated. We evaluated upper GI effects of over-the-counter doses of 2 FD ibuprofen products and 1 FD-APAP product. METHODS: In a randomized, placebo-controlled, endoscopist-blinded, 4-way crossover study, 28 healthy subjects received FD ibuprofen 2×200 mg liquid capsules 3 times daily (TID), ibuprofen 2×200 mg tablets TID, FD-APAP 2×500 mg tablets 4 times daily (QID), and placebo 2×500 mg tablets QID for 7 days. The primary end point was gastric mucosal damage assessed by endoscopy using the Lanza scale: 0=normal stomach or proximal duodenum, 1=mucosal hemorrhages only, 2=1 or 2 erosions, 3=numerous (3-10) erosions, and 4=large number of erosions (>10) or ulcer. Secondary end points included duodenal mucosal damage (Lanza scale); gastroduodenal mucosal injury, classified as present (gastric and/or duodenal endoscopy score ≥2) or absent (gastric and/or duodenal endoscopy score <2); and number of hemorrhages, erosions, and ulcers counted separately in the stomach and duodenum. RESULTS: Significantly greater gastric mucosal injury was observed after treatment with both ibuprofen products vs FD-APAP (p<0.0001 and p=0.0095, respectively). FD-APAP showed no difference from placebo (p=0.4794). The odds of having an incidence of gastroduodenal mucosal injury were over 6 times greater from FD ibuprofen liquid capsule treatment (odds ratio [OR]=6.19, 95% confidence interval [CI]: 1.60, 23.97) and over 3 times greater from ibuprofen tablet treatment (OR=3.19, 95% CI: 0.8, 12.74) vs FD-APAP. CONCLUSION: Treatment with 2 ibuprofen products was associated with significant gastric mucosal injury. Of the 4 treatments studied, FD ibuprofen liquid capsules had the highest risk of incidence of gastroduodenal mucosal injury. Treatment with FD-APAP did not induce any clinically or statistically significant gastroduodenal mucosal injury.

All-natural nitrite and nitrate containing dietary supplement promotes nitric oxide production and reduces triglycerides in humans.

There is an emerging paradigm that certain foods promote nitric oxide (NO) production from the stepwise reduction of nitrate to nitrite to NO, providing an endothelium independent source of bioactive NO. We hypothesize that a unique formulation containing nitrate-rich beetroot along with Hawthorn berry shown to have a robust nitrite reductase activity would improve NO status in humans and modify cardiovascular risk factors. The trial was conducted at the Houston Institute for Clinical Research in Houston, Texas. Inclusion criteria for this double-blinded, placebo-controlled study were patients older than 40 years with 3 or more of the following cardiovascular risk factors: hypertension, obesity, hyperlipidemia, smoking, sedentary, family history of cardiovascular disease, and diabetes. Subjects were instructed to take either the NO dietary supplement called Neo40 Daily® or placebo twice daily on an empty stomach for 30 days. Patients taking the NO dietary supplement twice a day for 30 days led to a significant increase in both plasma nitrite (P < .01) and nitrate (P < .0001), indicating an increase in systemic NO availability. There was a statistically significant reduction in 72% of patients with elevated triglycerides (>150 mg/dL) after 30 days compared with their starting levels before taking the NO dietary supplement (168 ± 17 mg/dL vs 232 ± 19 mg/dL, P = .02). The strategy of formulating a combination of natural products and botanicals chosen specifically for their NO activity shows promise in restoring NO homeostasis in human subjects at risk for cardiovascular disease for use as a dietary supplement.

Low-dose aspirin-induced ulceration is attenuated by aspirin-phosphatidylcholine: a randomized clinical trial.

OBJECTIVES: Relative contributions of local and systemic mechanisms of upper gastrointestinal (GI) injury following aspirin are unknown. Studies suggest that aspirin's GI risk is age related and that gastroprotection may be needed at therapy initiation. We determined acute gastroduodenal erosion and ulceration following low-dose aspirin and aspirin-phosphatidylcholine complex (PL2200) in subjects at risk of aspirin ulcers. METHODS: In a randomized, single blind, multicenter active-controlled study, we compared upper GI damage of aspirin and PL2200 in healthy subjects (n=204, ages 50-74 years) following 7 days of oral 325 mg once daily, immediate release aspirin or PL2200. RESULTS: Overall, 42.2% of aspirin-treated subjects developed multiple erosions and/or ulcers, whereas 22.2% treated with PL2200 developed such damage (P=0.0027). Gastroduodenal ulcers were observed in 17.6% of aspirin-treated compared with 5.1% of subjects treated with PL2200 (P=0.0069). CONCLUSIONS: Low-dose aspirin induced a surprisingly high incidence of acute gastroduodenal ulcers in at risk subjects, highlighting that aspirin's upper GI risk begins early and may require gastroprotection. Local mechanisms of GI protection are important as aspirin's preassociation with surface-active phospholipids significantly reduced mucosal damage. PL2200 may be an attractive alternative or complement to proton pump inhibitors in older patients who are at risk of aspirin-induced ulceration. Longer-term studies assessing clinical GI events are desirable to confirm the clinical GI safety profile of PL2200.

