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Background: Actions of various drugs have been tested on the gastric acid basal secretion and on the drug (Indomethacin)- induced gastric mucosal damage; however their physiological and pharmacological mechanisms have not been compared., Aims: The effects of capsaicinoids, atropine, cimetidine, omeprazole, famotidine and ranitidine were studied on gastric basal acid output, whereas the gastric mucosal preventive effects of capsaicinoids (capsaicin), atropine and cimetidine were tested on the indomethacin-induced gastric mucosal microbleedings in human healthy subjects. Results were presented by molecular pharmacological method; affinity (pD) and intrinsic activity (α-values) were calculated. Intrinsic activity curves are based on comparison to atropine effect (α(atropine)= 1.00). For evaluation of physiological and pharmacological effects of compounds molar doses of pD(2) (necessary doses to produce 50% inhibition) and pA(2) (50% inhibion on intrinsic activity) were calculated from affinity and intrinsic activity curves., Results: The pD(2) values for compounds were as follows: 5.88 for capsaicinoids, 5.40 for atropine , 2.23 for cimetidine, 3.33 for ranitidine, 3.77 for famotidine and 3.97 for omeprazole. α - value results for compounds were: 0.76 for capsaicinoids, and 1.00 for atropine, cimetidine, ranitidine, famotidine and omeprazole all equal to 1.00 on gastric acid basal secretion. The pD(2) values on indomethacin-induced gastric mucosal microbleeding were found as follows: 6.00 for capsaicinoids, 5.50 for atropine, and 3.50 for cimetidine, meanwhile α-values resulted 0.76 for capsaicinoids, 1.00 for atropine and cimetidine., Conclusions: Comparison classical antisecretory drugs acting on different pathways but in much more higher molar concentrations. The atropine and capsaicinoids act in about the same molar concentration which suggests a significant physiological role for capsaicin sensitive afferent nerves in the regulation of gastric basal acid secretion and in the prevention of chemically- induced gastric mucosal protection in human healthy subjects, suggesting a novel physiological pathway in regulation. These results clearly indicate the molecular pharmacological backgrounds of actions of classical antisecretory drugs and physiological role of capsaicin- sensitive afferent nerves in human healty subjects on the gastric basal secretion and on the prevention of drug-induced gastric mucosal damage.

Background and Aim: H2 histamine receptor antagonists (H2RAs) are widely used in patients with acid-related diseases, and the onset of antisecretory activity of H2RAs is reported to be faster than that of proton pump inhibitors (PPIs). The aim of this study was to compare the rapidity of onset of antisecretory activity of cimetidine and famotidine when orally administered., Methods: Fifteen healthy male Japanese volunteers (five H. pylori-positive and 10 H. pylori-negative) participated in a randomized cross-over study. All subjects were examined three times by ambulatory 6-h pH monitoring (from 17:30 to 23:30) with no medication or oral administration of 400 mg of cimetidine or 20 mg of famotidine. Drugs were administered at 19:30 after eating a standard meal, and plasma concentrations were also examined for 4 h periods., Results: The plasma concentration of cimetidine increased rapidly after oral administration, while that of famotidine increased gradually. Intragastric pH was increased and percentage time with pH < 4.0 decreased significantly 2 h after administration of either cimetidine or famotidine. There was no statistically significant difference in acid-suppressing effect between cimetidine and famotidine during the short-term post-administration period., Conclusion: Rapidity of antisecretory activity did not differ between oral cimetidine and famotidine administered orally.

This study assessed the duration of action of single doses of ranitidine (75 mg), cimetidine (200 mg), or placebo on intragastric acidity in healthy subjects. When dosed with placebo, mean daytime intragastric acidity (0-10 hr after dose) was 37.62 mmol/liter, decreasing to 17.21 mmol/liter (mean decrease 59%; P < 0.001 vs placebo) and 25.06 mmol/liter (mean decrease 35%; P < 0.001 vs placebo) when treated with ranitidine and cimetidine, respectively. Ranitidine inhibited intragastric acidity to a greater degree than cimetidine (P < 0.001). Mean nighttime (10-20 hr after-dose) intragastric acidity when dosed with placebo was 34.37 mmol/liter, decreasing to 29.06 mmol/liter (mean decrease 18%; P = 0.027 vs placebo) when dosed with ranitidine and remaining virtually unchanged at 33.85 mmol/liter (mean decrease 2%; NS vs. placebo) when dosed with cimetidine. Ranitidine inhibited acidity to a greater degree than cimetidine (P = 0.043). The inhibitory effect of ranitidine, 75 mg, on intragastric acidity can be detected from 0-15 hr after an oral dose. Cimetidine 200 mg has little inhibitory effect beyond 10 hr.

The effects on gastric pH of a single administration of 200 mg cimetidine (Tagamet HB) were compared to multiple doses of a liquid antacid (Mylanta) using a pH microelectrode. Gastric pH was monitored for 8 hr in 20 normal fasting volunteers in a crossover design to compare Tagamet HB (two 100-mg tablets administered as a single dose) with Mylanta Suspension, an initial 17.5-ml dose of antacid with additional doses given when gastric pH fell below 3.5. Both treatments increased the pH above 3.5 during the first hour following treatment, with Mylanta being more effective than Tagamet HB. Interestingly, to sustain the reduction in acidity during this 1-hr interval, a mean of 2.45 doses of antacid were administered. Although multiple doses of Mylanta kept the pH above 3.5 (for at least 25% of the time) for the first 4 hr, the single administration of 200 mg of Tagamet HB maintained gastric pH above 3.5 (greater than 25% of time) for the full 8 hr of the study. Compared to Mylanta, the percent of time gastric pH was >3.5 was significantly higher with Tagamet HB during the 3rd to 8th hour after dosing. This study demonstrates that 200 mg of cimetidine administered as Tagamet HB is significantly more effective and has a much longer duration of action in raising gastric pH >3.5 than six doses of Mylanta.

