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Biomedical subjects

J I Isenberg

Publications and source records attributed to J I Isenberg.

At least 55 records · Page 3Linked to original sources
PubMed1991

Effect of basal gastric acid secretion on the pharmacodynamics of ranitidine.

Twelve patients with inactive ulcer disease were administered placebo and ranitidine via bolus and continuous intravenous infusions, at doses ranging from 50 every 8 h, to 12.5 mg/h for 24 h. Gastric acid was collected for 20 min each h for 24 h, and ranitidine serum concentrations were measured approximately every 2 h, during each of the six study periods. Cosinor analysis of gastric acid secretion during placebo treatment revealed a significant circadian rhythm in all subjects. Mesor acid output ranged from 1.7 to 11.6 mmol/h (mean 5.6 +/- 2.8 mmol/h) and the amplitude ranged from 0.7 to 6.5 mmol/h (mean 2.8 +/- 1.6 mmol/h). Peak acid output (acrophase) occurred at 10 p.m. +/- 3 h. A pharmacodynamic model, relating ranitidine serum concentration to hourly acid secretion, was derived, which incorporated the circadian change in basal acid output. Data for this fractional response model included basal acid secretion--as determined by time of day, measured acid secretion, and associated serum ranitidine concentration. The 50% inhibitory concentration (IC50) for ranitidine ranged from 10-75 ng/ml, with a mean of 44 ng/ml. The variation in IC50 and in basal acid secretion combined to produce a wide variation in the pharmacodynamic response to ranitidine. The model-predicted serum concentrations, required to maintain acid secretion at 0.1 mmol/h, ranged from 250 to 1550 ng/ml, at the time of peak evening acid secretion. Despite a constant degree of acid inhibition by ranitidine during the day, higher serum concentrations are required during times of peak acid output to maintain adequate suppression of hydrogen ion secretion.

Adult↗
PubMed1990

Bolus or intravenous infusion of ranitidine: effects on gastric pH and acid secretion. A comparison of relative efficacy and cost.

STUDY OBJECTIVE: To compare the effects of intravenous bolus injection of ranitidine, continuous intravenous infusion of ranitidine, and placebo on gastric pH, acid secretion, and plasma ranitidine concentration during a 24-hour period, and to determine by survey the use, delivery methods, and costs of histamine H2-receptor antagonists in intensive care units. DESIGN: Double-blind, Latin-square randomized, prospective measurement of the gastric pH, acid output, and plasma ranitidine concentration over 24 hours in response to six treatment regimens in 12 patients with inactive duodenal ulcer. Eight regional hospitals were surveyed to obtain information on the use of histamine H2-receptor antagonists. INTERVENTIONS: Gastric acid secretion, pH, and plasma ranitidine were monitored for 24 hours on six separate days in response to placebo, intravenous bolus injection of ranitidine (50 mg every 8 hours and 75 mg every 12 hours), and continuous intravenous infusion of ranitidine (75, 150, and 300 mg every 24 hours). MEASUREMENTS AND MAIN RESULTS: Intravenous infusions were significantly more effective than bolus injections. After bolus injections, hourly gastric pH values fluctuated widely, from 7.6 to 1.6, whereas during continuous infusion of 150 mg and 300 mg, hourly pH values were 3.8 or greater. The gastric pH was greater than 4.0 in 75% +/- 5% and 83% +/- 6% of determinations done during continuous intravenous infusion of 150 mg and 300 mg, respectively. Fluctuations in the plasma ranitidine concentration corresponded with changes in gastric pH and acid secretion. Histamine H2-receptor antagonists were prescribed for about 75% of patients in intensive care units and were most commonly administered by bolus rather than infusion (5:1); the cost was approximately +40 per day less by infusion. CONCLUSIONS: On the basis of both efficacy and cost, intermittent bolus injections should be discontinued and replaced by continuous intravenous infusion in hospitalized patients requiring treatment with histamine H2-receptor antagonists. If ranitidine is used, either 150 mg or 300 mg administered as a 24-hour continuous infusion is most effective.

Adult↗
PubMed1990

Human duodenal mucosal bicarbonate secretion. Evidence suggesting active transport under basal and stimulated conditions.

