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Biomedical subjects

B I Hirschowitz

Publications and source records attributed to B I Hirschowitz.

At least 19 recordsLinked to original sources
PubMed1998

Intractable upper gastrointestinal ulceration due to aspirin in patients who have undergone surgery for peptic ulcer.

BACKGROUND & AIMS: Postsurgical ulcer recurrence is a challenging problem. The aim of this study was to define the role of aspirin in postsurgical ulcers. METHODS: We studied 30 patients with postsurgical ulcer and aspirin abuse. Preoperatively 13 had stenosis, 7 bleeding, and 7 perforation or penetration; 18 had undergone vagotomy and 11 gastrectomy. RESULTS: Of 30 patients, 15 admitted long-term aspirin use (1-4 g/day), whereas 15 denied use but had positive salicylate blood levels (15.1 +/- 2.25 mg/100 mL; >1 mmol/L). Gastrin or gastric secretion was normal in the 24 patients tested. On follow-up, 3 (10%) healed after surgery (all stopped taking aspirin), whereas 27 continued and had new ulcers; 12 (44%) developed stenosis, and 6 (23%) developed bleeding. A second operation was required in 16 patients who had continued aspirin abuse, which was surreptitious in 10 (63%). Thirteen of these 16 had recurrent ulceration (7 [43%] with stenosis and 1 with bleeding); 1 died and 2 stopped taking aspirin and healed. A third operation was required in 8 patients. All had continued aspirin abuse (75% surreptitiously), and all again had relapses (3 with stenosis); 1 underwent an unsuccessful fourth operation, and 3 died. CONCLUSIONS: With continued aspirin abuse, recurrent ulceration is the rule, and complications, especially stenosis, are common. Surreptitious aspirin abuse, if discovered, is a clear contraindication to elective ulcer surgery, because aspirin-abuse ulceration is incurable by gastric surgery.

Aspirin↗
PubMed1997

Daily omeprazole surpasses intermittent dosing in preventing relapse of oesophagitis: a US multi-centre double-blind study.

INTRODUCTION: Relapse of erosive oesophagitis occurs in almost all patients if treatment is stopped after initial healing. AIM: To assess the potential of different therapeutic regimens of omeprazole to prevent relapse of erosive reflux oesophagitis after initial healing with omeprazole. PATIENTS AND METHODS: Patients whose active erosive reflux oesophagitis (grade > or = 2) had healed (grade 0 or 1) after 4-8 weeks of open-label omeprazole 40 mg daily (phase I) were eligible to join a multi-centre, 6-month double-blind, placebo-controlled maintenance study (phase II), which included endoscopy, symptom assessments, serum gastrin measurements, and gastric fundic biopsies. During phase I, endoscopy was performed at weeks 0, 4, and 8. At the end of phase I, 429 of 472 patients (91%) were healed, and there were significant reductions in heartburn, dysphagia and acid regurgitation. Of the 429 patients who healed, 406 joined phase II and were randomized to one of three groups: 20 mg omeprazole daily (n = 138), 20 mg omeprazole for 3 consecutive days each week (n = 137), or placebo (n = 131). During phase II, endoscopy was performed at months 1, 3, and 6 or at symptomatic relapse. RESULTS: The percentages of patients still in endoscopic remission at 6 months were 11% for placebo, 34% for omeprazole 3-days-a-week, and 70% for omeprazole daily. Both omeprazole regimens were superior to placebo in preventing recurrence of symptoms (P < 0.001); however, omeprazole 20 mg daily was superior to omeprazole 20 mg 3-days-a-week (P < 0.001). Compared to baseline, omeprazole therapy resulted in no significant differences among treatment groups in the distribution of gastric endocrine cells. CONCLUSIONS: These results show that after healing of erosive oesophagitis with 4-8 weeks of omeprazole, relapse of oesophagitis and recurrence of reflux symptoms can be prevented in 70% of patients with a maintenance regimen of 20 mg daily, but that intermittent dosing comprising 3 consecutive days each week significantly compromises efficacy.

Anti-Ulcer Agents↗
PubMed1997

Zollinger-Ellison syndrome: pathogenesis, diagnosis, and management.

