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Background & Aims: The gastrointestinal side effects of nonsteroidal anti-inflammatory drugs (NSAIDs) are reduced by antisecretory agents. The effects of combination therapy on the gastrointestinal toxicity and therapeutic activity of free and phospholipid-associated NSAIDs were investigated in rats., Methods: Fasted rats, pretreated with either saline or an antisecretory dose of omeprazole, ranitidine, or cimetidine, were intragastrically administered saline, aspirin, or indomethacin. In ulcer models, gastric lesions in aspirin-treated rats and intestinal bleeding in indomethacin-treated rats were measured. For antipyretic and analgesic activity, rectal body temperature in febrile rats and the rats' pain sensitivity to pressure applied to an inflamed limb were measured, respectively., Results: NSAID-induced gastrointestinal ulceration and bleeding were reduced in rats pretreated with antisecretory agents and abolished in rats administered phospholipid-associated NSAIDs in combination with inhibitors of acid secretion. The antipyretic and analgesic activity of both NSAIDs was attenuated in rats pretreated with an antisecretory agent. This pH-dependent block in therapeutic activity was overcome if the NSAID was preassociated with a phospholipid to enhance the drug's lipophilic characteristics., Conclusions: Combination therapy of antisecretory agents and NSAIDs, chemically associated with phospholipids, has distinct advantages with regard to both low gastrointestinal toxicity and restored therapeutic activity.

Four different cimetidine dosage regimens--800 mg u.i.d. HS or nocte, 800 mg u.i.d. dinnertime, 400 mg q.i.d., and 800 mg b.i.d.--were investigated for the treatment of reflux esophagitis in three independent large-scale, double-blind, controlled multicenter trials in which more than 1100 patients participated. Analysis of the data shows that the percentage of endoscopic healing after 6 and 12 weeks of treatment was fairly constant in patients with the same endoscopic grade of severity of reflux esophagitis at the start of treatment, whether they were treated with 800 mg u.i.d. (HS or dinnertime), 800 mg b.i.d., or 400 mg q.i.d. Healing percentages after 12 weeks of therapy ranged from 79%-92% for grade I, from 65%-70% for grade II, and from 41%-54% for grade III. Differences within the three grades for the various treatment regimens did not reach statistical significance. Symptomatic improvement was evaluated with the Standardized Total Heartburn Index, which is based on frequency and severity of heartburn as well as on the number of patients in the study population experiencing heartburn at a given time in relation to the total heartburn load at the start of the study. All three treatment schedules resulted in a substantial reduction of the Standardized Total Heartburn Index. Treatment with cimetidine, 800 mg u.i.d., for 6-12 weeks was efficacious in the majority of patients with reflux esophagitis grade I-III. Symptom relief was superior with dosing after dinner time compared with dosing HS. A single dose of 800 mg administered after the evening meal approached the efficacy achieved with 400 mg q.i.d. Based on these objectives and symptomatic results, a u.i.d. cimetidine regimen appears to be the treatment of choice for the initial approach of a patient with reflux esophagitis. A u.i.d. regimen may enhance patient compliance, comfort, and safety as well as ease of prescription while also being less expensive.

The effects of cimetidine maintenance therapy on the socioeconomic life of patients with peptic ulcers in the 3 years after healing and the extent to which treatment was cost-effective were studied. Three hundred eleven patients with healed ulcers (184 gastric, 127 duodenal) were studied for periods of up to 3 years; 261 patients (152 gastric ulcer, 109 duodenal ulcer) completed the 3-year follow-up. Cimetidine (400 mg at night) was compared with placebo in a double-blind, randomized prospective study. Intention-to-treat analysis was used. In the placebo group, the major costs of ulcer disease in gastric ulcer patients were attributable to endoscopic procedures and absenteeism; in duodenal ulcer patients, the major costs were endoscopic procedures, absenteeism, and surgery. Cimetidine was cost-effective in both gastric ulcer and duodenal ulcer patients in the first 2 years after healing. Over the 3-year period it was also cost-effective, but no benefit was seen in the third year.