Guidelines for prevention of NSAID-related ulcer complications.

Guidelines for clinical practice are intended to indicate preferred approaches to medical problems as established by scientifically valid research. Double-blind, placebo-controlled studies are preferable, but compassionate use reports and expert review articles are used in a thorough review of the literature conducted through Medline with the National Library of Medicine. Only when data that will not withstand objective scrutiny are available is a recommendation identified as a consensus of experts. Guidelines are applicable to all physicians who address the subject, without regard to specialty training or interests, and are intended to indicate the preferable, but not necessarily the only, acceptable approach to a specific problem. Guidelines are intended to be flexible and must be distinguished from standards of care, which are inflexible and rarely violated. Given the wide range of specifics in any health-care problem, the physician must always choose the course best suited to the individual patient and the variables in existence at the moment of decision. These guidelines were developed under the auspices of the American College of Gastroenterology by a committee of experts in the field, reviewed by its Practice Parameters Committee, and approved by the Board of Trustees. The recommendations of these guidelines are therefore considered valid at the time of production based on the data available. New developments in medical research and practice pertinent to each guideline will be reviewed at an established time and indicated at publication to assure continued validity. Owing to the volume of new data on the subject of non-steroidal anti-inflammatory drug (NSAID)-related injury to the upper gastrointestinal tract, i.e., the advent of cyclooxygenase (COX)-2 inhibitors, new data on interactions between these agents, as well as traditional NSAIDs, with aspirin and H. pylori, it was elected by the Committee to confine these guidelines to upper gastrointestinal (GI) injury and to leave post-duodenal injury as the subject of a separate guideline.

A multicenter, randomized, double-blind, active-comparator, placebo-controlled, parallel-group comparison of the incidence of endoscopic gastric and duodenal ulcer rates with valdecoxib or naproxen in healthy subjects aged 65 to 75 years.

BACKGROUND: Compared with nonselective NSAIDs, cyclooxygenase (COX)-2-selective inhibitors have been associated with a lower incidence of gastroduodenal ulcers (in short-term endoscopic studies) and ulcer complications (in long-term trials). OBJECTIVE: The aim of this study was to compare the effects of valdecoxib 20 mg BID and naproxen 500 mg BID, administered for 6.5 days, on the upper gastrointestinal (UGI) mucosa of healthy older subjects (aged 65-75 years) as assessed by UGI endoscopy. METHODS: In this multicenter, double-blind, active-comparator, placebo-controlled, parallel-group study, eligible subjects who were free of NSAID or COX-2-selective inhibitor use for 2 weeks and who had normal UGI mucosa (mucosal grading score of 0, based on endoscopic evaluation of both the stomach and duodenum) were randomized. Serologic testing for Helicobacter pylori antibodies was conducted at baseline. No antiulcer medications were permitted. The primary end point was the incidence of gastroduodenal ulcers (gastric or duodenal mucosal grading score of 7, as indicated by any lesion with unequivocal depth > or =3 mm in diameter) after 6.5 days of blinded treatment with valdecoxib, naproxen, or placebo. Secondary end points were incidence of gastric ulcers, duodenal ulcers, and gastroduodenal erosions/ulcers, and the incidence of > or =11 gastroduodenal erosions/ulcers. All documented adverse events were self-reported by subjects or were observed by investigators. RESULTS: Sixty-one patients were randomized to receive valdecoxib, 60 to naproxen, and 60 to placebo. Mean (SD) subject age was 68.8 (3.25) years in the valdecoxib group, 68.6 (2.76) years in the naproxen group, and 68.6 (3.14) years in the placebo group (P = NS). In the valdecoxib and naproxen groups, 47.5% and 58.3% of subjects were female, respectively, compared with 56.7% of the placebo group (P = NS). Valdecoxib and placebo were associated with significantly lower incidences of gastroduodenal ulcers than naproxen (1.6% [1 gastroduodenal ulcer/61 patients] and 1.7% [1/59], respectively, vs 22.0% [13/59]; P < 0.001). Compared with naproxen, both valdecoxib and placebo were associated with significantly lower incidences of gastric (1.6% [1/61] and 1.7% [1/59] vs 15.3% [9/59]; both, P < 0.03) and duodenal ulcers (0% [0/61] and 0% [0/59] vs 8.5% [5/59]; both,P < 0.03). In all cases, the incidence of ulcers with valdecoxib was not significantly different from placebo. Results were similar for any erosions/ulcers, and when analyzed by H pylori status. The number of adverse events was low in each group. CONCLUSION: In these healthy older subjects (aged 65-75 years), valdecoxib 20 mg BID was associated with a significantly lower rate of gastroduodenal, gastric, and duodenal ulcers than naproxen 500 mg BID, even after 6.5 days of therapy.