Zollinger-Ellison syndrome (ZES) involves hypergastrinemia produced by gastrin-secreting tumor(s) of the pancreas or duodenum. Estimated to occur in 0.1-3 per million of the United States' population, the actual prevalence may be higher because ZES is often undetected with routine testing. ZES should be suspected in patients who present with persistent or complex duodenal or postsurgical ulcer, especially if accompanied by esophagitis, diarrhea, weight loss, and/or liver metastases. Twenty percent of ZES patients have multiple endocrine neoplasia type I, some of whom may also have elevated levels of serum calcium and a family history of ZES. Diagnostic tests include fasting serum gastrin concentration, gastric secretion analysis, with, if necessary, secretin stimulation of serum gastrin. Complete surgical tumorectomy for cure is impossible in as many as 70-90% of patients with ZES, who then require long-term medical therapy to reduce acid exposure. Basal acid output needs to be maintained at < 5 mEq/h for uncomplicated ZES and at < 1-2 mEq/h for complicated ZES or postgastrectomy. Proton pump inhibitors (omeprazole, lansoprazole) with careful clinical monitoring provide safe and effective acid control in patients with ZES.

Combined Modality Therapy↗
PubMed1996

Gastric secretion of acid and pepsin in patients with esophageal stricture and appropriate controls.

Most cases of esophageal stricture are associated with acid/peptic reflux esophagitis. While patients with strictures commonly have disordered lower esophageal sphincters and poor clearance and neutralization mechanisms, it is not known whether they also have abnormal gastric secretion. This study examined fasting, basal, and stimulated acid and pepsin secretion. With an endoscopic diagnosis of esophagitis, patients with stricture (< 12.5 mm) were matched for age, sex, concurrent gastrointestinal disease (duodenal ulcer, N = 9), Zollinger-Ellison syndrome (N = 6), and postgastric surgery state (N = 5), as well as the absence of ulcer disease (non-DU, N = 37). Fasting, basal, and pentagastrin-stimulated acid and pepsin secretion were measured. Overall, the 57 stricture patients had the same acid and pepsin secretion as their matched controls with esophagitis; the same was true for each of the subgroups (ZES, DU, non-DU, and postsurgical). Stricture patients weighed less and had a lower body mass index (P < 0.01). Patients with esophageal peptic stricture have the same acid and pepsin output as control patients matched for sex, age, background gastrointestinal disease, and the presence of esophagitis.

Endoscopy, Digestive System↗
PubMed1996

Gastric acid and pepsin secretion in patients with Barrett's esophagus and appropriate controls.

The objective of this study was to determine whether gastric secretion of acid and pepsin is different in the subset of esophagitis patients who also have Barrett's esophagus. Basal and stimulated gastric secretions were studied for 1 hr in the unstimulated state and 1 hr after pentagastrin 6 microg/kg subcutaneous injection. Because Barrett's patients are predominantly male, the 30 patients were matched with patients who had esophagitis, but not Barrett's, for sex (26 men, 4 women) and age as well as for background gastrointestinal disease (duodenal ulcer in 10, no ulcer disease in 17 and Zollinger-Ellison hypersecretors in 3). Patients with Barrett's weighed more than controls (P < 0.05). Acid and pepsin output in the basal and stimulated state were no different in Barrett's and their appropriately matched controls. Overnight fasting residue--volume, pH, acid and pepsin concentrations, and bile content--were also alike. The severity of esophagitis or prevalence of esophageal ulcer or stricture was not different between those with and without Barrett's and in neither was the grade of esophagitis related to acid or pepsin output. It is concluded that Barrett's esophagus patients do not have gastric secretions different from appropriately matched controls with esophagitis alone. When present, esophagitis due to reflux in Barrett's epithelium should be treated on its merits by appropriate reduction of acid exposure.

Barrett Esophagus↗
PubMed1996

Long-term treatment with lansoprazole for patients with Zollinger-Ellison syndrome.

