Proton pump inhibition. An effective, safe approach to GERD management.

Prescribed worldwide to treat gastroesophageal reflux disease (GERD), the proton pump inhibitors (PPIs) not only relieve acid reflux-related symptoms more rapidly than standard-dose or high-dose histamine2 receptor antagonists but also accelerate the rate of esophageal healing. Five PPIs--omeprazole, esomeprazole, lansoprazole, rabeprazole, and pantoprazole--are currently labeled by the Food and Drug Administration. These agents share a common mechanism of action and rarely exhibit clinically important interactions with other hepatically metabolized medications or pH-dependent drugs. Except for lingering concern about their long-term use in Helicobacter pylori-positive patients, the PPIs produce relatively few adverse effects when administered for the short or long term. Because primary care physicians are generally the first to treat patients with GERD, they may find it helpful to expand their knowledge of the pharmacologic effects of the PPIs. With an eye toward this end, Dr Berardi presents a cogent overview of PPI pharmacodynamics, pharmacokinetics, efficacy, drug interactions, and safety.

Therapeutic options for GERD: what's the correct approach?

GERD occurs as a clinical spectrum of symptoms and complications. The primary goal of GERD therapy is to lessen esophageal exposure to acid, thus relieving symptoms, promoting mucosal healing, and preventing relapse and complications. Because GERD tends to recur after therapy is stopped, patients with healed erosive esophagitis usually require long-term maintenance therapy. Pharmacists have an important role in advising patients about therapeutic options for GERD, including lifestyle modifications and the proper use of nonprescription and prescription medications.

A critical evaluation of proton pump inhibitors in the treatment of gastroesophageal reflux disease.

Proton pump inhibitors (PPIs) are the drugs of choice for treating gastroesophageal reflux disease (GERD). Their superiority to histamine2 receptor antagonists (H2RAs), cisapride, and sucralfate is directly related to their potent and prolonged suppression of gastric acid. The PPIs provide the most rapid relief of GERD symptoms and esophageal healing when compared with standard- or high-dose H2RAs or cisapride. Their superiority over H2RAs has also been demonstrated when used in maintaining esophageal healing and symptom relief. The cost effectiveness of standard-dose PPIs in the treatment of GERD has been well documented. High-dose PPI therapy may benefit patients with atypical GERD symptoms and may also be cost effective. Four PPIs are available in the United States: omeprazole, lansoprazole, rabeprazole, and pantoprazole. All 4 PPIs, when used in recommended dosages, are very effective for the acute and chronic treatment of GERD and demonstrate similar short- and long-term safety profiles. Subtle differences appear to exist, some of which are based on data obtained in vitro or from healthy volunteer studies and others on trends or relatively minor differences observed in selective clinical trials. In most cases, experience has not yet confirmed the clinical importance of these potential differences. The selection of a preferred PPI for a hospital or managed care formulary will most likely be based on the acquisition cost of the drug.

Evaluation of omeprazole, lansoprazole, pantoprazole, and rabeprazole in the treatment of acid-related diseases.

OBJECTIVE: To review the comparative efficacy and safety of the proton pump inhibitors (PPIs)--omeprazole, lansoprazole, pantoprazole, and rabeprazole--in the management of acid-related diseases. DATA SOURCES: English-language journal articles retrieved from a MEDLINE search from 1990 to the present using these index terms: proton pump inhibitors, omeprazole, lansoprazole, pantoprazole, rebeprazole, and each of the acid-related diseases. STUDY SELECTION: Clinical trials and pertinent review articles that discussed the pharmacology, pharmacokinetics, efficacy, and safety of PPIs in the management of acid-related disease. DATA EXTRACTION: By the authors. DATA SYNTHESIS: PPIs are substituted benzimidazoles that inhibit gastric acid secretion by covalently binding to the proton pump (H+/K+ ATPase). All undergo extensive hepatic metabolism and conjugation. The four agents differ in their metabolism by and effects on specific hepatic enzymes and thus in their ability to interact with other medications. PPIs are important agents used for eradicating Helicobacter pylori, in treating peptic ulcer disease, gastroesophageal reflux disease, Zollinger-Ellison syndrome, and upper gastrointestinal bleeding, and for preventing acid aspiration. Short-term side effects of the four agents are similar. The long-term safety of pantoprazole and rabeprazole appears similar to that of omeprazole and lansoprazole. Pantoprazole, which is in the final stages of approval for marketing in the United States, will be available in both an oral and injectable formulation. CONCLUSION: Based on superior efficacy profiles, PPIs are the drugs of choice in managing patients with peptic ulcer disease, gastroesophageal reflux disease, and Zollinger-Ellison syndrome. The decision to select one PPI versus another is most likely to be based on the agents' acquisition costs, formulations, FDA-labeled indications, and overall safety profiles. Intravenous or parenteral pantoprazole may become the preferred antisecretory agent for patients unable to take oral medications (e.g., critically ill patients and those with Zollinger-Ellison syndrome).