Radioiron absorption tests in human volunteers demonstrated a modest but significant 28% reduction in the absorption of dietary nonheme iron from a meal that was preceded by the administration of 300 mg cimetidine. More pronounced decreases of 42% and 65% were observed with 600 and 900 mg cimetidine, respectively. Antacid caused a 52% decrease in iron absorption whereas pentagastrin had no significant effect. Since 300 mg cimetidine reduces gastric acid secretion by 60%-80% but iron absorption by only 28%, it appears that under normal conditions more gastric acid is secreted than is required for optimal iron absorption; absorption falls only when acid secretion is markedly reduced. Cimetidine in the doses currently recommended would not be expected to have a major effect on iron nutrition, although the combination of high doses of cimetidine with antacids would impair nonheme iron absorption significantly.

In each of 7 healthy volunteers, the new furan H2-antagonist ranitidine (0.125, 0.25, 0.5, and 1.0 mg . kg-1 . hr-1) or the imidazole derivative cimetidine or normal saline were intravenously infused in the midhour of a 3-hr pentagastrin period (1.5 micrograms . kg-1 . hr-1 i.v.). With increasing doses of ranitidine, gastric acid secretion dropped dose dependently: 62, 78, 89, and 94%, respectively (P < 0.05 for all doses). A cimetidine dose of 0.82 mg . kg-1 . hr-1 (2.8 mumol . kg-1 . hr-1), equivalent to the highest ranitidine dose, led to a similar reduction of acid output (54%) as an eightfold smaller ranitidine dose. Apparently in human gastric mucosa, recognition of H2-receptors is not exclusively determined by the imidazole ring. Strong inhibitory efficacy of ranitidine was also reflected by the low calculated mean ID50 of 54 micrograms (0.15 mumol) . kg-1 . hr-1 and the IC50 of 36 ng/ml (0.1 microM). Acid inhibition by ranitidine involved both reduction in volume and acidity. The lowering effect on pepsin output was less pronounced though significant. Secretion of free N-acetylneuraminic acid and N-acetylneuraminic acid bound to glycoproteins did not change after H2-blocker administration indicating an unimpaired mucus secretion. In these short-term experiments, there were no obvious side effects or alterations in routine laboratory parameters including serum gastrin and prolactin attributable to either drug.

To examine for the possible involvement of histamine in the jejunal microvascular effects of ethanol, we investigated the effects of (a) intraluminal ethanol on histamine release by the jejunum and (b) simultaneous inhibition of both histamine1 and histamine2 receptors (using promethazine and cimetidine, respectively) on ethanol-induced intestinal plasma protein loss in rabbits. Ethanol increased histamine release by the jejunum both in vivo (p less than 0.01) and in vitro (p less than 0.05). To investigate the effect of antihistamines on ethanol-induced plasma protein loss, we determined the dose of blockers that would completely inhibit the histamine1 and histamine2 receptors. In the absence of antihistamines, ethanol caused a 10-fold increase in jejunal protein loss over the controls (p less than 0.001). Simultaneous inhibition of histamine1 and histamine2 receptors attenuated (p less than 0.025), but did not abolish, the ethanol-induced protein loss. These data are discussed in relation to the literature, and it is concluded that histamine may play a role in the jejunal microvascular effects of ethanol. As the ethanol-induced protein loss was not completely inhibited, other mediators or mechanisms were probably involved.

By speeding the fragmentation of meat, peptic digestion might accelerate gastric emptying. To examine this possibility, mongrel dogs prepared with chronic duodenal fistulas were fed steak and 99mTc-labeled chicken liver, measuring 99mTc in all chyme exiting from the stomach out the duodenal fistula allowed quantitation of the gastric emptying of 99mTc-liver. Emptying was studied during relatively uninhibited gastric propulsion when the proximal bowel was perfused with chyme or fat. When chyme was diverted, the speed of emptying varied with peptic activity in the stomach--that is, it was increased by orogastric perfusion with acid-pepsin (vs. a control perfusion of pH 7 buffer) or, alternately, was decreased from the unperfusion stomach by i.v. cimetidine (vs. i.v. saline). By contrast, no effect of altering peptic conditions was observed when chyme was allowed access to the proximal bowel (the more normal situation), or when the duodenum was perfused with fat. We conclude that duodenal inhibition may override the effect of peptic digestion on the emptying of liver. We postulate that inhibition of gastric contractions limits the grinding of liver into particles susceptible to peptic digestion.