BACKGROUND: Normalization of gastric secretion and cure of associated upper gastrointestinal lesions by resection of gastrinoma is possible in approximately 20% of patients with Zollinger-Ellison syndrome, leaving approximately 80% dependent on medical treatment with proton pump inhibitors for acid suppression. METHODS: Lansoprazole was given for 3-48 months (median 28 months) to 26 Zollinger-Ellison syndrome patients with peptic ulcer manifestations in all and oesophagitis in 13. Starting with 60 mg/day. the dose was individualized to lower basal acid output to less than 5 mmol/h for those with intact stomachs and less than 1 mmol/h in those who had prior gastrectomy or with oesophagitis. The patients were studied every 3 months for 1 year and then every 6 months with gastric analysis (basal and maximal acid and pepsin output) and endoscopy with biopsy for enterochromaffin-like (ECL) cells. RESULTS: Lansoprazole inhibited basal acid output by 95%, pepsin output by 65% and remained effective at the initial mean (66 +/- 4.3 mg/day) or smaller doses (56 +/- 12 mg/day) at 48 months. Mucosal lesions healed and symptoms (ulcer-type pain, diarrhoea, heartburn, weight loss) resolved rapidly, usually within a few weeks. Serum gastrin and ECL cell populations, which were elevated before treatment, remained statistically unchanged but one of the three multiple endocrine neoplasia I (MEN-I) patients developed a small carcinoid. Of the three patients with metastatic gastrinoma at diagnosis one has died and one has progressed, while the third has had stable liver metastases for 26 years. Ulcer-type relapses occurred in three of the five post-gastrectomy patients, one with fatal jejunal ulcer perforation despite adequate acid suppression. No biochemical or clinical adverse events due to lansoprazole were encountered. CONCLUSION: Lansoprazole effectively inhibits acid and pepsin secretion in Zollinger-Ellison syndrome patients without any demonstrated side-effects. Despite strict acid control, post-gastrectomy Zollinger-Ellison syndrome patients were more liable to ulcer relapse, while oesophagitis was not a marker for therapeutic difficulty.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed1996

Long-term treatment with lansoprazole of patients with duodenal ulcer and basal acid output of more than 15 mmol/h.

BACKGROUND: About 10% of patients with duodenal ulcers have marked gastric acid hypersecretion with basal acid output (BAO) of more than 15 mmol/h, which is in the range found in Zollinger-Ellison syndrome. PATIENTS AND STUDY DESIGN: We report long-term, up to 4 years, prospective treatment using lansoprazole in nine male patients with duodenal ulcers and a BAO of more than 15 mmol/h whose results are compared with those in 10 male Zollinger-Ellison syndrome patients with intact stomachs reported in detail in an accompanying paper. RESULTS: All 19 subjects, except one Zollinger-Ellison syndrome patient who had gastric and oesophageal ulcers, had a history of duodenal ulcers; 22% of those with gastric acid hypersecretion had oesophagitis compared with 60% of those with Zollinger-Ellison syndrome. Each subject had the dose of lansoprazole adjusted to give a BAO of less than 5 mmol/h. At 3-month intervals to 1 year, and then at 6-monthly intervals, basal and pentagastrin stimulated secretions were studied, in addition to gastroscopy with biopsy for gastric mucosal morphology. Basal and maximal acid and pepsin secretions were not different between gastric acid hypersecretion and Zollinger-Ellison syndrome patients before treatment. During treatment, BAO was reduced by over 90% to less than 2 mmol/h, while peak acid output was reduced by 70% in those with gastric acid hypersecretion and 90% in Zollinger-Ellison syndrome patients. Four gastric acid hypersecretion patients had relapses during treatment, three times in one patient and twice in another patient, but all responded to continued treatment with lansoprazole. Of the seven ulcer-related relapses in the gastric acid hypersecretion patients, four occurred with a BAO of less than 2 mmol/h and three with a BAO of 7.1-7.3 mmol/h; five of the seven relapses occurred in the absence of Helicobacter pylori. Lansoprazole remained effective at an average dose of approximately 70 mg/day, without causing any side-effects. CONCLUSION: Lansoprazole is apparently safe and effective for treating hypersecretion, whether due to hypergastrinaemia (Zollinger-Ellison syndrome) or not (non-Zollinger-Ellison syndrome hypersecretors).

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed1996

Reversible prolonged skin bleeding time in acute gastrointestinal bleeding presumed due to NSAIDs.