A randomized, placebo-controlled, 6-month study of once-weekly alendronate oral solution for postmenopausal osteoporosis.

OBJECTIVE: This study evaluated the overall safety and tolerability of once-weekly (OW) alendronate 70 mg oral solution (OS) versus OW placebo OS. METHODS: Postmenopausal, osteoporotic women were enrolled at 51 centers in the United States in a 6-month double-blind, randomized trial. Patients were randomized (1:1) to OW alendronate 70 mg OS or placebo OS. The primary end point was the proportion of patients reporting any upper gastrointestinal (UGI) adverse event (AE) at 6 months. Secondary end points included mean percentage change in urinary N-telopeptide of type I human collagen (NTx) and serum bone-specific alkaline phosphatase (BSAP) at 6 months. RESULTS: Initially, 454 women were enrolled; 392 (86.3%) completed the study. The mean (SD) age was 65.2 (10) years, and the mean (SD) time since menopause was 19.1 (12) years. The proportion of patients experiencing any UGI AE was significantly higher with alendronate OS (23.7%) compared with placebo solution (15.3%), with a treatment difference of 8.3% (95% CI, 0.8%-15.8%; P = 0.024). The proportion of patients experiencing any esophageal AE was 4.0% with alendronate and 3.0% with placebo (treatment difference, 1.0% [95% CI, -2.7% to 4.8%]). In addition, 4.5% of alendronate and 8.7% of placebo patients discontinued the study due to any clinical AE, and 3.3% of alendronate and 1.8% of placebo patients discontinued due to a UGI AE (difference, 1.5% [95% CI, -1.5% to 4.4%]). Alendronate OS produced significantly greater reductions in both NTx and BSAP than placebo (differences, -47.5% and -38.7%, respectively [both, P < 0.001]). CONCLUSIONS: In this 6-month study, patients receiving OW alendronate 70 mg OS had a higher rate of UGI AEs than placebo patients. However, rates of serious UGI AEs, discontinuations due to UGI AEs, and esophageal AEs were similar between groups. UGI AEs in the study were generally mild to moderate in severity and did not result in treatment discontinuation. In addition, OW alendronate 70 mg OS significantly reduced biochemical markers of bone turnover.

An assessment of the management of acute bleeding varices: a multicenter prospective member-based study.