Use of zinc tolerance test and 24-hour urinary zinc content to assess oral zinc absorption.

OBJECTIVES: The sensitivity of one plasma and two urinary methods to assess zinc absorption after oral dosing were compared over the dose range of 10 to 100 mg. METHODS: Eleven healthy subjects participated in this four-way crossover design study. After an overnight fast, the subjects received a single oral dose of zinc acetate corresponding to 10, 25, 50, or 100 mg of elemental zinc. Plasma zinc concentrations were measured at baseline (pre-zinc administration) and hourly intervals post-zinc administration for 9 hours. Urine was collected for 24 hours prior to and for 24 hours after zinc administration. During this 48-hour period, subjects consumed an isocaloric, caffeine-free diet containing 18 mg of elemental zinc per day. RESULTS: The area under the plasma zinc concentration versus time curve (PZAUC) increased linearly with doses between 10 and 50 mg, then flattened out. By contrast, urinary zinc excretion was approximately linear with doses in the 25 to 100 mg range, but no differences were observed in urinary zinc excretion after doses of 10 and 25 mg. CONCLUSIONS: Plasma zinc concentration is a useful method of evaluating oral zinc absorption from doses of 10 to 50 mg. Urinary zinc excretion is an alternative method of assessing zinc absorption, particularly when doses of 50 to 100 mg of elemental zinc are administered.

Effect of intragastric pH on the absorption of oral zinc acetate and zinc oxide in young healthy volunteers.

BACKGROUND: Zinc is an important nutrient and is necessary to maintain a multitude of physiologic processes. Mineral supplements that provide physiologic doses of zinc may be used when dietary zinc is inadequate. Zinc is also used in pharmacologic doses to treat zinc deficiency and diseases such as Wilson's disease and acrodermatitis enteropathica. Although there are several zinc salts available, they are not equal in solubility, which is thought to be a key factor in zinc absorption. Moreover, the solubility of the salts is affected by pH, which may vary between pH 1 and 7 under various physiologic conditions in the stomach. The objectives of this 2-way 4-phase crossover study were to evaluate the effect of high (> or = 5) and low (< or = 3) intragastric pH on the absorption of zinc from the acetate and oxide salt in young healthy volunteers. METHODS: After a 9-hour fast, 10 healthy subjects (5 males and 5 females) were given a single oral dose of 50 mg of elemental zinc as the acetate or the oxide salt and under either high or low intragastric pH conditions. In all phases, a Heidelberg capsule pH detector-transmitter was used to continuously monitor intragastric pH. During the high pH phases, single oral doses of famotidine 40 mg oral suspension were administered before the zinc to raise the intragastric pH above 5. Intragastric pH < or = 3 was maintained in the low pH phases. RESULTS: The mean plasma zinc area under the curve for zinc acetate at low pH (AL), zinc acetate at high pH (AH), zinc oxide at low pH (OL), and zinc oxide at high pH (OH) were 524, 378, 364, and 66 micrograms x h/dL, respectively. The highest zinc plasma concentrations occurred with the acetate salt at a low intragastric pH, while the lowest plasma concentrations occurred with the oxide salt at a high intragastric pH. The importance of pH to the dissolution of these salts was verified by in vitro tests. Twenty-four-hour urinary zinc excretion was the highest for the AL phase and lowest for the OH phase. CONCLUSION: This study indicates that intragastric pH and salt solubility-dissolution are important in the oral absorption of zinc. Specifically, the oxide salt is not an appropriate zinc salt to use in those patients with elevated intragastric pH.