The purpose of this research was to look for a possible mechanism whereby NSAIDs, and particularly ASA, might cause gastrointestinal bleeding. A total of 34 hospitalized GI bleeders and 29 age- and sex-matched controls were studied. Skin bleeding time (SBT) was measured within 6 h of coming to hospital and before any blood products were given. All patients and controls were questioned regarding current NSAID use. This history was supplemented by estimation of serum salicylate and of platelet cyclooxygenase activity to detect unreported current aspirin (ASA) use. Various aspects of platelet function were also tested by lumiaggregation in 28 controls and, after recovery, in 27 of the bleeders. Of 34 bleeders, 26 bled from the upper GI tract, (13 from peptic ulcer) and eight from the lower GI tract, 30 (88%) had a current intake of NSAIDs and of these 22 (73%) used ASA, some in combination with other NSAIDs, whereas 12 of 29 controls were using NSAID's, 11 of which were ASA. SBT in the bleeders was 9.0 +/- 1.02 min versus 4.8 +/- 0.42 min in the controls (p < 0.001). SBT measured 6.6 days later in 28 bleeders was 4.7 +/- 0.22 min (p < 0.0006), and of those tested after recovery all but one had fallen to 6.5 min or less. None had any residual constitutional platelet abnormalities as tested by lumiaggregation. By logistic regression, NSAID intake was strongly associated with prolonged SBT to > 6 min (odds ratio [OR], 16.7; p < 0.0002), whereas NSAID intake (OR 14.6; p < 0.0003) and SBT > 6 min (OR 1.8; p < 0.005) contributed to a bleeding outcome. Almost 90% of GI bleeders had recently consumed NSAIDs, mostly ASA, on an average 15 h before onset of bleeding. Although most of the nonbleeders who had used NSAIDs did not have a prolonged SBT, most of the bleeders who used NSAIDs had an abnormal elevation of SBT, suggesting a possible mechanism for GI bleeding. Retesting approximately 7 days after recovery from bleeding showed normalization of the SBT, indicating that the defect was transient and spontaneously reversible.

Acute Disease↗
PubMed1996

Nonsteroidal anti-inflammatory drugs and the gut.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used for analgesic, anti-inflammatory, and antithrombotic indications. Such use carries the risk of significant side effects on nontarget organs, especially the gut. Some of these effects may be serious, especially among the elderly, whose NSAID use is proportionately greatest. Upper gastrointestinal mucosal lesions range from trivial (petechiae and superficial erosions) to significant and potentially serious (chronic peptic ulcers, esophagitis, and small and large gut ulcers). The most serious side effects are perforation of peptic or gut ulcers and gastrointestinal bleeding, which NSAIDs may promote from both ulcerous and nonulcerous lesions of both the upper and lower gastrointestinal tract, ie, both acid-dependent and non-acid-dependent. Symptoms may be independent of observable lesions, and serious lesions may occur without previous symptoms. NSAIDs may also delay healing of peptic ulcers, even to the extent of intractability, and may cause recurrence after gastric surgery. Until we can separate the mechanisms whereby NSAIDs both cause injury and provide therapeutic benefits, the problem of side effects and their prevention or treatment remains unresolvable.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1996

Aspirin related gastrointestinal bleeders have an exaggerated bleeding time response due to aspirin use.

BACKGROUND: Gastrointestinal bleeding is related to non-steroidal anti-inflammatory drug (NSAID) use, especially aspirin, but only a small subset of users bleed. AIM: To look for risk factors or mechanisms whereby aspirin may promote gastrointestinal bleeding. PATIENTS: Sixty one patients with previous aspirin related upper gastrointestinal bleeding and 61 matched controls. METHODS: Patients and controls were given 375 mg of aspirin and sequential skin bleeding time and blood aspirin levels were measured. Additional studies included platelet lumiaggregation, von Willebrand factor, Factor VIII, and coagulation studies. RESULTS: Baseline skin bleeding time was similar in bleeders and controls, but bleeders had a more prolonged skin bleeding time after aspirin use. Hyper-response was more frequent in bleeders (30% v 9.3%; p < 0.01) and was associated with more than one previous separate bleeding event and a lower packed cell volume during the preceding bleeding episode. No differences were found in other factors studied. Logistic regression analysis identified prolonged skin bleeding time after aspirin use as an independent factor contributing to aspirin related gastrointestinal bleeding (RR = 5.4; 95% CI: 1.8 to 17.1). CONCLUSIONS: 30% of patients with a history of aspirin related gastrointestinal bleeding have an exaggerated prolongation of skin bleeding time in response to aspirin, which may be a risk factor for bleeding. This intrinsic defect or to subclinical von Willebrand disease or different aspirin metabolism.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1995

Pharmacological aspects of acid secretion.