OBJECTIVE: Bleeding from esophagogastric varices is a major complication of portal hypertension. Despite recent practice guidelines for the management of bleeding esophageal or gastric varices, the widespread application of these measures by gastroenterologists has not been evaluated. The purpose of this study was to continue the concept of membership-based research within diverse practice settings by expanding the American College of Gastroenterology (ACG) GI Bleeding Registry to assess the management and outcome of acute variceal bleeding. METHODS: All ACG members (domestic and foreign) were invited to participate during the 1997 Annual Fall meeting and by mail. Data were collected over 12 months. Information obtained included physician training, practice demographics, patient demographics, disease etiology and severity, clinical presentation, medications, transfusion needs, therapy, complications, and rebleeding within 2 wk. RESULTS: A total of 93 physicians/centers (79.6% domestic, 26.9% university and affiliated, 3.2% Veterans Affairs) participated. Complete demographic data were available for 725 of the 741 patients enrolled with index bleeding. The median age of these 725 patients was 52 yr and 73.3% were male. The most common single etiology for portal hypertension was cirrhosis (94.3%). The most common causes of cirrhosis were alcohol (56.7%), hepatitis C virus (30.3%), and hepatitis B virus (10.0%). Hemodynamic instability was noted in 60.7% of the patients (22.3% tachycardic, 9.7% orthostatic, 28.7% hypotensive). Index interventions included banding (40.8%; median five bands), sclerotherapy (36.3%), combination banding/sclerotherapy (6.2%), octreotide (52.6%; median 3 days), balloon tamponade (5.5%), transjugular intrahepatic portosystemic shunt (TIPS) (6.6%), liver transplantation (1.1%), surgical shunt (0.7%), and embolization (0.1%). Transfusion of packed red blood cells, fresh frozen plasma, and platelets was given in 83.4%, 44.7%, and 24.6% of the patients with index bleeding, respectively. Median transfusion was four units of packed red blood cells, three units of fresh frozen plasma, and 1.5 units of platelets. Rebleeding occurred in 92 of the 741 patients (12.6%) at a median of 7 days (mean 11 days) and was treated by banding (18.5%; median six bands), sclerotherapy (30.4%), octreotide (63%; median 2 days), balloon tamponade (17.4%), TIPS (15.2%), and surgical shunt (3.3%). Complications from the index bleeding and rebleeding within 2 wk included ulceration (2.6%, 2.2%), aspiration (2.4%, 3.3%), medication side effects (0.8%, 0%), dysphagia (2.3%, 0%), odynophagia (2.2%,0%), encephalopathy (13%,17.4%), and hepatorenal syndrome (2.4%, 2.2%), respectively. After the index bleeding, 46.2% of patients were treated with beta-blockers and 8.2% with nitrates. The majority of patients with index bleeding had Child's B cirrhosis (61.5%). Patients presenting with recurrent bleeding had mostly Child's B (46.7%) or Child's C cirrhosis (44.6%). The overall short-term mortality after index bleeding was 12.9%. CONCLUSIONS: Acute variceal hemorrhage occurs more often in patients with Child's B and C cirrhosis. Endoscopic banding is the most common single endoscopic intervention. Adjunctive pharmacotherapy is prevalent acutely and after stabilization. Both morbidity and mortality may be lower than reported in previous studies.

14 day endoscopy study comparing risedronate and alendronate in postmenopausal women stratified by Helicobacter pylori status.

OBJECTIVE: Bisphosphonates are effective treatment for osteoporosis but have been associated with gastrointestinal (GI) mucosal injury. This study compared the incidence of gastric ulcers after treatment with risedronate, a pyridinyl bisphosphonate, or alendronate, a primary amino bisphosphonate, in healthy postmenopausal women stratified by Helicobacter pylori status. METHODS: Subjects were randomized to receive risedronate 5 mg (n = 318) or alendronate 10 mg (n = 317) daily for 14 days. Endoscopy and evaluator-blind assessments of the esophageal, gastric, and duodenal mucosa were performed at baseline and on Days 8 and 15. RESULTS: Overall, gastric ulcers > or = 3 mm were observed in 18 (6.0%) of 300 evaluable subjects in the risedronate group and 36 (12.1%) of 297 in the alendronate group during treatment (p = 0.013). On Day 8, the incidences of gastric ulcers in the risedronate and alendronate groups were 3.6% and 6.6%, respectively (p = 0.133), and on Day 15, they were 3.3% and 8.7% (p = 0.008). The incidence of gastric ulcers was not affected by H. pylori status. Mean gastric endoscopy scores at Days 8 and 15 were significantly lower in the risedronate group than in the alendronate group (p < 0.001). Mean esophageal and duodenal endoscopy scores were similar in the 2 groups at Days 8 and 15. When the treatment groups were combined, gastric endoscopy scores were significantly higher among H. pylori negative than H. pylori positive subjects at Days 8 and 15 (p < 0.05). Upper GI adverse events were reported by 18 (5.7%) subjects in the risedronate group (19 events) and 28 (8.8%) subjects in the alendronate group (32 events). Symptoms did not predict the presence of mucosal damage. CONCLUSION: Risedronate was associated with a significantly lower incidence of gastric ulcers than alendronate. H. pylori infection did not increase the incidence of bisphosphonate related gastric ulcers. The findings from this 14 day study in healthy volunteers support the hypothesis that bisphosphonates may differ from one another in their potential to produce upper GI mucosal damage.

The upper GI safety and tolerability of oral alendronate at a dose of 70 milligrams once weekly: a placebo-controlled endoscopy study.