When the proximal duodenum of animals or humans is perfused with isoosmolar NaCl, bicarbonate enters the luminal effluent. In addition, duodenal bicarbonate output is stimulated by luminal acidification and prostaglandins of the E class. The hypothesis that in vivo human duodenal bicarbonate transport persists in the absence of a plasma-to-lumen bicarbonate gradient and therefore is probably an active transport process was tested. In healthy subjects, a 4-cm segment of the proximal duodenum was isolated from gastric and pancreaticobillary secretions. Net duodenal bicarbonate secretion remained similar to basal levels during luminal perfusion with either 24 or 32 mM bicarbonate (each isoosmolar with plasma by the addition of NaCl). In addition, peak increases in acid-induced bicarbonate outputs with luminal perfusion of 154 mM NaCl and 32 mM NaHCO3 (+122 mM NaCl) were similar. Moreover, prostaglandin E2-stimulated bicarbonate secretion with perfusion of 154 mM NaCl and 32 mM NaHCO3 (+122 mM NaCl) was similar. It was concluded that in humans, proximal duodenal mucosal bicarbonate transport remains unaltered in the absence of a plasma-to-lumen bicarbonate gradient at rest and after stimulation with HCl or prostaglandin E2. These observations suggest that human proximal duodenal bicarbonate secretion involves active transport.

Adult↗
PubMed1990

Proximal duodenal prostaglandin E2 release and mucosal bicarbonate secretion are altered in patients with duodenal ulcer.

Proximal duodenal mucosal bicarbonate production is impaired in patients with duodenal ulcer disease. Because prostaglandins of the E class increase human proximal duodenal bicarbonate secretion, this study tested the hypothesis that endogenous prostaglandin E2 production is defective in patients with duodenal ulcer. Ten patients, five with active and five with inactive duodenal ulcer disease, were studied along with 10 normal volunteers. The proximal 4 cm of duodenum, the bulb, was isolated and continuously perfused with 154 mmol/L NaCl. Basal bicarbonate secretion was measured for 30 minutes. The test segment was then acidified with a physiological amount of HCl (2 mmol over 5 minutes), and acid-stimulated bicarbonate secretion was measured by pH/PCO2 and back-titration for 55 more minutes. Prostaglandin E2 was measured in the effluents by a radioimmunologic assay validated by gas chromatography-mass spectrometry. Compared with the normal subjects after luminal acidification, the duodenal ulcer patients had significantly greater PGE2 release and decreased total 1-hour bicarbonate output. The peak 5-minute acid-stimulated bicarbonate responses were not significantly different between the duodenal ulcer patients and normal subjects. After luminal acidification, PGE2 output remained elevated in the duodenal ulcer patients but returned promptly to basal in the normal subjects. Furthermore, the ratio of bicarbonate secreted to the amount of PGE2 released was significantly less in the ulcer patients. These findings suggest that patients with duodenal ulcer disease have an impaired mucosal bicarbonate response to endogenous PGE2. The increased acid-stimulated PGE2 response in duodenal ulcer patients suggests a compensatory phenomenon in response to the diminished mucosal bicarbonate production.

Bicarbonates↗
PubMed1990

Should safety concerns with available ulcer treatment influence drug selection?

With the identification of the parietal cell receptors for gastric acid secretion coupled with the introduction of cimetidine in 1977, treatment of acid-peptic diseases was transformed from empiric therapy to an approach based on a clearer understanding of human physiology. Today, physicians are confronted with an array of antiulcer agents that differ within their drug class (e.g., the H2-receptor antagonists) as well as in their mechanisms of action (e.g., neutralize acid, alter mucosal defensive factors, or suppress acid secretion). With minor exceptions, the clinical efficacy of the available antiulcer drugs can be regarded as comparable. Thus, the safety profile becomes the next consideration when choosing among similarly effective drug products. Of the available antiulcer agents, the H2-receptor antagonists as a class have an excellent safety profile, as indicated by more than 25 years of cumulative clinical experience and postmarketing surveillance. Important safety issues with currently available antiulcer drugs, i.e., H2-receptor antagonists, sucralfate, prostaglandin E analogues, and the newest antiulcer agent, omeprazole, are reviewed to place them into perspective for the clinician.