Background: Because of their tolerance and safety, low doses of H2-receptor antagonists are now increasingly used in some countries for self-care medication of gastro-oesophageal reflux symptoms., Aim: The purpose of this randomized, double-blind, placebo-controlled, five-way crossover study was to determine and to compare the effects of low doses of ranitidine and cimetidine both on gastric pH and on oesophageal acid exposure., Methods: Gastric and oesophageal pH were simultaneously monitored in 20 healthy subjects using two glass pH electrodes, after placebo and single doses of ranitidine 75 mg and cimetidine 200 mg (effervescent and tablet forms), for 4 h before and after a meal., Results: During the fasting period, median gastric pH rose significantly with both drugs, but more rapidly with the effervescent forms; the oesophageal acid exposure was significantly decreased by all drug regimens. After the meal, although there was no significant difference in gastric pH values, oesophageal acid exposure was significantly decreased in comparison with placebo with both forms of ranitidine (P < 0.05), and also for ranitidine tablets in comparison with cimetidine tablets (P < 0.05)., Conclusions: Low doses of ranitidine and cimetidine increase gastric pH, with a more pronounced effect for ranitidine. Effervescent formulations of both drugs induce a slightly more rapid initial increase in pH than tablets. Ranitidine demonstrates a more prolonged effect than cimetidine and decreases oesophageal acid exposure monitored after a meal ingested 4 h after the drug intake.

Background: Amongst the low-dose H2-receptor antagonists available for the self-medication of dyspepsia, both famotidine 10 mg and cimetidine 200 mg have been shown to raise intragastric pH, but there is a delay after ingestion before significant effects can be demonstrated. A new effervescent preparation of cimetidine 200 mg releases an acid buffer which has a more rapid effect on intragastric pH., Aim: To investigate the relative abilities of low-dose famotidine and effervescent cimetidine to raise intragastric pH after a single postprandial evening dose., Methods: Twenty-four healthy subjects (12 men, 12 women, median age 32 years) completed a three-period crossover trial of famotidine 10 mg, effervescent cimetidine 200 mg and placebo. After a standard meal was given at 18.30 h to subjects fasted for 5.5 h, drug or placebo was given at 19.30 h. Intragastric pH was recorded with combined glass electrodes from 18.00 to 07.30 h by digital recorders., Results: Over the 12 h post-dose period the mean area under the pH/time curve (AUC) after famotidine 10 mg was 3.73, after cimetidine 200 mg effervescent 2.79, and after placebo 2.07. Over the same period the median pH and percentage of time that recordings were above pH 3 were 3.45 and 52.5 after famotidine 10 mg, 2.40 and 33.8 after cimetidine 200 mg effervescent, and 1.68 and 15.9 after placebo. Both active treatments were significantly different from placebo by each measure (P < 0.001), and famotidine 10 mg was significantly more effective than cimetidine 200 mg effervescent by each measure over the 0-12 h period (P < 0.001). Comparisons of mean AUCs for each 15 min period after dosing showed that decrease in acidity was significantly greater after cimetidine 200 mg effervescent than after famotidine 10 mg for the first 60 min. In the later post-dose period only famotidine 10 mg raised pH for all time points to 12 h, whilst the effect of effervescent cimetidine 200 mg was detectable to = 8 h., Conclusions: Inhibition of gastric acidity over the 12 h post-dose period was significantly greater and endured longer after famotidine 10 mg than after effervescent cimetidine 200 mg, but for the 60 min period immediately after dosing the effect on intragastric pH was significant following effervescent cimetidine 200 mg but not famotidine 10 mg. This suggests effervescent formulations of H2-receptor antagonists with an acid buffer have a more rapid effect on intragastric pH than film-coated tablets.

We compared the usefulness of proton pump inhibitors (PPIs) every other day, with H2-blocker, in terms of inhibitory effect on gastric acid secretion. The dosages were as follows; cimetidine (CIM), 800mg and 400mg every day; omeprazole (OPZ) 20mg, and lansoprazole (LPZ), 30mg every other day. We continuously measured intragastric pH and calculated the time that pH was maintained at pH4 or more (pH4 holding time). The pH4 holding time as a part of total measurement time was significantly longer in the PPI every other day groups than in the H2-blocker groups, but there were no significant differences between the groups during the night. In PPI every other day groups, pH4 holding time of daytime period was suggested to be longer than on H2-blocker groups. In conclusion, their efficacy was greater than in the CIM group, and they appear to have a broad range of applications to the treatment of peptic ulcer.