The aim of the study was to determine the effectiveness of cimetidine in a dose of 400 mg twice daily in the prevention of gastric ulcer recurrence over a 2-yr period. The trial was double-blind and placebo-controlled; 24 patients received cimetidine and 25 received placebo. All had had a gastric ulcer within the prior 6 wk, and healing was demonstrated by endoscopy or by barium meal. The patients were contacted at monthly intervals, and if symptoms were present, investigations were performed. Annual barium meal examinations or endoscopy were also performed in all except 7 patients. In the placebo group, there was rapid recurrence within the first 12 mo; 12 of the 13 recurrences that occurred in this group over the 2-yr period took place within the first 12 mo. In the cimetidine-treated group, there were eight recurrences over the 2-yr period, five of which occurred in the first year. Log rank comparison showed a significant benefit due to cimetidine at 1 yr, but not over the 2-yr period.

In a double-blind, randomized, multicenter trial 150 consecutive outpatients with endoscopically verified duodenal ulcer were treated with either a low-dose antacid regimen (1 tablet q.i.d.; acid-neutralizing capacity, 120 mmol/day), or cimetidine (800 mg nocte). After 4 wk of treatment control gastroscopy showed ulcer healing in 54 of 76 patients (71.1%) in the antacid group, as compared with 58 of 74 patients (78.4%) in the cimetidine-treated group. The difference in healing rate of 7.3% (95% confidence interval, -6.5% to +21.1%) was not statistically significant. The symptomatic effect, measured as number of days and nights with ulcer pain, was also quite similar in the two treatment groups. However, the number of days with pain was significantly lower in the first week of treatment in the antacid group (p less than 0.01). Thus, the efficacy of a low-dose antacid tablet regimen approximated that of cimetidine (800 mg nocte) in the treatment of duodenal ulcer patients.

Sixty-one cases of the Zollinger-Ellison syndrome, encountered over a 2-year period, have been treated with cimetidine, half of them for over 1 year. Two-thirds of the patients responded to 300 mg of the drug every 6 hr by mouth. Others required up to 600 mg every 6 hr. In adequate doses the drug was highly effective: it controlled pain and dyspepsia, restored weight, abolished diarrhea, and allowed healing of ulcers and other inflammatory conditions. Missed or reduced doses led to rapid return of symptoms. Progression of the basic neoplastic process, with associated secretory drive, was unimpeded. Patient acceptance of the drug was 100 percent, and apart from minor transient abnormalities, gynecomastia (5 cases) and liver dysfunction (3 cases), which resolved while treatment continued, no serious adverse effects were seen. Of 61 patients 48 are still on the drug, 3 who were well controlled were treated surgically, 5 died for reasons unrelated to therapy, and 5 had significant problems. The drug provides an alternative to total gastrectomy and can be recommended with confidence for the suitably selected patients. The drug was also beneficial in some cases of the short bowel syndrome, systemic mastocytosis, and endogenous hyperhistaminemia due to leukemia.

Forty-six patients with Zollinger-Ellison syndrome were studied prospectively to determine a safe and effective method and criterion for controlling gastric acid hypersecretion during periods when oral antisecretory agents could not be used. In each patient it was possible to reduce acid secretion to less than or equal to 10 mEq/h after an i.v. bolus of 150 or 300 mg of cimetidine and a stepwise titration of cimetidine given by continuous infusion. The mean dose given by i.v. infusion was 2.9 mg/kg body wt.h but there was a wide range (0.5-7.0 mg/kg body wt.h) and the minimal dose had to be determined individually for each patient. The minimal i.v. cimetidine dose did not correlate with basal or maximal acid output or fasting gastrin concentration, but correlated closely with either the previous oral dose of cimetidine (r = 0.96, p less than 0.001) or the previous oral dose of ranitidine or famotidine (r = 0.95, p less than 0.001). To study the efficacy and safety of an i.v. infusion of cimetidine, 34 patients undergoing surgery were maintained on i.v. cimetidine for a mean of 12 days (range 1-83 days). One-half of the patients did not require dose adjustment, whereas the remainder required an average of 2 adjustments, usually in the first 3 postoperative days. No patient developed complications attributable to gastric acid hypersecretion in the postoperative period, and there was no detectable neurologic, hematologic, or hepatic toxicity. This study demonstrates that a continuous i.v. infusion of cimetidine adequately inhibits gastric acid hypersecretion in patients with Zollinger-Ellison syndrome. However, high doses were frequently required, the dose had to be determined in a stepwise fashion individually for each patient, and the i.v. dose correlated with the previous oral dose. Reducing acid secretion to less than or equal to 10 mEq/h was a safe criterion during surgery and continuous i.v. cimetidine was safe and effective in achieving this degree of control for up to 83 days.