Antacids↗
PubMed1990

Effect of enprostil on the gastroduodenal mucosa of healthy volunteers.

Enprostil is a synthetic dehydro-prostaglandin E2 with gastroduodenal ulcer-healing and mucosal-protective properties. One hundred and three healthy volunteers were randomized to receive capsules of enprostil 35 micrograms b.d. (the clinically recommended dose), enprostil 70 micrograms b.d., or placebo b.d. All underwent endoscopic assessment of the gastroduodenal mucosa, scored using a 0-4 scale, at baseline and on Days 3, 7, 14, 21 and 28 of dosing. Mean and median maximum scores demonstrated a dose response, and the mean maximum scores were statistically significantly higher for both enprostil groups on each endoscopy day when compared with placebo. The majority of enprostil-treated subjects had petechial haemorrhages. The proportion of volunteers with small white-based mucosal breaks (erosions) was significantly higher for the fundus in the enprostil 70-microgram group on Days 21 and 28 when compared with placebo, but there were no significant differences between treatment groups for any area on the other study days. The 70-microgram dose was associated with significantly more gastrointestinal adverse events than the 35-microgram dose, which was similar to placebo. There were no significant differences between groups for large white-based mucosal breaks (ulcers). We conclude that oral enprostil produced gastric mucosal petechial haemorrhages, primarily in the fundus of the stomach. Gastric mucosal petechial haemorrhages are probably without clinical significance because they are very common in the general population (10-15%) and do not progress to erosions and ulcers.

Double-Blind Method↗
PubMed1990

Human duodenal mucosal bicarbonate secretion--physiological and clinical aspects.

Over the past few years, we have addressed some of the components that regulate human duodenal bicarbonate secretion (DBS) using a technique for the isolation of a 4-cm duodenal segment from gastric, pancreaticobiliary and distal intestinal secretions. Our observations are summarized as follows. Resting DBS is, to a large extent, maintained by vagal innervation; atropine decreases basal bicarbonate secretion by approximately 80%. Luminal acidification with HCI (H+) is a major physiological stimulus of DBS, resulting in a prompt and significant increase of 3- to 4-fold. H(+)-stimulated DBS is likely to be mediated, at least in part, by prostaglandins of the E class, and by VIP. Each of the latter stimulates DBS independently in a dose-related manner. Since atropine is without effect on the response induced by luminal H+ and sham feeding, in both cases DBS is probably stimulated via a non-cholinergic pathway(s). Moreover, since basal, H(+)- and PGE2-stimulated proximal DBS are unaltered when the plasma-to-lumen bicarbonate concentration gradient is abolished, it may be concluded that DBS in humans involves active transport processes. It is significant that compared to normal subjects, patients with duodenal ulcers show markedly diminished basal and H(+)-stimulated proximal DBS. Furthermore, there is surprisingly little overlap between duodenal ulcer (DU) patients and normal subjects. These findings suggest that an intrinsic cellular or subcellular defect in proximal duodenal mucosal bicarbonate secretion is present in patients with duodenal ulcer disease.

Acid-Base Equilibrium↗
PubMed1989

Cyclooxygenase inhibition with indomethacin increases human duodenal mucosal response to prostaglandin E1.

In humans, prostaglandins of the E1 class stimulate duodenal mucosal bicarbonate secretion, whereas the cyclooxygenase inhibitor, indomethacin, decreases both mucosal PGE2 and bicarbonate production. The purpose of this study was to determine whether a synthetic prostaglandin E1, enisoprost, diminished the inhibitory effects of indomethacin on mucosal bicarbonate secretion. In seven healthy subjects the proximal 4 cm of duodenum was isolated by occluding balloons. The isolated test segment was perfused with 154 mM NaCl (2 ml/min, 37 degrees C). Each subject participated in four separate tests in random order. Indomethacin, 50 mg, or placebo was given 13 and 1 hr before testing. After measuring basal bicarbonate secretion, either 100 micrograms of prostaglandin E1 or placebo (in 154 mM NaCl) was perfused into the test segment over 30 min. As anticipated, PGE1 significantly increased duodenal mucosal bicarbonate secretion, and indomethacin decreased resting bicarbonate secretion. Indomethacin pretreatment significantly enhanced (P less than 0.03) the mucosa's response to PGE1 compared to PGE1 alone. These results further support the observations that endogenous prostaglandins, in part, regulate human proximal duodenal bicarbonate secretion. Furthermore, suppression of endogenous prostaglandin generation results in an increased sensitivity of the duodenal mucosa to PGE1.