Gastric mucosal surface pH was measured endoscopically in patients with peptic ulcer, erosive gastritis, or nonulcer dyspepsia following intravenous administration of either 200-mg cimetidine, 50-mg ranitidine, or 40-mg famotidine. The mean baseline pH in the three treatment groups before drug administration ranged from 0.85 to 0.99, with no significant difference between groups. Following treatment with cimetidine, ranitidine, and famotidine, the mean response times for the mucosal surface pH values to increase to 3.5 were 10.1 +/- 5.9 minutes, 11.2 +/- 6.8 minutes, and 17.3 +/- 6.7 minutes, respectively. The corresponding response times to reach pH levels of 6.0 were 16.0 +/- 9.4 minutes, 17.0 +/- 5.4 minutes, and 31.2 +/- 21.7 minutes, respectively. The response times to pH levels of 3.5 and 6.0 were significantly faster in patients who received cimetidine compared with patients who received famotidine (P = 0.0088 to pH 3.5 and P = 0.046 to pH 6.0). The differences between cimetidine and ranitidine were not significant. These findings suggest that at recommended clinical doses, intravenous cimetidine provides rapid elevation of the gastric mucosal surface pH compared with other histamine2-receptor antagonists. This finding may be particularly relevant in the emergency care of patients with severe peptic ulcer disease (eg, patients with gastrointestinal hemorrhage).

Aims: To compare the effects on intragastric acidity of a single evening dose of either standard or effervescent formulations of ranitidine (300 mg) or cimetidine (800 mg)., Methods: Twelve healthy subjects were studied, using a four-period randomized cross-over design and an ambulatory intragastric pH monitoring technique. The subjects received a standard evening meal at 17.00 hours and one of the H2-receptor antagonist formulations was given at 23.00 hours., Results: Both effervescent formulations caused a transient rapid increase in intragastric pH, reaching a maximum at about 3 min after ingestion. After both effervescent formulations a significantly higher pH was measured during the first 45 min after ingestion (P < 0.05), compared to the regular formulations. The onset of action of the H2-receptor antagonists was similar for both formulations of ranitidine and the effervescent cimetidine, but tended to be slower for the regular cimetidine (P = 0.06). Nocturnal intragastric pH was significantly increased by all four formulations, but more effectively so by the two ranitidine formulations. The duration of action (taken as time with pH > 4) of both ranitidine formulations was longer than that of both cimetidine formulations (P < 0.002)., Conclusions: A single evening dose of 300 mg ranitidine produces a stronger decrease of nocturnal gastric acid secretion than 800 mg cimetidine. The effervescent formulations of both drugs offer the advantage of a rapid decrease (within minutes) of intragastric acidity, with preservation of the sustained systemic effect.

Parenteral control of gastric acid hypersecretion in patients with Zollinger-Ellison syndrome is increasingly required; however, existing methods of determining the required dose are cumbersome and not applicable in all centers. A previous study suggested that the required parenteral dose of histamine H2-receptor antagonists correlated with the previous oral dose. In the present study, in 31 patients with Zollinger-Ellison syndrome we evaluated the hypothesis that an effective parenteral histamine H2-receptor antagonist dose could be predicted from the previous oral dose. Twenty-three patients were taking oral ranitidine (mean 1.3 g/day), six patients famotidine (152 mg/day), and two patients cimetidine (1.8 g/day). Each patient was treated with a continuous intravenous infusion of the equivalent dose of ranitidine (mean dose 1 mg/kg/hr with 35% requiring 0.5 mg/kg/hr, 49% 1 mg/kg/hr, 3% 1.5 mg/kg/hr, 10% 2 mg/kg/hr, and 3% 2.5 mg/kg/hr. This dose of ranitidine acutely controlled acid secretion (< 10 meq/hr) in all patients. To evaluate long-term efficacy and safety, 20 patients were maintained on this dose through the peri- and postoperative periods. Mean duration was 7.1 days with 25% treated 3-5 days, 40% 6-8 days, 30% 8-10 days, and 5% > 10 days. The predicted dose continued to control acid secretion in 95% of patients with one patient requiring one dose adjustment. No biochemical, clinical, or hematological toxicity was seen, although ranitidine was stopped in one patient because of skin rash. These results demonstrate that the parenteral dose of ranitidine required to control acid secretion in patients with Zollinger-Ellison syndrome can be predicted from the oral dose.(ABSTRACT TRUNCATED AT 250 WORDS)

The success of omeprazole in the healing of duodenal ulcer has been attributed to its profound and almost around-the-clock inhibition of acid, but the relevance of reducing meal-stimulated acid secretion exclusively has recently been emphasized in several clinical trials. For this reason, we used 24-h continuous intragastric pH monitoring to compare the pharmacodynamic effects of placebo, three fractioned premeal doses of cimetidine 400 mg and omeprazole 20 mg mane. Fifteen patients with duodenal ulcer in clinical remission were randomized to receive the above medications in single-blind fashion on three separate occasions, at least 2 wk apart. Both active regimens produced higher pH values (p < 0.05-0.001) than placebo, but omeprazole was much more effective than cimetidine (p < 0.01-0.001) during the various time intervals analyzed (24 h, evening, nighttime, daytime). The greater effectiveness of omeprazole was confirmed by its longer-lasting antisecretory action, insofar as the drug increased gastric pH above 3.0 units for about 21 h, whereas the daytime cimetidine regimen maintained this threshold for 7.30 h (p < 0.001) over the circadian cycle. As these markedly different pharmacodynamic effects have been proven to produce similar fast rates of duodenal ulcer healing in clinical trials, it is reasonable to assume that a small but well addressed reduction of gastric acidity can ensure the same therapeutic benefit as a strong and continuous acid inhibition. In this light, the acid peaks in response to meals seem to be important pathophysiological events, whose control is sufficient to permit quick ulcer healing.

