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A scintigraphic and pharmacokinetic study of the behavior of Bronchoretard forte (theophylline, CAS 58-55-9) was carried out in 8 healthy male volunteers to evaluate the sensitivity of the preparation to changes in gastric pH. The volunteers were pretreated with ranitidine (CAS 66357-35-5) (150 mg b.i.d.) or placebo for three days prior to and on the study day to reduce gastric acidity. The effect of the pretreatment with ranitidine on gastric pH was measured on the day before study begin and the mean pH was significantly increased compared to the placebo (ranitidine pH 2.2 +/- 2.4; placebo pH 1.6 +/- 2.0, p < 0.01 Wilcoxon Signed Rank test). All subjects were pretreated with theophylline for 3 days (500 mg b.i.d.) to achieve steady state. On the study day, the volunteers swallowed two theophylline sustained release capsules, radiolabelled by inclusion of indium-111 micronised Amberlite resin, and the gastrointestinal transit was followed continuously for 14 h using gamma scintigraphy with a further image at 24 h. Blood samples were taken from each subject throughout the study to determine the pharmacokinetic profile of theophylline in the sustained release formulation. No significant differences were found in the gastrointestinal transit of the labelled microparticulates between the data obtained from the group treated with ranitidine and that from the placebo group. Plasma theophylline concentration profiles were identical for the two treatments. These data indicate that the theophylline sustained release formulation is not sensitive to the effects of major changes in gastric H+ concentration.

In a randomized double-blind parallel study the gastroduodenal tolerability of 300 mg acetylsalicylic acid (ASA) daily has been evaluated in the presence of placebo, 15 mg lansoprazole (CAS 103577-45-3, Agopton) and 300 mg ranitidine daily (8 a.m.) in 30 healthy volunteers using upper gastrointestinal tract endoscopy. The treatment periods lasted 14 days. Endoscopic controls were performed at entry and repeated at day 14. At entry, the mean endoscopic score averaged 1.0 +/- 0.0 (+/- SEM) in the ASA/placebo (n = 10), in the ASA/ lansoprazole 15 mg (n = 10) and the ASA/300 mg ranitidine group. In the placebo experiments 300 mg ASA daily induced marked gastroduodenal lesions at day 14 (lesion score of 10.1 +/- 1.4) (+/- SEM). Concomitant administration of 15 mg lansoprazole daily offered significant protection against 300 mg ASA daily on day 14 (3.6 +/- 1.2) (p < 0.05), 300 mg ASA plus 300 mg ranitidine daily reduced the damaging score to 5.8 +/- 1.3 (p n.s. vs ASA/placebo). Our data suggest that co-administration of 15 mg lansoprazole daily reduces significantly gastroduodenal lesions evoked by 300 mg ASA.

Influence of Ranitidine and Famotidine on the Intragastric pH-profile in Healthy Volunteers/Randomised cross-over study of ranitidine effervescent tablets (300 mg) versus famotidine film coated tablets (40 mg). A controlled cross-over trial was carried out to compare the duration of time until the onset of action and its intensity following administration of ranitidine (R, Sostril, CAS 76824-35-6) effervescent tablets (300 mg) and famotidine (F, CAS 76824-35-6) film coated tablets (40 mg). Twelve volunteers (4 female, 8 male) participated in the study. The efficacy of the test medications was assessed by pH-metry during 12 h. The evaluation of the measurements showed that a pH-value 3.5 was reached 100 s after administration of R and 3,392 s (56.5 min) after F (p < 0.01). The median pH-values were significantly higher after R during the first 2 h. The AUC-values (area under the curve; pH-time) for 1, 2 and 4 h were calculated by the trapezoid rule. The intake of R resulted in significantly higher areas than that of F. After reaching the pH-value of 3.5 this value remained stable during the complete period of measurement (R = 12 h, F = 11 h). The faster onset of pH-value elevation could correspond clinically with a faster onset of pain relief.