Alprostadil↗
PubMed1989

Effect of VIP antagonist on VIP-, PGE2-, and acid-stimulated duodenal bicarbonate secretion.

Vasoactive intestinal peptide (VIP), prostaglandin E2 (PGE2), and luminal acidification are each potent stimulants of duodenal mucosal bicarbonate secretion. The present experiments were performed to determine whether the recently described VIP antagonist, [4Cl-D-Phe6,Leu17]VIP, suppresses VIP-stimulated duodenal mucosal bicarbonate secretion and to determine whether VIP serves as a mediator of bicarbonate secretion stimulated by acid or PGE2. In anesthetized rats, the effects of intravenous VIP, intraluminal PGE2, and intraluminal HCl on duodenal mucosal bicarbonate secretion both in the presence and absence of [4Cl-D-Phe6,Leu17]VIP were measured. The VIP antagonist inhibited duodenal bicarbonate secretion stimulated by both intravenous VIP and luminal acidification but not luminal PGE2. These findings suggest that VIP could be one mediator of acid-induced duodenal bicarbonate secretion and that the mechanism of PGE2-stimulated bicarbonate secretion is independent of VIP.

Animals↗
PubMed1989

The effect of vasoactive intestinal peptide, secretin, and glucagon on human duodenal bicarbonate secretion.

Duodenal luminal acidification increases duodenal mucosal bicarbonate production and also releases both secretin and vasoactive intestinal peptide (VIP). The effect of these two structurally similar peptides on human duodenal bicarbonate production has not been examined in humans. Our purpose was therefore to assess the effect of VIP and secretin and also glucagon, a homologous hormone, on human duodenal bicarbonate secretion. A 4-cm portion of either proximal or distal duodenum was isolated and perfused with iso-osmolar NaCl. Pure porcine VIP (200 and 400 pmol/kg-h intravenously) significantly increased proximal duodenal bicarbonate secretion. Although secretin (0.01 to 0.18 CU/kg-h intravenously) markedly increased pancreatic bicarbonate secretion, it failed to alter duodenal mucosal bicarbonate output in either the proximal or the distal duodenum. Glucagon (1 to 8 micrograms/kg-h intravenously) did not affect proximal duodenal mucosal bicarbonate output. It is concluded that VIP, but neither secretin nor glucagon, significantly stimulates human duodenal mucosal bicarbonate secretion.

Adult↗
PubMed1989

Gastric ulcer recurrence: follow-up of a double-blind, placebo-controlled trial.

Following a multicenter, double-blind trial comparing cimetidine, antacid, and placebo for the treatment of gastric ulcer, patients whose ulcers had healed were followed prospectively to assess the frequency of ulcer relapse. Fifty-eight patients entered the follow-up study. Patients were encouraged to discontinue smoking and excessive ethanol intake, but were not maintained on antiulcer medications. Clinical evaluation was performed at monthly intervals; repeat endoscopy was performed at the time of symptom recurrence or at 6 to 9 months after ulcer healing. Gastric ulcer recurred in 20 of 58 patients (35%). While 15 (75%) with ulcer recurrence had symptoms, 5 (25%) had asymptomatic recurrences. There were no differences in the incidence of ulcer relapse or symptom recurrences between groups. We conclude that gastric ulcers recur in approximately one-third of patients within 9 months of ulcer healing.

Adult↗
PubMed1987

Impaired proximal duodenal mucosal bicarbonate secretion in patients with duodenal ulcer.