Gastric pH and volume were measured in four groups of 15 patients scheduled for elective surgery. The patients were randomly allocated to receive either no antacid, oral omeprazole 40 mg the evening before surgery, oral omeprazole 40 mg 2 h before surgery, or effervescent cimetidine 800 mg, 2 h before surgery. Anaesthesia was induced with thiopentone (4-6 mg kg-1), fentanyl (0.03 mg kg-1) and vecuronium (0.1 mg kg-1) and maintained with nitrous oxide in oxygen (50/50) and isoflurane. After induction of anaesthesia and on completion of surgery, gastric pH (mean +/- SEM) and volume were measured using a glass electrode and a phenol red dilution technique. Gastric pH were significantly higher in the three treated groups than in control (P < 0.01). Omeprazole and cimetidine were equally effective in reducing volume and pH of the gastric juice at the beginning and at the end of anaesthesia. Nevertheless 14.2 and 28.5% of patients who received omeprazole respectively the day before or the morning of surgery remained at risk of aspiration pneumonitis (gastric pH < 2.5 and gastric volume > 25 ml).

The effect of two doses (37.5 mg/hr and 50 mg/hr) of continuously infused cimetidine on gastric acid secretion and pH control over 24 hours was compared with that of placebo in 21 adult males with active duodenal ulcer or scarring from healed duodenal ulcer. This single-center, double-blind, three-way crossover trial consisted of three treatment periods separated by 5- to 7-day washout periods. Gastric contents were continuously aspirated through a nasogastric tube during the second half of each study hour. Volume, pH, and titratable acidity were measured from the aspirates collected during the last 20 minutes of each aspiration period. The median pH, volume (ml), and titratable acidity (mEq/hr) values for the 37.5-mg/hr infusion were 5, 16.0, and 0.24, respectively (P < 0.05 versus placebo). For the 50-mg/hr infusion, the respective values were 5.3, 15.8, and 0.14 (P < 0.05 versus placebo); and for placebo, the values were 1.4, 30.5, and 6.83. The median percent of time that the pH was > or = 4 was 65%, 65%, and 0% for the 37.5-mg/hr, 50-mg/hr, and placebo infusions, respectively (P < 0.05 versus placebo). The 37.5-mg/hr and 50-mg/hr intravenous doses of continuously infused cimetidine are commonly used in the hospital setting to treat intractable ulcers or prevent upper gastrointestinal bleeding in critically ill patients. The results of this study demonstrate that both doses are similarly effective in maintaining intragastric pH and acid secretion at levels generally recognized as being effective.

To investigate the effect of 6 weeks administration of proton pump inhibitor (omeprazole) and H2-receptor antagonist (cimetidine) on gastric histamine synthesis and acid secretion, we studied experimentally in the rat stomach. Then gastric mucosal histamine concentration, histidine decarboxylase (HDC) activity and serum gastrin concentration, and HDC positive cell number were examined in time-course. The 6 weeks administration of omeprazole caused more increase of HDC positive cells than cimetidine. After cessation of administration with omeprazole, high plasma gastrin level immediately reduced. However the increase of gastric mucosal HDC activity and histamine concentration were prolonged, compared with cimetidine. These findings suggest to affect differently between omeprazole and cimetidine on gastric acid secretion after cessation of long-term treatment.

The efficacy of oral cimetidine for gastric acid suppression in pediatric patients was examined in a double-blind study. Twenty-seven patients with gastroesophageal reflux-related gastrointestinal symptoms, pulmonary symptoms, or both were given randomly determined doses of cimetidine. Response was evaluated by continuous intragastric monitoring with a pH probe. Twenty-three patients were given cimetidine doses of 5,7.5, and 10 mg/kg; eight of these patients were also given additional doses of 15 mg/kg. Four patients received only 10 and 15 mg/kg, because of previous poor clinical response to the lower dosages. The onset of gastric pH greater than 4 was delayed more than 2 hours in 50% of patients with responses to the 5 mg/kg dose. Of the patients with responses to the 10 mg/kg dose, 75% had showed a rise in gastric pH greater than 4 within 2 hours. With respect to the duration of gastric acid suppression, 70% of patients receiving 5 mg/kg doses and 52% of those receiving 7.5 mg/kg doses did not have a sustained a response for more than 2 hours, whereas 75% of patients receiving 10 mg/kg doses had gastric acid suppression for longer than 2 hours. Of the patients receiving 15 mg/kg doses, 75% had a response for more than 2 hours; 50% of these patients had a response for more than 3 hours. We conclude that recommended doses of cimetidine for children may not be optimal for adequate gastric acid suppression.

The correlation between serum gastrin levels and gastric acid secretion during 4 weeks of cimetidine administration (once daily) was investigated. Serum gastrin levels and gastric acid secretion were estimated on the 7th, 14th, 21st and 28th day after cimetidine administration (25 mg.kg-1, intragastrically). At the mentioned time intervals gastric acid secretion stimulated by histamine and pentagastrin was also studied. It was found that on the 14th and 21st day after cimetidine administration serum gastrin levels were significantly elevated. Basal gastric acid secretion after cimetidine administration was significantly decreased at all the observed time intervals. Histamine-stimulated gastric acid secretion was increased on the 14th, 21st and 28th day after cimetidine administration. Hypoacidity was not followed at all time intervals by hypergastrinaemia (only on day 14 and 21 after cimetidine).