Circadian Dependency of Ibuprofen Gastropathy and Protective Effect of Ranitidine/An endoscopic, controlled double-blind pilot study. In a randomized parallel double-blind study, the gastric and duodenal effects of 600 mg S(+)-ibuprofen (CAS 15687-27-1) daily in the presence and absence of 300 mg ranitidine (CAS 66357-35-5) was evaluated in 20 healthy volunteers undergoing upper GI-endoscopy. Drugs were taken over a period of 7 days either at 8 a.m. (n = 10) or at 8 p.m. (n = 10). Endoscopic controls were performed at entry and repeated after 7 days of treatment. A damage score according to Lanza et al. was used. At entry both groups showed comparable mucosal damages. 8 a.m.-group: ibuprofen/placebo (stomach) 0.9 +/- 0.1 and 0.0 +/- 0.0 (duodenum); ibuprofen/ranitidine 0.8 +/- 0.1 (stomach) and 0.1 +/- 0.1 (duodenum). 8 p.m.-group: ibuprofen/placebo 0.9 +/- 0.1 (stomach) and 0.2 +/- 0.1 (duodenum); ibuprofen/ranitidine 0.9 +/- 0.1 (stomach) and 0.1 +/- 0.1 (duodenum). After 7 days of treatment the lesion score increased in the ibuprofen/placebo-group in the 8 a.m.-group to 3.2 +/- 1.2 (stomach) and to 0.7 +/- 0.5 (duodenum), and in the 8 p.m.-group to 8.4 +/- 1.9 (stomach) and to 2.9 +/- 1.2 (duodenum). The corresponding values in the ibuprofen/ranitidine-group were 1.8 +/- 0.8 (stomach) and 0.1 +/- 0.1 (duodenum) (8 a.m.-group) as well as 5.1 +/- 1.4 (stomach) and 0.1 +/- 0.1 (duodenum) (8 p.m.-group). The difference between the morning and the evening dose of ibuprofen as well as ranitidine protection reached statistical significance when the corresponding data were pooled (p < 0.05). Our data suggest that the gastrolesive effects of S(+)-ibuprofen are dependent of the time of drug ingestion; protection by ranitidine, however, was time-independent.

Protective Effects of Ranitidine in Stomach and Duodenum against Piroxicam / An endoscopically controlled double-blind study In a randomized parallel double-blind study the gastroduodenal effects of 20 mg piroxicam (CAS 36322-90-4) daily in the presence and absence of 300 mg ranitidine nocte was evaluated in 28 healthy volunteers undergoing upper gastrointestinal endoscopy. Drugs were taken over a period of 14 days. Endoscopic controls were performed at entry, and repeated after 7 and 14 days of treatment. A damaging score according to Lanza et al. was used. At entry, both groups displayed comparable mucosal damages in the stomach (0.9 +/- 0.1) and in the duodenum (0.4 +/- 0.2). After 14 days the mean lesion score increased in the piroxicam/placebo group to 6.3 +/- 1.6 in the stomach and to 4.0 +/- 1.4 in the duodenum. The corresponding values in the piroxicam/ranitidine group were 3.4 +/- 1.0 (stomach) and 0.4 +/- 0.2 (duodenum). This protection afforded by ranitidine was significant when compared with placebo (p < 0.05). Our data suggest that 300 mg ranitidine at night markedly protect the stomach and the duodenum against piroxicam.

In recent years there have been some reports of tolerance occurring in man with the antisecretory effect of H2 antagonists. We, therefore, studied the effect of 300 mg and 600 mg ranitidine (CAS 66357-35-5) daily and increasing i.v. doses of pentagastrin (0.37 microgram/kg, 0.75 microgram/kg, and 1.5 micrograms/kg body weight) on gastric acid output (mmol HCl/30 min) in 9 healthy volunteers. The study design was double-blind, randomized and cross-over. Pentagastrin stimulation was performed on day 1, day 8, and day 16. Increasing i.v. doses of pentagastrin induced an almost identical enhancement of volume secretion, total acid output as well as titratable acidity on the 3 study days. A 16-days treatment period with 300 mg and 600 mg ranitidine led to 80% and 90% inhibition of pentagastrin stimulated acid output. The degree of inhibition evoked by 300 mg and 600 mg ranitidine against pentagastrin was not statistically different during the 16-days treatment period; i.e. no significant tolerance did occur within 16 days. Our data suggest that, in contrast to intragastric acidity measurements, no significant decline of inhibitory effectiveness of ranitidine against i.v. pentagastrin could be observed in healthy male volunteers.