This study was undertaken to determine if the cytoprotective effect of prostaglandin and the H2 histamine receptor antagonist cimetidine involves protection against disruption of the gastric mucosal barrier. Groups of anesthetized, vagotomized rats received one of the following parenterally: saline (control), mepyramine--an H1 histamine receptor antagonist, cimetidine, cimetidine and mepyramine, or 16,16 dimethyl prostaglandin E2. Parameters of barrier disruption were then determined before and after exposure of the gastric mucosa to 40mM acetylsalicylic acid. At the end of the study, gastric lesions were scored according to size and number. Lesion score and fall in potential difference were significantly lower in rats receiving cimetidine, cimetidine and mepyramine, and prostaglandin. Other parameters of barrier disruption--H+ back diffusion, Na+ and K+ influx, and protein outpouring--exhibited the same pattern and correlated with change in potential difference. We conclude that both prostaglandin and cimetidine, but not mepyramine, protect against barrier disruption by topical aspirin, and this may be a factor in the mechanism of their cytoprotective action.

Famotidine, a new, potent, long-acting histamine H2-receptor antagonist was compared with cimetidine and ranitidine in 9 patients with Zollinger-Ellison syndrome. The mean minimum daily requirement of famotidine to control gastric acid hypersecretion was 0.24 g (range 0.08-0.48 g) compared with 2.1 g (range 0.6-3.6 g) for ranitidine and 7.8 g (range 1.2-13.2 g) for cimetidine. Equally potent doses of the three drugs had similar onsets of action, but the duration of action of famotidine was 30% longer than the duration of action of either ranitidine or cimetidine (p less than 0.05). Eight patients were treated for up to 9 mo (mean 6 mo) with good control of gastric acid hypersecretion and with no evidence of biochemical or hematologic toxicity. These studies demonstrate that famotidine is nine times more potent than ranitidine and 32 times more potent than cimetidine, has a longer duration of action than ranitidine or cimetidine, and is both safe and effective in the long-term therapy of Zollinger-Ellison syndrome.

The effects on fasting gastric pH of eight medical regimens were evaluated during a 10-h period in 8 duodenal ulcer patients. Our goal was to find a regimen that would produce sustained, fasting achlorhydria (pH greater than 7.0) in every patient. The effects of commonly prescribed bolus doses of cimetidine, antacid, or their combination were studied first. Mean gastric pH with cimetidine (300 mg/6 h intravenously), antacid (30 ml/h intragastrically), and their combination was 3.5, 4.6, and 6.8, respectively. Although mean pH with the combination was significantly higher than with either drug alone (p less than 0.05), sustained achlorhydria was not achieved. Next we tested constant-infusion regimens of cimetidine (50 mg/h intravenously), antacid (0.5 ml/min intragastrically), and their combination. Whereas infusions of cimetidine or antacid alone produced mean pH levels of 4.3 and 5.2, respectively, not significantly different from their bolus counterparts, the combination regimen resulted in a mean pH of 7.4. However, sustained achlorhydria was still not produced in each patient. Only when the dose of cimetidine infusion was doubled to 100 mg/h and administered with a constant infusion of antacid was sustained achlorhydria achieved in each patient.