Intravenous histamine H2-receptor antagonists and parenteral nutrition: patterns of use.

Patterns of use of i.v. histamine h2-receptor antagonists (H2RAs) and parenteral nutrient solutions in patients receiving both given separately or as admixtures were studied. Consecutive adult patients at a university teaching hospital were placed in an "admixed group," consisting of all those who received an i.v. H2RA as a parenteral nutrient solution additive, or a "nonadmixed group," consisting of all those who received an i.v. H2RA and a parenteral nutrient solution as separate infusions. Data were collected for many variables, including interruptions in therapy, route and method of administration, indication for use, total daily dose of H2RA, patient demographic data, and any additional anti-ulcer drugs prescribed. A total of 128 patients received 158 regimens of therapy, 60 regimens in the admixed group and 98 in the nonadmixed group. There was at least one interruption in i.v. H2RA therapy for 32% of the admixed-group regimens and 33% of the nonadmixed-group regimens. When an interruption occurred, patients in the admixed group missed an average of 40% of their daily H2RA dose, compared with 53% for the nonadmixed group. No alternative anti-ulcer drug was given on 10 (23%) of the 42 days when intensive care patients had an interruption in H2RA therapy, versus 33 (55%) of the 60 days of H2RA interruption for non-intensive-care patients. Interruptions in i.v. H2RA therapy occurred more frequently when the H2RA was a component of the nutrient solution than when it was given as a separate infusion. Supplemental anti-ulcer therapy was typically not provided during interruptions in H2RA therapy, regardless of the method of administration.

Comparative evaluation of the hemodynamic effects of oral cimetidine, ranitidine, and famotidine as determined by echocardiography.

STUDY OBJECTIVE: To evaluate the influence of cimetidine, ranitidine, famotidine, and placebo on cardiac performance as determined by echocardiography. DESIGN: Randomized, four-way crossover trial. SETTING: Echocardiography laboratory at a university hospital. PARTICIPANTS: Twelve healthy volunteers. INTERVENTIONS: Volunteers received oral treatment with placebo, cimetidine 800 mg, ranitidine 300 mg, or famotidine 40 mg once/day for 7 days. MEASUREMENTS AND MAIN RESULTS: On the seventh day of each study phase, 2 hours after administration of the final dose, each subject underwent cardiac echocardiography and Doppler flow studies. No significant differences were detected in ejection fraction, peak flow velocity, or percentage fractional shortening among the treatment phases. A large degree of variability in ejection fraction was observed, with some subjects experiencing marked decreases. CONCLUSION: The histamine-2 (H2)-receptor antagonists had no effect on the hemodynamic variables as determined by echocardiography. The variability in the hemodynamic response may in part explain the conflicting results reported in the literature. It also raises the question as to whether certain individuals are more sensitive to the potential cardiac effects of H2-receptor antagonists.

The effect of competitive and non-linear plasma protein binding on the stereoselective disposition and metabolic inversion of ibuprofen in healthy subjects.

The stereoselective disposition and metabolic inversion of ibuprofen were studied in 12 healthy subjects under conditions of competitive and non-linear plasma protein binding. Each subject received each of four oral treatments according to a Latin-square design: 300 mg R(-)-ibuprofen, 300 mg S(+)-ibuprofen, 300 mg R(-)(-)+300 mg S(+)-ibuprofen, and 300 mg R(-)(-)+600 mg S(+)-ibuprofen. For a given treatment, the partial clearance of S(+)-ibuprofen was greater than that of R(-)-ibuprofen for all stereoisomeric drug species. Likewise, the unbound partial clearances of S(+)-ibuprofen were greater for most stereoisomeric drug species. There was also less difference among treatment groups when partial clearances were referenced to unbound as opposed to total plasma concentrations of enantiomer. The unbound intrinsic clearance and fractional inversion of R(-)-ibuprofen were unchanged across the four treatments, and chiral inversion was systemic, averaging 69%. In conclusion, stereoselective differences exist for the partial and composite clearances of R(-)- and S(+)-ibuprofen even when corrected for differences in plasma protein binding. However, differences among treatment groups for a particular elimination pathway are largely due to ibuprofen's non-linear binding.