The secretion of gastric acid is regulated both centrally and peripherally. The finding that H2-receptor antagonists are able to reduce or abolish acid secretion due to vagal, gastrinergic, and histaminergic stimulation shows that histamine plays a pivotal role in stimulation of the parietal cell. In the rat, the fundic histamine is released from the ECL cell, in response to gastrin, acetylcholine, or epinephrine, and histamine release is inhibited by somatostatin or by the H3-receptor ligand, R-alpha-methyl histamine. The parietal cell has a muscarinic, M3, receptor responsible for [Ca]i regulation. Blockade of muscarinic receptors by atropine can be as effective as H2-receptor blockade in controlling acid secretion. However, general effects on muscarinic receptors elsewhere produce significant side effects. The different receptor pathways converge to stimulate the gastric H+,K(+)-ATPase, the pump responsible for acid secretion by the stomach. This enzyme is an alpha,beta heterodimer, present in cytoplasmic membrane vesicles of the resting cell and in the canaliculus of the stimulated cell. It has been shown that acid secretion by the pump depends on provision of K+Cl- efflux pathway becoming associated with the pump. As secretion occurs only in the canaliculus, this K+Cl- pathway is activated only when the pump inserts into the canalicular membrane. Transport by the enzyme involves reciprocal conformational changes in the cytoplasmic and extracytoplasmic domain. These result in changes in sidedness and affinity for H3O+ and K+, enabling active H+ for K+ exchange. The acid pump inhibitors of the substituted benzimidazole class, such as omeprazole, are concentrated in the canaliculus of the secreting parietal cell and are activated there to form sulfenamides. The omeprazole sulfenamide, for example, reacts covalently with two cysteines in the extracytoplasmic loops between the fifth and sixth transmembrane and the seventh and eighth transmembrane segments of the alpha subunit of the H+,K(+)-ATPase, forming disulfide derivatives. This inhibits ATP hydrolysis and H+ transport, resulting in effective, long-lasting regulation of acid secretion. Therefore, this class of acid pump inhibitor is significantly more effective and faster acting than the H2 receptor antagonists. K+ competitive antagonists bind to the M1 and M2 transmembrane segments of the alpha subunit of the acid pump and also abolish ATPase activity. These drugs should also be able to reduce acid secretion more effectively than receptor antagonists and provide shorter acting but complete inhibition of acid secretion.

Amino Acid Sequence↗
PubMed1994

Ingestion of aspirin prevents platelet-induced human fibroblast growth. Implications for peptic ulcer healing.

Because aspirin (ASA) may affect peptic ulcer healing through actions on platelets (for example, by inhibiting release of growth factors), human foreskin fibroblast mitogenesis was used for two bioassays (24-h growth with 3H-thymidine incorporation and 5- to 6-day cell proliferation) for serum derived from collagen-aggregated platelet-rich plasma (PRP) or platelet-poor plasma (PPP) or from clotted whole blood (WBS). Blood was taken from five normal subjects before and 6 h after ingestion of ASA. After ASA ingestion serum (WBS or PRP) was less mitogenic (p < 0.01) by both bioassays, whereas PPP serum was not mitogenic either before or after ASA. In vitro, neither ASA nor salicylic acid alone at levels normally found in plasma with ASA use inhibited fibroblast growth. We conclude that ASA ingestion inhibits the mitogenic action of platelets on fibroblast culture by inhibiting the release of putative growth factors. Such an effect might explain the adverse effects of ASA on ulcer healing.

Aspirin↗
PubMed1994

Effects of cholinergic, histaminergic, and peptidergic stimulation on pepsinogen secretion by isolated human peptic cells.