The concept of two classes of histamine receptor, H1 and H2, is introduced and the chemical derivation of histamine H2-receptor antagonists is outlined briefly. Starting from the structure of histamine, chemical modification led eventually to burimamide, the first described histamine H2-receptor antagonist. Further stepwise modifications ultimately afforded metiamide and cimetidine. In vitro studies show that cimetidine is a specific competitive histamine H2-receptor antagonist. In vivo, it is a potent inhibitor of histamine-stimulated gastric acid secretion in rats and dogs after both intravenous and oral administration. It is equally potent as an inhibitor of pentagastrin-stimulated secretion. The evidence suggests that cimetidine inhibits gastric acid secretion through blockade of histamine H2-receptors in the gastric mucosa. Cimetidine has been shown to have low acute toxicity. Repeated dose studies of up to 24 months in rats and up to 12 months in dogs have been carried out and the results are presented and discussed. There is no known toxic effect which would limit the usefulness of cimetidine in man.

The bioavailability of parenteral cimetidine was tested in 12 volunteers in a balanced three-way crossover study. Blood levels and urinary excretion were compared after intramuscular and intravenous injection and oral administration of 300 mg of cinetidine. The results indicated that the intramuscular and intravenous routes are virtually interchangeable for parenteral cimetidine, and that the oral liquid, although exhibiting a reduced area under the blood level curve as compared with the parenteral doses, nevertheless demonstrated equivalence with respect to the time the blood level remained above 0.5 microgram per ml. The 300-mg cimetidine tablet formulation was found in another group of 12 volunteers to be bioequivalent to a 300-mg dose of oral liquid.

The effect of representative agents of three classes of antisecretory compounds; prostaglandins, histamine H2-receptor antagonist, and anticholinergic agents, on acute gastric mucosal lesions produced by topical aspirin (200 mg/kg) plus HCl (150 mM) in the pylorus-ligated rat was studied. Acid was given exogenously so as to negate any antisecretory effect of the drugs studied. Both nonantisecretory and antisecretory doses of each agent as determined by preliminary secretory studies were employed. The postaglandin analogue 16,16-dimethyl prostaglandin E2, the H2-receptor antagonist cimetidine, and the anticholinergic agent probanthine, in both doses studied, all significantly reduced lesion formation. The H1-receptor antagonist mepyramine neither protected by itself nor enhanced the protective effect of cimetidine. Pepsin release into the gastric content increased with increasing mucosal damage. However, addition of pepsin to the gastric instillate had no effect on severity lesions in any group, which indicates that the increased pepsin was the result of, and not the cause of, the mucosal damage. The findings indicate that all three classes of antisecretory agents studied are also cytoprotective, i.e., they can protect against gastric mucosal injury by topical aspirin plus HCl by some mechanism other than inhibition of acid and pepsin secretion.

We conducted a double-blind, randomized, parallel group study in 169 patients with acute duodenal ulcers to compare omeprazole, 20 mg daily, with cimetidine, 600 mg twice daily. After 2 wk, 58% of the omeprazole-treated patients and 46% of the cimetidine-treated patients were completely healed (p = 0.056). After 4 and 6 wk 84% and 88% healed with omeprazole, and 80% and 89% healed with cimetidine (p = NS). After 2 wk, pain was completely gone in 62% of the omeprazole-treated patients versus 46% of the cimetidine-treated patients (p = 0.04). Clinical or laboratory adverse events were reported in 6 (7%) of the omeprazole-treated patients and 11 (13%) of the cimetidine-treated patients (p = NS). An adverse event caused withdrawal of 1 patient on omeprazole (anxiety and depression) and 2 patients on cimetidine (diarrhea and fall in hemoglobin). We conclude that omeprazole (20 mg daily) resulted in a trend toward more rapid ulcer healing compared with a relatively high dose of cimetidine (600 mg b.i.d.), and was preferred by patients for relief of ulcer pain.

Eighty-five patients with endospcopically confirmed duodenal or pyloric canal ulcers entered a double blind trial with 1200 mg of cimetidine per day or placebo for 6 weeks. Eighty-four per cent of patients treated with cimetidine and 38 percent of those receiving placebo healed their ulcers (P less than 0.001). Measurement of basal acid output and maximal acid output before and after treatment showed no significant change but patients who failed to heal their ulcers had a higher basal acid output and maximal acid output than those who healed. Patients who smoked or drank alcohol had the same healing rate as abstainers. Sity-seven patients with duodenal ulceration healed by a 6-week course of cimetidine were randomly allocated to 400 mg of cimetidine twice daily or placebo in the maintenance trial. Actuarial analysis of the number of relapses in each group demonstrates that cimetidine is highly effective in preventing relapse.