In vivo interaction of ketoconazole and sucralfate in healthy volunteers.

Absorption of ketoconazole is impaired in subjects with an increased gastric pH due to administration of antacids, H2-receptor antagonists, proton pump inhibitors, or the presence of hypochlorhydria. Sucralfate could provide an attractive alternative in patients receiving ketoconazole who require therapy for acid-peptic disorders. Twelve healthy human volunteers were administered a single 400-mg oral dose of ketoconazole in each of three randomized treatment phases. In phase A, ketoconazole was administered orally with 240 ml of water. In phase B, ketoconazole and sucralfate (1.0 g) were administered simultaneously with 240 ml of water. In phase C, ketoconazole was administered with 240 ml of water 2 h after administration of sucralfate (1.0 g) orally with 240 ml of water. A 680-mg oral dose of glutamic acid hydrochloride was administered 10 min prior to and with each dose of ketoconazole, sucralfate, or ketoconazole plus sucralfate. Simultaneous administration of ketoconazole and sucralfate led to a significant reduction in the area under the concentration-time curve and maximal concentration of ketoconazole in serum (78.12 +/- 12.20 versus 59.32 +/- 13.61 micrograms.h/ml and 12.34 +/- 3.07 versus 8.92 +/- 2.57 micrograms/ml, respectively; P < 0.05). When ketoconazole was administered 2 h after sucralfate, the observed ketoconazole area under the concentration-time curve was not significantly decreased compared with that of ketoconazole alone. The time to maximal concentrations in serum and the ketoconazole elimination rate constant were not significantly different in any of the three treatment phases. In patients receiving concurrent administration of ketoconazole and sucralfate, doses should be separated by at least 2 h.

pH-related changes in the absorption of dipyridamole in the elderly.

The bioavailability of dipyridamole, a poorly soluble weak base, was evaluated in 11 healthy, older subjects (> or = 65 years), 6 with a low fasting gastric pH (control) and 5 with a fasting gastric pH > 5 (achlorhydric), in a randomized, crossover design. Subjects received 50 mg dipyridamole as a single oral dose both with and without pretreatment with 40 mg famotidine (control subjects) or 1360 mg glutamic acid HCl (achlorhydric subjects). Gastric pH was monitored by Heidelberg radiotelemetric capsule. Gastric emptying of 99mTc-radiolabeled orange juice was measured. Gastric pH appeared to be a primary determinant in dipyridamole absorption in the elderly. Elevated gastric pH resulted in compromised dipyridamole absorption compared to low-gastric pH conditions in all cases. The administration of glutamic acid hydrochloride to achlorhydric subjects prior to the dose of dipyridamole corrected for the decreased Cmax and AUC(0-36) exhibited in achlorhydric subjects without pretreatment. Tmax and ka were slower in achlorhydrics, although pretreatment with glutamic acid HCl tended to normalize these parameters. Based on these results, it would be beneficial for achlorhydrics to take glutamic acid hydrochloride prior to taking dipyridamole and other medications which need a low gastric pH for complete absorption. The administration of 40 mg famotidine was successful in elevating the gastric pH to > 5 in all subjects and maintained it at > 5 for at least 3 hr in all subjects tested.(ABSTRACT TRUNCATED AT 250 WORDS)

High viscosity hydroxypropylmethylcellulose reduces postprandial blood glucose concentrations in NIDDM patients.