This clinico-pharmacological trial aimed to prove equivalence between the known film-coated tablets of ranitidine (Sostril Filmtabletten) and the novel dispersible tablets for the preparation of a drinkable solution (Sostril Aquatabs) on a pharmacodynamic level. Therefore, the influence of single oral doses of the two ranitidine preparations (2 X 150 mg p.e.m. each) and placebo on the gastric hydrogen ion concentration was studied in 12 healthy volunteers using a randomized cross-over design. pH-values of the gastric juice were measured and recorded continuously for 24 h. Median pH-values for the entire study period were 2.20, 2.15 and 1.40 for dispersible tablets, filmcoated tablets and placebo, respectively. During the night-time median pH-values of 3.45 for both ranitidine preparations and 1.40 for placebo were calculated. From these results it can be concluded that the novel dispersible tablets are equivalent to the ranitidine filmcoated tablets with regard to their pharmacodynamic potency.

The effects of cimetidine and ranitidine on plasma levels of amitriptyline and chlordiazepoxide were examined in a biphasic study with 12 young male volunteers. During the first phase all subjects received a fixed combination of 2 X amitriptyline (25 mg) and chlordiazepoxide (10 mg) daily for one week. After the last dose blood samples were drawn up to 72 hours in order to detect plasma levels of the drugs and their main metabolites. Following a wash-out-period of 7 days two groups of 6 subjects, each were formed in a randomized order. In addition to the mentioned medication 3 X 200 mg plus 1 X 400 mg of cimetidine daily or 2 X 150 mg of ranitidine daily were administered for one week. After discontinuation of amitriptyline/chlordiazepoxide the medication with H2-blockers was kept and blood samples were collected again for plasma analysis. Plasma level detections were carried out employing HPLC. The change of the area under the plasma level-time curve (AUC), total clearance and terminal half-life served as parameters indicating interaction. Under treatment with cimetidine plasma levels of amitriptyline and chlordiazepoxide were significantly (5%) increased, whereas such effects could not be observed with ranitidine. Due to these interactions under the conditions of coadministration of H2-blockers and amitriptyline and/or chlordiazepoxide the use of ranitidine is recommended.

12 healthy volunteers participated in this double-blind, randomized, cross-over study. All subjects were given indomethacin (50 mg tid) or acemetacin (60 mg tid) for 6 days in the presence and absence of ranitidine 300 mg at night. At day 6 120 minutes after the last morning dose an endoscopy was performed and the appearance of the gastric and duodenal mucosa was noted. In the indomethacin experiments mean lesion score averaged 2.2 +/- 0.2 (+/- SEM) when placebo was coadministered. In the corresponding acemetacin-series the lesions score was 1.6 +/- 0.1 (+/- SEM). A reduction in mucosal damage occurred in both NSAID-groups when ranitidine 300 mg at night was given concurrently: The mucosal lesions score was reduced to 1.7 +/- 0.2 and to 1.0 +/- 0.1 (+/- SEM), respectively. This protection afforded by ranitidine was significant when compared with placebo (p less than 0.05). In 8 subjects plasma concentrations of acemetacin and indomethacin were determined on day 1 and day 5. The AUC-values of indomethacin and acemetacin in the presence and absence of ranitidine were almost identical when analysed by the paired T-test. The mean plasma concentrations of both antirheumatic agents did not show any difference when coadministered with placebo or ranitidine. Our data suggest that 300 mg ranitidine at night improves the gastroduodenal tolerability of both indomethacin and acemetacin without affecting main pharmacokinetic parameters of both antirheumatics.