The effect of a new effervescent formulation of 800 mg cimetidine on intragastric acidity was studied in 10 fasting healthy male volunteers. Using a randomised, cross-over design, the effect of this new cimetidine formulation was compared with that of a standard dose of a liquid aluminium/magnesium hydroxide antacid (Maalox). Intragastric pH was continuously monitored with a combination glass electrode and a digital data recorder. After a baseline period of 1 h the effect of the drugs was studied for 5 h. Both drugs increased the intragastric pH instantaneously, but the effect of Maalox ceased after 45.3 +/- 31.0 min (mean +/- SD), whereas that of effervescent cimetidine persisted for the entire 5 hr study period. Time with pH greater than 3.5, time with pH greater than 2, greater than 3, greater than 4, greater than 5 and greater than 6, and areas under the pH-time curves were significantly (P less than 0.001) higher for effervescent cimetidine than for Maalox. It is concluded that the new cimetidine formulation studied effectively combines, at least in healthy male volunteers, the immediate effect of a pH buffer with the prolonged systemic effect of an H2 blocker.

The effects of 100 mg and 200 mg bedtime doses of cimetidine on nocturnal gastric acid secretion were examined in nine healthy subjects in a double blind, placebo controlled, randomised three way crossover study. Treatment was given at 23.00 hours and the gastric contents continually aspirated from midnight until 07.00 hours the following morning. Hourly aliquots were analysed for pH and acid output. Relative to placebo the 100 mg and 200 mg doses of cimetidine respectively increased mean pH by 2.22 and 2.63 units/h (P less than 0.001) with mean acid output decreasing by 0.95 and 0.98 mmol/h (P less than 0.001). Whilst mean pH was higher and mean acid output was lower for 200 mg cimetidine compared to 100 mg cimetidine the difference was not statistically significant. Mean hourly pH was consistently above pH 3 for 100% of the time for both doses of cimetidine whereas mean pH failed to reach this value at anytime on placebo. Low doses of cimetidine taken at bedtime effectively reduced nocturnal gastric acid secretion in healthy individuals.

Study Objective: To evaluate and compare the preinduction effects of intravenously (IV) administered cimetidine alone and combined with metoclopramide on gastric contents and postoperative nausea and vomiting in outpatients undergoing elective surgery., Design: Patients were allocated randomly to 4 groups with 20 patients in each group., Setting: Ambulatory surgery at a university-affiliated city hospital., Patients: Eighty patients undergoing elective gynecologic or orthopedic procedures were studied., Interventions: Outpatients in Group 1 and inpatients in Group 2 served as controls. Outpatients in Group 3 received 300 mg of cimetidine, and outpatients in Group 4 received 300 mg of cimetidine and 10 mg of metoclopramide. All drugs were administered IV as an infusion over a 15-minute period, 30 to 45 minutes prior to induction of anesthesia., Measurements and Main Results: After induction of general anesthesia and endotracheal intubation, stomach contents were retrieved and volume and pH measured. Group 1 outpatients had a large residual gastric volume of 29.2 +/- 15.9 ml, with a very low pH of 2.32 +/- 1.23 and 15% frequency of postoperative vomiting. These patients are at high risk of developing significant pneumonitis in the event of the aspiration of gastric contents. The combination of cimetidine and metoclopramide in Group 4 provided the optimal, or safest, condition--i.e., high gastric pH [6.15 +/- 0.71 (p less than 0.005)] and low gastric volume [11.6 +/- 7.37 ml (p less than 0.001)], with no postoperative vomiting., Conclusions: The combination of cimetidine and metoclopramide given to ambulatory patients during the preinductive phase may prevent severe pulmonary consequences should aspiration occur and is more effective in this regard than cimetidine alone.

Stress-related gastric mucosal damage is a common occurrence in intensive care unit (ICU) patients. Because of the significant morbidity and mortality associated with this mucosal damage, many ICU patients routinely receive prophylactic therapy, usually with histamine H2-receptor antagonists (H2RAs). Gastric acid secretion occurs in a circadian pattern, with late afternoon and evening surges. H2RAs by continuous infusion may control this uneven pattern of secretion more effectively than H2RAs given by bolus injection. More studies are needed to identify the target ICU population for prophylactic treatment.

We examined the effect of cimetidine in altering gastric microflora in patients undergoing gastric resection for peptic ulcer disease. Ten patients had administration of cimetidine stopped at least six hours before surgery. Their mean gastric pH was 2.02 +/- 1.51, and 0.4 +/- 0.97 organisms were isolated per patient. Ten patients were maintained on a regimen of cimetidine and their mean gastric pH was 5.69 +/- 1.80, with 3.2 +/- 1.62 organisms isolated per patient. We reached the following conclusions: cimetidine alters the gastric pH of preoperative patients; cimetidine therapy is associated with an increase in gastric flora; stopping administration of cimetidine six hours before surgery reacidifies the stomach, decreases the number of organisms isolated from the stomach, and decreases the risk of septic complications.

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.