The ability of high viscosity hydroxypropylmethylcellulose (HPMC) to reduce postprandial glucose concentrations was assessed in patients with non-insulin-dependent diabetes (NIDDM) and healthy volunteers. The study design consisted of a two-way crossover, single-dose administration of 10 g prehydrated high viscosity HPMC, or placebo, with a standard carbohydrate-rich meal. In patients with NIDDM, HPMC reduced blood glucose concentrations at the 60-, 75-, 90-, 120- and 150-min sampling intervals, with an average reduction in the maximum postprandial blood glucose concentration, Cmax, of 24% (P < 0.05). The time at which the maximum concentration was reached, Tmax, remained unchanged. The area under the blood concentration versus time plot, AUC0-6h, was reduced by an average of 15% (P < 0.05). The blood concentration profile of insulin followed that of glucose. Concentrations were significantly lower than in the placebo phase only at the 120-min sampling time, while pharmacokinetic parameters (Cmax, Tmax and AUC0-6h) were unchanged. These results suggest that alterations in the blood glucose profile are mediated by luminal events rather than by changes in hormonal response. In contrast to the NIDDM patients, neither the pharmacokinetic parameters nor the blood glucose concentrations at specific sampling times were significantly affected by the co-administration of HPMC in healthy volunteers. Overall, the results of this study suggest that HPMC may be a useful adjunct in the management of NIDDM.

High-molecular-weight hydroxypropylmethylcellulose. A cholesterol-lowering agent.

BACKGROUND: We assessed the efficacy of a high-molecular-weight hydroxypropylmethylcellulose (K8515) as a cholesterol-lowering agent, the dose-response profile of its action, and the ability of adult subjects to tolerate its ingestion at effective doses. METHODS: These studies were conducted at the Clinical Research Center of The University of Michigan Hospitals, Ann Arbor. Efficacy was assessed in 10 normal and 12 mildly hyperlipidemic subjects in double-blind, randomized crossover trials of 1 and 2 weeks' duration, respectively. The dose-response profile was studied in 12 mildly hypercholesterolemic subjects in a nonrandomized control trial with doses given in escalating order. Tolerance was assessed by a questionnaire of adverse effects and bowel movement habits in all subjects. RESULTS: We found that 10 g of K8515 ingested in a prehydrated form three times a day with meals lowered total cholesterol levels by an average of 1.45 mmol/L (56 mg/dL) (32%) in normal subjects within 1 week. In two studies in subjects with mildly elevated cholesterol levels (with entry levels ranging from 5.35 mmol/L [207 mg/dL] to 6.70 mmol/L [260 mg/dL]), average reductions of 1.00 mmol/L (39 mg/dL) (18%) and 1.15 mmol/L (45 mg/dL) (20%) were observed within the same period. The effect was primarily due to a reduction in low-density lipoprotein cholesterol levels. Low-density lipoprotein levels in normal subjects were an average of 1.10 mmol/L (42 mg/dL) (38%) lower after a week of 10 g of K8515 three times a day with meals, and in the two studies in subjects with mild hyperlipidemia, the reductions in low-density lipoprotein levels after 1 week were 0.95 mmol/L (37 mg/dL) (23%) and 1.05 mmol/L (40 mg/dL) (25%). Although there was a tendency for high-density lipoprotein cholesterol levels to decrease, this was significant only in normal subjects. Decreases in cholesterol levels were not accompanied by any rise in triglyceride levels. Dose-response studies in those with mildly elevated cholesterol levels indicated that it is possible to achieve a 15% decrease in low-density lipoprotein cholesterol levels within 1 week at a dose of 6.7 g three times a day, with minimal adverse effects. CONCLUSION: These results suggest a role for high-molecular-weight hydroxypropylmethylcellulose in the clinical treatment of mild hypercholesterolemia.

Peptic ulcer disease: an update.

Peptic ulcers can develop when there is an imbalance between gastric acid secretion and gastroduodenal mucosal defense. Investigators are looking at the role of Helicobacter pylori in the development of peptic ulcer disease; eradication of the microorganism may reduce recurrence. Approved drug therapy includes H2-receptor antagonists, omeprazole, sucralfate, and antacids. Recommendations for treating and counseling patients are provided.

Stereoselective, competitive, and nonlinear plasma protein binding of ibuprofen enantiomers as determined in vivo in healthy subjects.