An inhibition of acetylcholinesterase activity by ranitidine and cimetidine as described by Hansen and Bertl (Z. Gastroenterol. 21: 164, 1983; Arzneimittelforsch. 33: 161, 1983) could only be confirmed by use of 1000-fold higher concentrations of the H2-antagonists (ID50 for ranitidine: 3,2 X 10(-4) M, for cimetidine: 3,1 X 10(-2) M) than those reported by the authors. The discrepancy may be explained by the fact that the authors did not consider the dilution factor in their method. In a typical therapeutic situation in 8 patients with ranitidine 150 mg twice daily and cimetidine 400 mg twice daily an inhibiton of the acetylcholinesterase could not be demonstrated. The inhibition of the acetylcholinesterase activity by H2-antagonists is of no practical relevance.

Cells were isolated by use of collagenase, EDTA and pronase form human gastric mucosa obtained at peptic ulcer surgery (n = 61) or at Whipple's operations (n = 6). Enriched parietal cell fractions were prepared by isopycnic centrifugation with Percoll. H+ production, intracellular instrinsic factor and histamine content were maximal in the low density fraction containing 75% parietal cells and--among other nonparietal cell types--mast cells. H+ production, intrinsic factor secretion and adenylate cyclase-activity responded to histamine stimulation in a concentration dependent manner. Response was blocked by histamine H2 receptor antagonists (rantidine, famotidine). Dibutyryl cAMP and the phosphodiesterase inhibitor IMX were the most powerful stimuli whereas carbachol, hexoprenaline and pentagastrin were less effective. Prostaglandin E2 and 6-keto-PGF2 alpha occurred in the highest concentrations in the low density cell fraction. PG production increased linearly for 15 min and seemed to be influenced by the intracellular calcium level.

The potency and duration of action of a single dose of etintidine, ranitidine and cimetidine were compared in placebo-controlled studies. In addition, the effect of a single night-time dose of etintidine (600 mg) on gastric acid secretion and basal hormone levels was assessed before, during and after a 28-day treatment. Nocturnal gastric acidity (23.00-07.00) was inhibited from 41.04 +/- 5.0 mmol/l to 12.9 +/- 2.8 mmol/l by 300 mg etintidine, to 6.50 +/- 2.5 mmol/l by 600 mg etintidine and to 8.58 +/- 2.5 mmol/l by 800 mg cimetidine nocte. Etintidine and cimetidine did not reduce H+-concentrations during the following day. Pentagastrin-stimulated acid output was virtually not affected after 600 mg etintidine and 800 mg cimetidine as well. By contrast, stimulated acid secretion was still suppressed by about 50% following 300 mg ranitidine. Basal levels of testosterone, prolactin etc. remained unchanged by 28-day etintidine (600 mg dose at night) treatment. Clinical studies are needed to examine the place of the single dose of etintidine (600 mg) at night for the short-term treatment of duodenal ulcer.

Many drugs potentiate the action of non depolarizing relaxants. These interactions are of clinical importance if such drugs are administered during the perioperative period. H2 Antagonists are increasingly often used for premedication. Cimetidine inhibits the elimination of a number of drugs used in the perioperative period. We therefore investigated whether H2 antagonists enhanced neuromuscular blockade by vecuronium, a medium short acting non depolarizing muscle relaxant. METHODS. The study was carried out in 24 female patients (ASA class I or II) scheduled for microsurgical procedures. Neuromuscular transmission was recorded electromyographically using four stimulations every 20 s to the ulnar nerve. After induction with thiopentone, anesthesia was maintained with fixed concentrations of volatile anesthetics. Fentanyl was administered for additional analgesia. Vecuronium was used as the sole muscle relaxant. Fixed repetitive doses of vecuronium (0.8-1.2 mg) were injected whenever the T1 returned to 25%. This time interval was defined as the T1-25 period. The study proper started when the T1-25 period had stabilized. After two control periods, six patients in each group received either 200 or 400 mg cimetidine or 100 mg ranitidine. The fourth group was the control group. The T1-25 periods and the maximal EMG depression were recorded automatically for at least two further periods. The first measured period was recorded as 100% and the length of each other periods was calculated as a percentage of the control period. This method enables an intraindividual comparison of the length of the T1-25 period and the maximal EMG depression before and after administration of the H2 antagonists. A two-tailed Student's t-test was used to test statistical significance, P less than 0.05 being accepted as significant. RESULTS. In the control group and in the group with 200 mg cimetidine or 100 mg ranitidine no statistical significant prolongation of the T1-25 period or of the maximal EMG depression could be observed, while after 400 mg cimetidine there was significant prolongation (mean 161 +/- 14.8%) of the T1-25 period and significantly greater EMG depression compared with the pre-cimetidine values. In the groups with 200 mg cimetidine or 100 mg ranitidine few patients showed prolongation of the T1-25 period up to 130%. DISCUSSION. Our results confirm experimental studies that have shown cimetidine to enhance aminoglycoside--relaxant interactions. Because we found an immediate response to the administration of the H2 antagonists, the interaction cannot be on the elimination side; it must be at the neuromuscular junction. Experimental investigation has shown that calcium reverses the cimetidine effects. It is therefore probable that the cimetidine--relaxant interaction occurs at the presynaptic level. Careful observation seems to be necessary if H2 antagonists, especially cimetidine, are administered intraoperatively at the same time as drugs that also enhance