Nizatidine (LY139037), a selective histamine H2-receptor antagonist, is a potent inhibitor of gastric acid secretion. It was 17.8 times as active as cimetidine on histamine (10(-5) M)-induced secretion from the isolated gastric mucosa of the bullfrog. Nizatidine was 8.9 times as active as cimetidine on basal acid secretion of the chronic gastric fistula rats after s.c. administration. Against acid secretion from the vagally innervated gastric fistula and Heidenhain pouch of dogs stimulated with submaximal doses of histamine, methacholine and gastrin, nizatidine was, respectively, 6.5, 5 and 4.7 times as active as cimetidine by i.v. administration. Nizatidine was very well absorbed from the gut and was 5 to 10 times as active as cimetidine on gastric acid secretion of dogs induced by submaximal and maximal doses of histamine when given p.o. Equal molar doses of nizatidine showed equal peak effects when given i.v., s.c. or i.m. Pharmacological data indicate that nizatidine is safe and effective as an agent for the control of excessive gastric acid secretion.

A sensitive and specific high pressure liquid chromatographic procedure for ranitidine estimation is described and pharmacokinetic studies in six healthy volunteers reported. Each subjects received 20 mg of ranitidine i.v.; 20 mg, 40 mg and 100 mg orally having fasted overnight and 100 mg with a standard meal. Following the i.v. dose, ranitidine plasma concentrations fell biexponentially with a distribution half-life of 6.1 +/- 0.9 min and a terminal elimination half-life of 1.9 +/- 0.1 h. The volume of distribution was 115 +/- 7 1 and the systemic plasma clearance 709 +/- 62 ml/min. After 20 mg oral doses the systemic availability was high (88 +/- 10%). Bioavailability was unaffected by food and AUC increased linearly with dose to 100 mg. Renal excretion of unchanged ranitidine was between 50 and 70% and a further 1-3% was excreted as desmethylranitidine. In separate studies, the inhibitory action of cimetidine and ranitidine on pentagastrin stimulated gastric acid output was compared in seven duodenal ulcer patients. Results so far indicate that ranitidine 150 mg i.v. produces a more pronounced and more prolonged suppression of pentagastrin stimulated gastric acid output than cimetidine 200 mg i.v. (p less than 0.001). Ranitidine produced a sustained near total (greater than 90%) suppression in acid output in the period 60 to 120 min after drug administration, whereas acid output with cimetidine was less and fell from 82 to 54% in the same period.

Gastric alkalization of critically ill patients is associated with bacterial and fungal overgrowth in gastric contents. We studied the incidence of gastric colonization and its relation to other infections and antibiotic therapy in 25 critically ill ICU patients. All patients received 12-h NG Mylanta II and 15 received an H2-receptor antagonist. All patients had bacterial colonization of NG contents within 4 days of ICU admission and 10 had Candida colonization within 8 days. There were 70 NG isolates and the same isolates were found in tracheobronchial secretions (n = 46), blood (n = 4), urine (n = 4), and wounds (n = 8). Tracheobronchial colonization was preceded by NG colonization with the same organism in 12 instances (11 patients), was concurrent with NG colonization in 20 instances (14 patients), was followed by NG colonization in 14 instances (11 patients), and had no similar NG isolate in 18 instances (11 patients). NG culture of the same organism preceded four of eight positive blood cultures. In 35 of 70 NG isolates and five of 11 subsequent tracheobronchial isolates, colonization occurred despite concurrent appropriate antibiotics. We conclude that colonization of alkalinized NG contents is universal, is a common source of infection in other areas, and is not prevented by systemic antibiotic therapy. Local antibiotic therapy may be important in controlling this important source of infection.

The pentagastrin-induced acid response, alone and versus different doses of cimetidine, was studied in humans. The inhibitory effect of the histamine H2-receptor antagonist cimetidine could only in part be counteracted by increasing doses of pentagastrin. The maximal gastric acid response was significantly decreased by cimetidine, and the ED50 values for pentagastrin showed a minor but still statistically significant increase, indicating both a competitive and a non-competitive inhibition by cimetidine of pentagastrin-induced gastric acid secretion. The pA2 characterization of the receptor mediating the pentagastrin-induced gastric acid response gave a value of 6.2, compared with the pA2 value of the human H2 receptor of 6.1. This suggests that the pentagastrin-induced gastric acid response in humans is mediated via the histamine H2-receptor.

The new histamine-H2-receptor agonist, impromidine, was assessed for its effect on gastric acid secretion using a dose-response format. Maximal acid output and ED50 were calculated for infusions of impromidine in the Heidenhain pouch dog (0.05-1.6 x 10(-8) mol/kg/hr) and in man (0.39-6.22 x 10(-8) mol/kg/hr). Analysis of the responses was carried out by nonlinear regression using the logistic function. This allowed the data to be analyzed without making assumptions about the steepness of the curve which in man was almost twice that found in the dog (1.8:1). The ED50 in the dog was 0.26 +/- 0.029 x 10(-8) mol/kg/hr. The control dose-responses could be inhibited in a competitive manner by histamine-H2-receptor antagonists. Analysis of the control curve and three curves in the presence of increasing doses of antagonist was carried out by fitting all the curves simultaneously to calculate an in vivo ID50. In the dog, the antagonist was tiotidine (0.05, 0.1 and 0.2 x 10(-6) mol/kg/hr) and the ID50 was 0.012 +/- 0.002 x 10(-6) mol/kg/hr. In man, cimetidine (1.05, 2.10 and 4.2 x 10(-6) mol/kg/hr) was used to inhibit secretion. The calculated ID50 was 0.63 +/- 0.085 x 10(-6) mol/kg/hr. Comparison of the effect of cimetidine and tiotidine against both impromidine and histamine showed that the ID50 was the same for both stimulants. Impromidine proved to be a potent stimulant of gastric acid secretion acting via the H2-receptor to produce readily definable dose-response curves in the dog and in man.