OBJECTIVE: Alendronate (10 mg daily) has been shown in long term clinical trials to be an effective treatment for postmenopausal osteoporosis. A weekly dosing regimen of alendronate is preferred by both patients and physicians, as it has the potential to provide greater convenience and enhance compliance. In a 1-yr clinical trial, alendronate (70 mg once weekly) was equally efficacious and at least as well tolerated as the 10-mg daily dose in the treatment of postmenopausal osteoporosis, despite the higher unit dosage required. We conducted a randomized, double blind, placebo- and active-controlled endoscopy study to confirm the results of this clinical trial. We hypothesized that mean endoscopic gastric erosion scores would be similar in subjects receiving alendronate (70 mg once weekly) and those receiving a placebo. METHODS: Two hundred seventy-seven subjects (90 men and 187 women) were randomized to one of three treatment groups: 1) alendronate (70 mg once weekly) for 10 wk (N = 126), 2) placebo (once weekly) for 10 wk (N = 126), or 3) placebo (once weekly) for 10 wk followed by aspirin (650 mg q.i.d.) for the last week as the positive control (N = 25). Esophagogastroduodenoscopy was performed 5 to 7 days after the last dose of alendronate or matching placebo. RESULTS: The mean gastric erosion scores (Lanza scale) were similar in subjects given alendronate (70 mg once weekly) and those given a placebo (0.32 vs 0.35, respectively; 95% CI for difference = -0.22-0.16, p = 0.75), whereas scores in both groups were significantly lower than in those given aspirin (3.09; p < 0.001). Endoscopic gastroduodenal ulcers occurred in no alendronate (0%), two placebo (1.7%), and five aspirin (23.8%) subjects. The mean erosion scores in the esophagus and duodenum of alendronate and placebo subjects were also similar. The incidences of upper GI symptoms were similar in the alendronate and placebo subjects and did not suggest a relationship with endoscopic lesions. CONCLUSIONS: Alendronate (70 mg once weekly) was not associated with any increase in endoscopic lesions in the upper GI tract relative to a placebo.

Gastrointestinal adverse effects of bisphosphonates: etiology, incidence and prevention.

The bisphosphonate class of drugs are now utilized extensively in the treatment of patients with osteoporosis and Paget's disease. Gastrointestinal (GI) adverse effects, especially those associated with esophageal injury, have been of increasing concern to clinicians. Studies in humans and animals have shown that the mucosal erosion and ulceration seen with bisphosphonates is a result of direct contact with these agents. Numerous endoscopic studies in healthy volunteers and postmenopausal women have also demonstrated the potential of bisphosphonates to cause stomach and duodenal ulcers. However, serious GI adverse events have not been noted in several large efficacy trials. Esophageal injury has for the most part been avoided by appropriate administration instructions, and gastroduodenal injury appears to be an acute phenomenon not associated with significant complications, except in certain high-risk situations, for example in the presence of existing distal esophageal disease or motility disorders, or with concurrent use of nonsteroidal anti-inflammatory drugs or anticoagulants. From the standpoint of GI safety, the bisphosphonates are well tolerated and not associated with serious adverse events.

Effects of Aluminum/Magnesium Hydroxide and Calcium Carbonate on Esophageal and Gastric pH in Subjects with Heartburn.

This single-blind crossover trial compared the effects of single oral doses of two antacids on esophageal and gastric pH in subjects with heartburn. Gastric and esophageal pH were assessed in 83 subjects from 1 h before to 4 h after a refluxogenic meal. Subjects received two chewable tablets of a high-potency aluminum/magnesium hydroxide [Al(OH)3/Mg(OH)2] formulation (Mylanta Double-Strength(TM)) or a calcium carbonate [CaCO3] formulation (Tums E-X(TM)), or placebo 1 h after the meal. Both antacid formulations significantly increased esophageal pH, as compared with placebo. Onset of action was faster with the Al(OH)3/Mg(OH)2 formulation than with the CaCO3 in 41 subjects, slower in 13 subjects, and identical in 29 subjects. Area under the esophageal pH--time curves after dosing were significantly greater for Al(OH)3/Mg(OH)2 than for CaCO3 (p < 0.05) and significantly greater for CaCO3 than for placebo (p < 0.05). The duration of Al(OH)3/Mg(OH)2 action in the esophagus was 82 min and 60 min for CaCO3 (p < 0.05). In the stomach, only Al(OH)3/Mg(OH)2 increased gastric pH compared with placebo. After ingestion of calcium carbonate, gastric pH usually remained at or below placebo values, a finding consistent with a calcium carbonate-induced "acid rebound." The duration of Al(OH)3/Mg(OH)2 action in the stomach was 26 min. These findings demonstrate the efficacy and relative superiority of this particular aluminum/magnesium hydroxide formulation compared with the calcium carbonate preparation at increasing esophageal and gastric pH. However, the magnitude and duration of action of both antacids on esophageal pH, in contrast to minimal effects on gastric pH, suggest strongly that the lower esophagus is the primary site of antacid activity in relief of heartburn.