The defensive factors that prevent the human duodenal mucosa from acidic and peptic damage have not been fully evaluated. To determine whether duodenal mucosal bicarbonate production was altered in patients with inactive duodenal ulcer, we measured basal and acid-stimulated bicarbonate output from the duodenal bulb and the distal duodenum in healthy subjects and patients with inactive duodenal ulcer. As compared with 16 normal subjects, the 12 patients had significantly less mean (+/- SE) basal proximal duodenal mucosal bicarbonate secretion (185 +/- 13 vs. 107 +/- 18 mumol per centimeter per hour; P less than 0.001). Moreover, in response to a physiologic amount of hydrochloric acid (2 mmol per five minutes) instilled directly into the duodenal bulb, peak proximal duodenal bicarbonate output in the patients was 41 percent of the normal response (263 +/- 65 vs. 642 +/- 77 mumol per centimeter per hour; P less than 0.01). There was little overlap between groups. In contrast, bicarbonate outputs in the distal duodenum were similar in the two groups. We conclude that most patients with duodenal ulcer disease have decreased proximal duodenal mucosal bicarbonate production at rest, in response to hydrochloric acid, and in relation to peak gastric acid secretion. Impaired proximal duodenal mucosal bicarbonate secretion may be an important factor in the development and natural history of duodenal ulcer.

Adult↗
PubMed1987

Cimetidine decreases aspirin-induced gastric mucosal damage in humans.

Aspirin induces gastric mucosal damage in animals and humans. The purpose of this study was to examine whether cimetidine protects the human gastric mucosa from acute aspirin-induced damage. Eight healthy subjects were studied on 4 separate days. Cimetidine, 400 mg, or placebo was given orally 1 hour before initial endoscopy. The stomach was isolated and atropine given to suppress basal acid secretion. Each study consisted of four 15 min periods during which an acidic test solution was instilled into the stomach. During the second period only, either aspirin (1300 mg, 36 mmol) or control for aspirin (36 mmol HCl) was added to the test solution. Ion fluxes and gastric mucosal potential difference were measured, and endoscopy performed following each test. After placebo, aspirin significantly altered hydrogen ion flux and potential difference versus basal and control. Cimetidine decreased the damaging effect of aspirin. Endoscopic scores increased after aspirin plus placebo, whereas they remained unchanged after aspirin plus cimetidine. Therefore, cimetidine decreased aspirin-induced gastric mucosal damage in humans. As gastric acidity was identical during all studies, the effect of cimetidine was independent of gastric acid secretion.

Adult↗
PubMed1987

The impact of H2-receptor antagonists on the complications, morbidity and mortality of peptic ulcer disease.

The epidemiology and character of peptic ulcer has changed over the last 20 years, with only some of the change being due to the introduction of H2-receptor antagonists in the mid-1970s. There is evidence that duodenal ulcer was declining before this change in therapeutics. H2-receptor antagonists have, however, greatly reduced the morbidity and the time off work due to peptic ulcer disease. There is no strong evidence, however, that mortality due to peptic ulcer disease, which was already relatively small, has been reduced. The incidence of complications such as gastric haemorrhage, perforation and obstruction, may have increased in elderly patients. This may be associated with independent variables, such as increased use of non-steroidal anti-inflammatory drugs.

Histamine H2 Antagonists↗
PubMed1987

Increased sensitivity of gastric acid secretion to gastrin in cirrhotic patients with portacaval shunt.

We studied acid secretory responses to exogenous pentagastrin and to exogenous and endogenous gastrin in 12 stable cirrhotic subjects with portacaval shunt, 12 unshunted cirrhotics, and 12 normal subjects. Basal and stimulated serum gastrin concentrations as well as basal and maximum acid outputs were similar in the three groups. At low doses of either exogenous pentagastrin or gastrin-17 (G17), cirrhotics with portacaval shunt secreted significantly greater amounts of gastric acid than unshunted subjects. After low doses of intragastric peptone, cirrhotics with portacaval shunt secreted significantly more acid than unshunted cirrhotics and normal subjects. At each measured serum gastrin concentration after either exogenous G17 or intragastric peptone meals, cirrhotics with portacaval shunt secreted more acid than the unshunted control groups and their dose-response curve was significantly shifted to the left. Thus, in cirrhotic patients with portacaval shunt, gastric acid secretion is abnormally sensitive to both exogenously administered or endogenously released gastrin.

Aged↗