Four "extra-effort" drug regimens were tested to determine which most nearly eliminated 24-hr gastric acidity in 8 patients with duodenal ulcer. The regimens included two 300 mg cimetidine tablets with meals and at bedtime; one 300 mg cimetidine tablet plus an anticholinergic drug with meals and at bedtime; 300 mg cimetidine with meals and at bedtime plus liquid antacid 1 and 3 hr after meals and at bedtime; and 300 mg cimetidine, an anticholinergic drug, and antacid, taken simultaneously as each meal was finished and at bedtime. No regimen completely eliminated gastric acidity. However, compared to standard cimetidine therapy (300 mg four times daily) which led to a median 24-hr pH of 2.6, each "extra-effort" regimen except cimetidine plus an anticholinergic was significantly better in reducing gastric acidity. During the daytime hours, cimetidine with meals plus antacid 1 and 3 hr after meals was most effective (median pH 5.0). However, the more convenient regimen of cimetidine, an anticholinergic drug, and antacid was almost as effective (median pH 4.3). None of the "extra-effort" regimens was significantly more effective than standard cimetidine therapy during the hours of sleep.

The published world literature on the efficacy of cimetidine, a histamine H2-receptor antagonist, in the treatment of duodenal ulcer is reviewed. In eight prospective randomized double blind placebo-controlled studies, cimetidine was administered to 348 duodenal ulcer patients with an incidence of endoscopically verified healing incidence of 37 percent in 300 placebo-treated patients. Healing rates were similar in patients receiving cimetidine in doses ranging from 0.8 to 2.0 g per day. It appears that at least 3 to 4 weeks of cimetidine therapy are needed to achieve healing rates of about 70 percent. In most trials, cimetidine was superior to placebo in achieving symptom relief in patients with duodenal ulcer. The drug has not been shown to result in acid rebound after cessation of therapy. There are no published prospective studies on the question of whether treatment with cimetidine results in increased ulcer for the short term treatment of duodenal ulcer. More data are required for an assessment of long term therapy with cimetidine.

Sixty patients who had been referred for elective ulcer surgery, and in whom a remission had been induced, entered a prospective double blind controlled trial of a single daily dose of 400 mg of cimetidine given at bedtime, or placebo. Eighty per cent of patients receiving placebo suffered symptomatic relapse and recurrence of duodenal ulceration at endoscopy within 6 months. The mean interval to relapse was 10 weeks. On the other hand, only 27 percent of patients had a recurrence during the 6-month period on low dose cimetidine therapy. No significant toxic or other side effects which could be attributed to the drug were observed.

Cimetidine has been associated with gynecomastia as a side effect. Because other antiandrogens have been linked to the development of breast enlargement in men, the suggestion by earlier workers that cimetidine possessed antiandrogenic properties prompted us to study the endocrine effects of cimetidine in rats. Cimetidine directly antagonized the effects of exogenously administered testosterone on androgen target tissues. Ventral prostate and seminal vesicle weights were less in cimetidine-treated castrate adult male rats androgenized with testosterone-filled subcutaneous silastic capsules than in vehicle-injected controls. Cimetidine possessed no intrinsic androgen-like bioactivity in prepubertal male rats when given in doses of 50 mg/kg/day for 1 wk. Cimetidine competitively inhibited DHT binding to its cytoplasmic receptor and decreased specific nuclear uptake of [3H]dihydrotestosterone in rat ventral prostate slices. No effects on plasma gonadotropin or testosterone concentrations were observed. We conclude that cimetidine is a nonsteroidal-antiandrogen and that this property may contribute to the production of gynecomastia in cimetidine-treated men.

The efficacy of cimetidine (1.6 g per day) was evaluated using a double blind placebo-controlled trial in 24 patients with moderate or severe peptic reflux esophagitis. The results show that cimetidine is superior to placebo when using endoscopic and histological criteria. Improved patient symptomatology and lower antacid comsumption failed to reach statistical significance. No change in the abnormally low lower esophageal sphincter pressure was observed at the end of the trial. No clinical side effects or significant biochemical changes were noted during the trial.