The plasma protein binding and competitive inhibition parameters of R(-)- and S(+)-ibuprofen were determined in vivo in 12 healthy subjects. Subjects participated in a 4 x 4 Latin square design in which oral solutions of drug were administered as 300 mg R(-)-ibuprofen, 300 mg S(+)-ibuprofen, 300 mg R(-)- + 300 mg S(+)-ibuprofen, and 300 mg R(-)- + 600 mg S(+)-ibuprofen. Unlabeled ibuprofen enantiomers were quantitated using a stereospecific reversed-phase HPLC assay, and plasma protein binding experiments were performed using radiolabeled 14C-enantiomers and an ultrafiltration method at 37C. At therapeutic drug concentrations, the protein binding of each enantiomer was greater than 99%. Furthermore, the binding of ibuprofen enantiomers was stereoselective and mutually competitive, as well as nonlinear. The bound-free data were fitted to a model in which the non-linearity of plasma protein binding and competition between enantiomers for binding sites could be accommodated. There were substantial differences in the affinity of ibuprofen enantiomers for protein binding sites (RP2 = 0.358 +/- 0.185 vs. SP2 = 0.979 +/- 0.501 micrograms/ml; mean +/- SD) but no differences in their binding capacity (RP1 = 160 +/- 86 vs. SP1 = 161 +/- 63 micrograms/ml). Although statistically significant, the differences in competitive inhibition parameters were more modest (SKI = 0.661 +/- 0.363 vs. RKI = 0.436 +/- 0.210 micrograms/ml). As a result, the intrinsic binding (i.e., P1/P2) of R(-)-ibuprofen was greater than S(+)-ibuprofen, and the unbound fraction was significantly greater for S-enantiomer vs. R-enantiomer after a given dose of R-ibuprofen or racemate.

Upper gastrointestinal pH in seventy-nine healthy, elderly, North American men and women.

Gastric and duodenal pH levels were measured in 79 healthy, elderly men and women (mean +/- SD = 71 +/- 5 years) under both fasted and fed conditions using the Heidelberg capsule technique. The pH was recorded for 1 hr in the fasted state, a standard liquid and solid meal of 1000 cal was given over 30 min, then the pH was measured for 4 hr postprandially. Results are given as medians and interquartile ranges: fasted gastric pH, 1.3 (1.1-1.6); gastric pH during the meal, 4.9 (3.9-5.5); fasted duodenal pH, 6.5 (6.2-6.7); and duodenal pH during the meal, 6.5 (6.4-6.7). Although fasted gastric pH, fasted duodenal pH, and duodenal pH during the meal differ statistically from those observed in young subjects, the differences are not expected to be clinically significant in terms of drug absorption for the majority of elderly subjects. Following a meal, gastric pH decreased from a peak pH of 6.2 (5.8-6.7) to pH 2.0 within 4 hr in most subjects. This rate of return was considerably slower than in young, healthy subjects. Nine subjects (11%) had a median fasted gastric pH > 5.0, and in five of these subjects the median pH remained > 5.0 postprandially. In this group, drugs and dosage forms which require an acidic environment for dissolution or release may be poorly assimilated.

Absorption of flurbiprofen in the fed and fasted states.

The oral absorption of flurbiprofen, an antiinflammatory nonsteroidal compound, was compared in the fasted vs the fed state. When ingested as an aqueous solution of the sodium salt, absorption kinetics followed a monoexponential pattern in half of the subjects and a bimodal pattern with a lag time before the onset of the second phase of absorption in the other half of the subjects. When ingested in the free acid form as a tablet either with water (fasted state) or with water 15 min after 330 ml of apple juice (fed state), flurbiprofen absorption was always bimodal, and the lag time before the onset of the second phase was shown to be dependent on the gastric emptying time (r = 0.623, P less than 0.01). The gastric emptying times were significantly longer when the drug was administered in the fed state (average GET = 57 min in the fasted state and 102 min in the fed state; P less than 0.01). These results suggest that gastric emptying effects are one important way in which absorption of drugs can be affected by meal intake.