Today, the reduction of nocturnal acid secretion is believed to be the most important point in duodenal ulcer therapy. This is supported by the fact that during the day gastric acid secretion is largely buffered by meals. Moreover, independently of food intake the intragastric H+ activity during the day is lower than during the night. During nighttime (2300-0700 h) there was a mean hourly H+ activity of 38 mmol/l--that is, a 65% increase compared with daytime H+ activity with meals--and still a 30% increase without meals. Nocturnal acidity can be suppressed best by single large bedtime doses of H2-receptor antagonists. Cimetidine, 800 mg at night, reduces nocturnal intragastric acidity by 85%; 300 mg ranitidine at night and 40 mg famotidine at night reduce it by 95%. The first clinical trials show that a single nighttime dose of cimetidine or ranitidine is at least as effective in promoting ulcer healing as is twice daily administration.

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.

The 24-h intragastric pH, titrated hydrogen ion concentration, and pepsin concentration were studied in nine peptic ulcer patients during administration of placebo and of 800 mg cimetidine given as two or four equal doses. Cimetidine, 400 mg twice daily, was more effective in reducing acidity during morning (p less than 0.05) and overnight (p less than 0.01) than cimetidine, 200 mg four times daily, which, however, was the most effective regimen during the afternoon (p less than 0.05-0.01). During the 24-h period pH values equal to or above 5 were observed for less than 1 h with placebo treatment, for 1.8 h with cimetidine, 200 mg four times daily, and for 4.7 h with cimetidine, 400 mg twice daily. A new histamine H2-receptor antagonist, oxmetidine, was studied in six other patients, also during a 24-h period. Both 400 mg twice daily and 200 mg four times daily of oxmetidine were superior to placebo (p less than 0.05) in reducing intragastric acidity during the entire 24-h period.

Effects of 4 weeks of treatment with oral cimetidine, 100 mg/kg twice daily, on gastric secretion and plasma gastrin levels were studied in rats. Pylorus ligation-induced and pentagastrin-stimulated gastric secretions were little changed at days 1, 3, and 10 after cessation of cimetidine treatment as compared to the controls. Histamine-stimulated acid secretion was significantly higher in the cimetidine-treated group than in the controls at day 3 after cimetidine treatment but was unchanged at days 1 and 10. A single oral administration of cimetidine at 100 mg/kg significantly increased plasma gastrin levels 4 hr after the treatment in refed rats but not at 2 and 8 hr later. Plasma gastrin levels significantly decreased at days 3 and 10 after cessation of cimetidine treatment as compared to the controls. Thus, while prolonged treatment with cimetidine induces a transient increase in response of parietal cells to histamine and a reduction of food-stimulated gastrin release, it does not seem to induce other appreciable changes in gastric secretion.

Ten duodenal ulcer patients were studied during four 36 h periods, receiving either ranitidine 150 mg twice daily, or ranitidine 200 mg twice daily, or cimetidine 200 mg t.d.s. and 400 mg at night, or placebo. Conditions during the four experimental days were standard. Mean 24 h intragastric hydrogen ion activity on placebo (41.8 +/- 1.5 mmol 1(-1)) was decreased to 21.6 +/- 1.2 mmol 1(-1) on cimetidine, and to 13.1 +/- 1.0 and 12.1 +/- 1.1 mmol 1(-1) by the two dose levels of ranitidine. Nocturnal acid output was decreased by 70% by cimetidine and by 90 and 89% by the two dose levels of ranitidine. In this test system ranitidine was more than four times as potent as cimetidine. Greater decreases in daytime acidity and nocturnal acid secretion were produced by twice-daily ranitidine than by the standard four daily doses of cimetidine

We compared the effect of oral and intravenous ranitidine, a new H2-receptor antagonist, with that of cimetidine on pentagastrin-stimulated gastric acid secretion in normal subjects. Ranitidine in intravenous doses of 20, 60, and 100 mg and oral doses of 100, 150, and 200 mg inhibited acid secretion. Only the 100 mg iv ranitidine dose was substantially more effective than cimetidine. Comparable dose-related decreases in gastric secretory volume were observed. Acid inhibition correlated strongly (r = 0.90) with plasma ranitidine concentration, with the estimated plasma concentration producing 50% inhibition (IC50) being 95 ng/ml. Maximal acid inhibition achieved was 87.3%. We conclude that ranitidine is a potent inhibitor of gastric acid secretion and should be a valuable addition to the medical treatment of acid-peptic disease.

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.

1. The effect of cimetidine on the basal gastric acid secretion of the rat has been investigated in an anaesthetized lumen-perfused preparation. 2. Six rats previously given large doses of cimetidine orally showed no significant difference in basal gastric acid secretion when compared with six control rats. 3. Intravenous administration of 1 mg and 8 mg of cimetidine failed to inhibit significantly basal gastric acid secretion. 4. Although rats with a basal gastric acid secretion above 2.5 micro Eq/10 min. showed a consistent small reduction in basal gastric acid secretion after intravenous cimetidine, this was not seen in rats with a basal gastric acid secretion below 2.5 micro Eq/10 min. 5. THese results contrast sharply with the pronounced inhibition of basal gastric acid secretion by cimetidine in man and the possible reasons for this are discussed. 6. The results are also contrasted with previous work on gastric fistula rats which showed higher basal gastric acid secretion and significant inhibition by cimetidine.