Cimetidine inhibits basal and nocturnal acid secretion and acid secretion stimulated by histamine, pentagastrin, caffeine, insulin, sham feeding, and food. Cinetidine (300 mg) inhibits basal acid secretion in duodenal ulcer patients by 95% for at least 5 hr. When taken at bedtime, cimetidine inhibits nocturnal acid secretion by greater than 80% for most of the night. Cimetidine markedly inhibits food-stimulated acid secretion and is more effective than anticholinergic drugs. However, to get adequate suppression of food-stimulated acid secretion throughout the day, cimetidine should be given with each meal. Cimetidine has no effect on nocturnal serum gastrin concentration, but, when stimulated by food, serum gastrin concentration is higher after cimetidine than after placebo.

The effects on fasting serum gastrin concentrations of hourly doses of magnesium and aluminum hydroxide antacid, with and without intravenous cimetidine, were determined in 8 patients with duodenal ulcer disease. Gastrin levels rose significantly over 10 h when antacid was given either as a bolus of 30 ml every hour or as a constant infusion of 0.5 ml/min (36 +/- 5 pg/ml and 33 +/- 6 pg/ml to 108 +/- 32 pg/ml and 109 +/- 22 pg/ml, respectively, p less than 0.05). This effect was specific for some component of the antacid and not for neutralization of acid per se, inasmuch as sodium bicarbonate, infused to keep gastric pH at levels at or above those of antacid, produced no significant rise in serum gastrin concentration. When intravenous cimetidine was administered simultaneously with intragastric antacid, gastrin levels did not rise. This occurred even though intragastric pH levels were actually higher with cimetidine plus antacid than with antacid alone. The ability of intravenous cimetidine to block antacid-induced hypergastrinemia was counteracted by infusing simultaneously both hydrochloric acid and antacid into the stomach. Since hydrochloric acid reacts with magnesium and aluminum hydroxide to form ionic magnesium and aluminum chloride, cimetidine most likely blocks antacid-induced hypergastrinemia by reducing acid secretion from the stomach and thereby limiting the generation of ionic magnesium and aluminum.

Although most patients with Zollinger-Ellison syndrome can be effectively treated with histamine H2-receptor antagonists, many patients require large doses of drug to inhibit gastric acid secretion adequately. The purpose of the present study was to compare the pharmacokinetics of a 1200-mg oral dose of cimetidine in 9 patients with Zollinger-Ellison syndrome requiring more than 2.4 g/day of cimetidine with 5 age-matched normal volunteers receiving intravenous pentagastrin infusions. Poor responsiveness to cimetidine in patients with Zollinger-Ellison syndrome has several different causes. The concentration of cimetidine in the blood required to inhibit gastric acid secretion by 50% was markedly increased in 3 of the patients with Zollinger-Ellison syndrome, suggesting parietal cell resistance. One patient showed a substantial decrease in cimetidine absorption and 4 patients had delayed cimetidine absorption. Thus 7 of the 9 patients with Zollinger-Ellison syndrome who required more than 2.4 g/day of cimetidine to inhibit gastric acid secretion had abnormal cimetidine pharmacokinetics.

Previous studies suggest that antacids are more effective than intravenous cimetidine in maintaining the gastric pH above 4.0 in acutely ill patients. We hypothesized that this was because blood levels of cimetidine are not sustained at therapeutic levels with the bolus doses. The purpose of this study was to compare gastric pH and serum cimetidine levels when cimetidine was administered as bolus versus infusion. We studied 23 acutely ill patients who received intravenous cimetidine given as boluses and primed infusions. The gastric pH could be maintained above 4.0 with infusions of up to 50 mg/h (1200 mg/day) in 20 patients, compared with only 5 patients with bolus administrations of up to 300 mg every 6 h (1200 mg/day). The differences in ability to maintain the gastric pH above 4.0 were entirely due to the reduced ability of bolus infusion to maintain an adequate serum level. Neither technique could maintain the pH above 4.0 in 3 patients, all of whom had received cimetidine recently. A gastric pH greater than 4.0 correlated directly with a therapeutic serum cimetidine level. We conclude that infusions of cimetidine are better able to sustain therapeutic blood levels and, therefore, are superior to bolus cimetidine in maintaining gastric pH above 4.0. Some patients, however, may not respond to cimetidine even if therapeutic levels are achieved and may require supplemental antacids.