The deleterious effects of acetylsalicylic acid (ASA) on gastric mucosa have been well documented in experimental and clinical studies. With a direct endoscopic assay system we evaluated in healthy volunteers whether pretreatment with prostaglandin analogues (misoprostol, rioprostil), omeprazole and ranitidine prevented ASA-induced gastric mucosal injuries. Ranitidine (2 X 150 mg/d) in large antisecretory doses almost completely abolished these changes (p less than 0.05). By contrast, misoprostol (4 X 50 micrograms/d and 4 X 200 micrograms/d), rioprostil (3 X 100 micrograms/d), omeprazole (5 mg and 10 mg/d) as well as ranitidine in non-antisecretory doses (2 X 25 mg/d) did not reduce gastric mucosal injury after single-dose ASA administration. The results of this trial indicate that socalled cytoprotective doses of prostaglandins, omeprazole and ranitidine in contrast to animal findings are not effective in preventing acute ASA-induced mucosal damage.

PABA-serum and urine-concentration were studied in patients with normal, pathologic and pharmacologically inhibited pancreatic function. Secretin-pancreozymine test was selected as reference method. In patients with normal pancreas function and volunteers, PABA-serum-concentration was characterized by a rapid increase during the first 1 1/2 hours. A maximum increase of 32.42 +/- 10.04 mumol/l was reached after 90 minutes. In patients with exocrine pancrease insufficiency, difference to the control group was greatest after 30, 60, 90, and 120 min. Pharmacologic inhibition of the exocrine pancreas using pirenzepine also resulted in a significantly reduced PABA-serum-concentration after 30, 60 and 90 min. In correspondence to the delayed and smaller serum PABA increase, urine-PABA-concentrations were also diminished. Our results indicate that the optimal interval to differentiate between normal and impaired pancreas function with use of serum PABA determination is at 90 min after test begin.

After obtaining their informed consent, 60 patients (ASA groups I or II), 18 to 60 years of age were randomly allocated to six groups of 10 persons each. Anesthesia was induced in groups 1, 4, 5 and 6 with 2-3 mg kg-1 thiopentone and in groups 2 and 3 with 0.2-0.3 mg kg-1 etomidate. 20 min before induction, patients in groups 3 and 5 received 5 mg kg-1 cimetidine, and patients in group 6 received 1.25 mg kg-1 ranitidine. Induction of anesthesia was supplemented by 0.002 mg kg-1 fentanyl and 0.01 mg kg-1 lormetazepam. After beginning neuromuscular monitoring, 0.08 mg kg-1 vecuronium was injected and the intubation accomplished when the first twitch of the train of four (TOF) was suppressed of a rate greater than 90%. The anesthesia was maintained with supplemental doses of 0.002 mg kg-1 fentanyl and 0.01 mg kg-1 lormetazepam, if necessary, and the use of a nitrous oxide/oxygen mixture (2.4:1.6 l min-1). A train of four supramaximal nerve stimuli was applied to the ulnar nerve proximal to the wrist and the twitch responses were electrically recorded on the hypothenar musculature (Relaxograph, Datex). The frequency of the train was 2 Hz with an interval of 20 s between trains. The time from the injection of vecuronium to several degrees of neuromuscular recovery was statistically significantly prolonged after 5 mg kg-1 cimetidine (groups 3 and 5) in comparison to the other groups.(ABSTRACT TRUNCATED AT 250 WORDS)