The importance of nocturnal acid secretion has long been acknowledged. The aim of therapy at present is to control acid secretion throughout the entire 24-h period. However, the fact that in DU patients a 400-mg nighttime dose of cimetidine is more effective than a 200-mg one, along with the observation that poorly responsive patients also show little decrease in H+ activity, suggests that a larger single nocturnal dose is an effective primary treatment for DU patients. In studies investigating the effects of different regimens of H2 antagonists on 24-h H+ activity and nocturnal acid secretion in DU patients and healthy volunteers, 400 mg cimetidine twice daily was compared with 800 mg cimetidine at night, 150 mg ranitidine twice daily, 300 mg ranitidine at night, and placebo. In 12 DU patients no significant difference was observed between twice daily or nighttime cimetidine and twice daily or nighttime ranitidine in the reduction of 24-h H+ activity. Cimetidine at night was significantly more effective than the twice daily regimen in reducing nocturnal acid output. Ranitidine, 300 mg at night, decreased nighttime H+ activity more than 800 mg cimetidine at night, although no significant differences in overnight acid output were observed. In another study of four DU patients and four volunteers, 400 mg cimetidine twice daily was compared with 800 or 1200 mg cimetidine at night, 150 mg ranitidine at night, and placebo. All treatments were equally effective at night but had no effect during the day. Hence, early reports seem to confirm that daytime administration of H2 antagonists is unnecessary.

Duodenal ulceration is presumed to be induced and maintained by imbalance between aggressive and defensive factors. Development of drugs for correction of this imbalance has recently concentrated on maximum inhibition of acid secretion e.g. via H2-receptor antagonists but has led to re-evaluation of antacids and antimuscarinics. It has been shown that about the same percentage of ulcers can be healed using low antacid doses or antimuscarinics (e.g. pirenzepine) or doses of H2-receptor antagonists which do not inhibit acid secretion maximally as can be healed using higher doses of H2-receptor antagonists. Avoidance of the intragastric bacterial overgrowth and its consequences and the disturbance of the acid-gastrin feedback mechanism which may follow maximum gastric acid suppression could provide a rationale for use of anti-ulcer therapy based on moderate reduction of gastric acid secretion.

Both pirenzepine and cimetidine have been shown to be beneficial in the healing of duodenal ulcers. The aim of the present study was to determine the effects of 50 mg of pirenzepine BID and 600 mg of cimetidine BID, either alone or in combination, on 24-hour intragastric acidity, nocturnal gastric secretory volume and acid output, and serum gastrin profile in patients with duodenal ulcers. Eight asymptomatic patients with healed duodenal ulcers received placebo, pirenzepine, cimetidine, or cimetidine plus pirenzepine for one week each in a sequential order. All measurements were performed over a 24-hour period on the last day of each treatment week. Compared with pirenzepine, cimetidine was associated with lower hydrogen ion (H+) activities after breakfast, during the night, and over the 24-hour period. Pirenzepine alone failed to suppress H+, but the combination of cimetidine plus pirenzepine resulted in more prolonged acid suppression, with lower H+ after lunch, than did cimetidine alone. The effect of cimetidine on the suppression of nocturnal acid secretory volume and acid output was further enhanced by the addition of pirenzepine. The fasting serum gastrin concentrations were similar in all treatments, excluding one patient with antral G-cell hyperplasia; the postprandial gastrin responses were similarly higher with cimetidine and cimetidine plus pirenzepine than with pirenzepine. The findings suggest an added benefit of combination therapy with cimetidine and pirenzepine that may be useful in patients who fail to respond to single-agent therapy.

Recently it has been reported that anticholinergics were able to increase the inhibitory effect on gastric secretion of specific histamine H2-receptor antagonists. The aim of the present study was to determine the degree of increased inhibition of gastric acid secretion and also to introduce an exact method for measuring the gastric acid output. Maximal gastric acid secretion provoked by continuous pentagastrin infusion 3.4-4.0 micrograms X kg-1 h-1) was dose-dependently inhibited by intravenous (i.v.) atropine (0.002; 0.003; 0.004 mg X kg-1) and cimetidine (1.0; 1.5; 2.0 mg X kg-1). A potentiated synergism was observed on the simultaneous administration of atropine and cimetidine, suggesting the good effect of a low dose combination of atropine and cimetidine in the therapy of peptic ulcer.

We have studied nocturnal acid secretion in patients with duodenal ulcer who met predetermined criteria of poor clinical response to cimetidine. Different groups of patients were investigated receiving either no treatment, cimetidine 1 g/day, cimetidine 2 g/day or cimetidine 1 g/day combined with atropine 4.8 mg/day. The results were compared with those obtained from other patients with duodenal ulcer who were studied in our department but who were not classified as according to their clinical response to cimetidine. The results show that despite adequate absorption, cimetidine has a decreased effect at controlling acid secretion in the poor responders and that increasing the dose of drug does not improve response. Control of acid output was, however, dramatically improved when cimetidine was combined with atropine which suggests that patients who do not respond to H2-receptor blockade should be treated by a combination of cimetidine with an anticholinergic agent.