BACKGROUND: Whereas pepsin secretion by the human stomach has been extensively investigated, the characteristics of the peptide cell cannot be fully understood from in vivo studies. We therefore studied isolated human peptic cells to test directly cellular responses to different agents. METHODS: Eight endoscopic biopsy specimens yielded 10(6) cells, > 90% pure and > 95% viable. Secreted pepsinogen was measured with a sensitive hemoglobin digestion method at pH 2. RESULTS: Pepsinogen secretion was concentration-dependently stimulated by acetylcholine (ACh) (EC50 = 0.3 microM), cholecystokinin (CCK)-8 (2 nM), histamine (2 microM), and gastrin-I (30 nM) but not by bombesin or pentagastrin. ACh stimulation was inhibited 40 times more potently by atropine (IC50 = 12 nM) than by pirenzepine (IC50 = 0.5 microM). Histamine was inhibited by 10(-4) cimetidine. CCK-8 stimulation was inhibited 80% by the CCK-A-selective antagonist L364,718 (IC50 = 12 nM) but not by the CCK-B-selective antagonist L365,260. CONCLUSION: Isolated human peptic cells from endoscopic biopsy specimens secrete pepsinogen in response to ACh > CCK-8 > histamine > gastrin-I. The human peptic cell muscarinic-cholinergic receptor is not of the M1 subtype, and the CCK-8 response is predominantly mediated by a CCK-A receptor subtype.

Acetylcholine↗
PubMed1994

Nonsteroidal antiinflammatory drugs and the gastrointestinal tract.

Nonsteroidal antiinflammatory drugs (NSAIDs) are used in large amounts for analgesic, antiinflammatory, and antithrombotic indications. This use is not without side effects on the gut and other organs, and some of these side effects may be serious and even lethal. No NSAID has been shown to be without side-effect potential. Use increases with age, and age poses additional risks to patients with side effects. The most serious side effects are perforation of peptic and gut ulcers and gastrointestinal (GI) bleeding, which NSAIDs, and especially acetylsalicylic acid (ASA; aspirin), may promote from both ulcer and nonulcer lesions of both the upper and lower GI tract (i.e., both acid- and nonacid-dependent). Upper GI mucosal lesions range from trivial--petechiae and superficial erosions--to significant and potentially serious deep (chronic) peptic ulcers, esophagitis, and, less commonly, small and large gut ulcers. Symptoms may occur independently of observable lesions, and serious lesions may occur without any prior symptoms. The risk of ulceration due to therapeutic doses of NSAIDs is estimated at 5- to 10-fold. NSAIDs also delay healing of conventional peptic ulcers. Moreover, ASA abuse, often surreptitious and discoverable by serum salicylate level measurement, may cause totally intractable gastric or duodenal ulceration. Surgery is contraindicated because relapse is inevitable and progressively more serious. The rational use of NSAIDs is discussed, and prophylactic and treatment strategies are proposed. None seems entirely satisfactory, and the best prophylaxis would be to avoid the use of NSAIDs except for proven indications. Until the mechanisms whereby NSAIDs both cause injury and provide therapeutic benefits can be separated, the problem of side effects and their prevention or treatment remains unresolvable.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1993

Vagal effects on acid and pepsin secretion and serum gastrin in duodenal ulcer and controls.

To study whether the vagus sustains basal secretion and stimulates acid and pepsin differently in duodenal ulcer (DU) and non-DU, we tested 144 patients with DU and 92 nonulcer controls, using 1-hr basal secretion followed by 15 min of modified sham feeding (MSF) and after 1 hr followed by a reference maximum elicited by 6 micrograms/kg pentagastrin given subcutaneously and observed for another 1 hr. Of all subjects, 97.5% responded to MSF by raising basal acid output (BAO) at least 15%. MSF added amounts of acid equal to 26-30% of peak acid output and 30-43% of peak pepsin output, regardless of diagnosis or level of basal secretion (including hypersecretors). Speed and duration of responses were similar in DU and controls. MSF did not substantially alter serum gastrin. Males secreted more acid and pepsin than females under all conditions, differences that persisted in DU but not in controls when outputs were corrected for body weight. Male DU but not female DU patients secreted more than corresponding controls. Sham feeding is an effective stimulus with similar characteristics in controls and DU patients. There was no evidence for saturation of vagal pathways in basal hypersecretors. MSF stimulation does not appear to involve gastrin. Hypersecretion in DU derives largely from responses in male DU.

Adult↗