The inhibition of 7-ethoxycoumarin deethylase activity by four different H2-receptor antagonists was studied using rat liver microsomes. The compounds tested represent two classes of H2-antagonists, i. e. structures with (cimetidine and oxmetidine) and without (ranitidine and SKF 93479) an imidazole ring. The microsomes were prepared from untreated and phenobarbital-treated animals. It was found that all four compounds, even those without an imidazole ring, inhibited deethylase activity. The compounds inhibited in the following order: SKF 93479 (90%) greater than cimetidine (58%) = oxmetidine (58%) greater than ranitidine (23%). In microsomes from phenobarbital-induced animals, the inhibitory activity of oxmetidine was increased 5-fold. Only the inhibitory potency of cimetidine was increased by preincubation of the H2-antagonist with the microsomes prior to the addition of the substrate.

The potency and duration of a single dose of ranitidine and famotidine were compared in placebo-controlled studies. In addition, the effect of a single night-time dose of famotidine (40 mg) on gastric acid secretion and basal hormone levels was assessed before, during and after a 28-day treatment. Basal acid secretion was depressed by about 73% and 76% 12 hours after 300 mg ranitidine and 40 mg famotidine respectively. Pentagastrin-stimulated acid output was reduced by about 26% and 29%. 20 hours after both drugs, basal secretion was still inhibited by about 60%, whereas no effect on stimulated acid secretion could be detected. Nocturnal gastric acidity (23.00-07.00) was inhibited from 35.8 +/- 4.6 mmol/l to 1.8 +/- 0.5 mmol/l (94% inhibition) by 40 mg bedtime famotidine , and to 1.7 +/- 0.5 mmol/l (95% inhibition) by 300 mg ranitidine. Both drugs significantly reduced H+ concentrations during the following day. On day 29, i.e. 12 hours after the last famotidine dose, basal and stimulated acid secretion was reduced by some 50% and 26% respectively. On day 35, gastric acid output had returned to pretreatment values. Basal levels of prolactin, testosterone etc. were unchanged by 28-day famotidine treatment. Rantidine and famotidine may therefore be used as a single night-time dose in the acute treatment of peptic ulcer disease.

In a randomized, double-blind, placebo-controlled, comparative cross-over study, we studied the effect of four H2-receptor antagonists on intragastric 24-hour acidity, nocturnal volume and acid output. Ten healthy male volunteers were administered 300 mg or 150 mg nizatidine, 800 mg cimetidine, 300 mg ranitidine, 40 mg famotidine, or placebo on several days, in each case at 9:000 PM. Nocturnal intragastric H+ concentration (mmol/l) (11:00 PM to 7:00 AM) was significantly reduced by all H2 blockers compared with placebo. We obtained the following inhibition rates: Cimetidine 67%; ranitidine 95%; famotidine 89%; nizatidine 80% (300 mg) and 69% (150 mg). Nocturnal acid (mmol/l) and volume output (ml/h) were also significantly (compared with placebo) inhibited by all four H2-receptor antagonists. Inhibition of nocturnal acid secretion was almost identical on nizatidine 300 mg nocte, ranitidine 300 mg nocte, famotidine 40 mg nocte, and cimetidine 800 mg nocte. Nizatidine 300 mg nocte and 150 mg nocte exclusively reduced acid secretion at night, without an aftereffect into the following day (8:00 AM to 6:00 PM). These results suggest that the clinical efficacy of these H2-receptor antagonists is identical with respect to healing peptic ulcer disease and providing freedom from pain. It is generally accepted today that gastric acid inhibitors used in the treatment of peptic ulcer disease should interfere with daytime gastric acid secretion as little as possible, particularly since the acid protects the stomach from bacteria ingested with the food during the day.