Control of intragastric acidity with over-the-counter doses of ranitidine or famotidine

BACKGROUND: Histamine H2-receptor antagonists are available over the counter for the treatment of heartburn. AIM: To compare the effects of low doses of ranitidine and famotidine on intragastric acidity in a three-way crossover study. METHODS: Healthy subjects (12 male, 12 female) were dosed on three occasions with single oral doses of placebo, ranitidine, 75 mg, and famotidine, 10 mg, 1 h after lunch. The pH of gastric aspirates was then measured for 20 h. Subjects ate standard meals and snacks. Analysis of variance was used to determine the statistical significance of differences in acidity (mmol/L) during the day (12.30-22.30 hours) and night (22.30-08.30 hours). RESULTS: Ranitidine and famotidine were superior (P < 0.05) to placebo in decreasing acidity for daytime and night-time intervals. There were no significant differences in mean gastric acidity between ranitidine and famotidine during the daytime (11.37 mmol/L vs. 13.42 mmol/L, respectively) and night-time (23.57 mmol/L vs. 24.74 mmol/L, respectively). Intragastric acidity after ranitidine was significantly lower than that after famotidine in the first 2.5-h period following dosing (4.32 mmol/L vs. 9.28 mmol/L; P < 0.05). CONCLUSIONS: Lunchtime doses of ranitidine and famotidine decreased acidity during day- and night-time periods. The effect of ranitidine was significantly greater for the first 2.5 h after dosing.     

Comparison of famotidine with cimetidine and ranitidine

The pharmacodynamic, therapeutic, and toxicologic properties of famotidine are evaluated and compared with those of cimetidine and ranitidine. Famotidine, an H2-receptor antagonist with a thiazole nucleus, is approximately 7.5 times more potent than ranitidine and 20 times more potent than cimetidine on an equimolar basis. Therapeutic trials indicate that famotidine 20 mg b.i.d. or 40 mg at bedtime is as effective as standard doses of cimetidine and ranitidine for healing duodenal ulcers. A dose of 40 mg at bedtime appears to heal benign gastric ulcers. A single nocturnal dose of 20 mg is effective in preventing duodenal ulcer relapse. Further studies are required that compare the efficacy of famotidine with cimetidine and ranitidine in the treatment of gastric ulcers and in the prevention of recurrent duodenal ulcers. The overall incidence of adverse effects observed with famotidine appears to be similar to that reported for cimetidine and ranitidine. Like ranitidine, famotidine does not have antiandrogenic effects or substantially inhibit the hepatic metabolism of drugs. Because of its increased antisecretory potency and lack of antiandrogenic effects at higher doses, famotidine may be the H2-receptor antagonist of choice in treating Zollinger-Ellison syndrome. Additional clinical experience, as well as cost and safety factors, will determine the place of famotidine in treating and preventing acid-peptic disorders.     

Impact of food intake on the antisecretory effect of low-dose ranitidine and famotidine

BACKGROUND: Over-the-counter status has recently been approved for low-dose H2-antagonists in several countries. Insufficient information is currently available on the effect of food in low-dose H2-antagonist therapy. AIM: Compare the antisecretory efficacy of low-dose ranitidine and famotidine in fasting and non-fasting volunteers. METHODS: Twenty volunteers were randomized into a double-blind, placebo-controlled, multiple-step crossover study comparing the antisecretory efficacy of 75 mg ranitidine, 10 mg famotidine and placebo over 12 h using intragastric pH-metry. Two standard meals were given after 4 h and 8 h of medication. Fifteen volunteers also participated in a second study comparing the antisecretory effect of both drugs, both with and without meals. RESULTS: In non-fasting subjects, the percentage of time with pH > 4 was similarly elevated for both drugs compared with placebo over the first 8 h: ranitidine 39.3%, famotidine 29.5%, placebo 9.5% (P < 0. 001); but not for the last 4 h after the second meal (P > 0.05). Comparing the first 4-h period with the second, the percentage of pH > 4 was significantly reduced for both drugs in the second period in the subjects given food at the end of the initial 4-h period (ranitidine 56.9% vs. 26.6%, P = 0.005; famotidine 46.6% vs. 13.3%, P < 0.001). It remained more or less constant, however, for the second 4-h period in fasting subjects (ranitidine 41% vs. 28.1%, P = 0.46; famotidine 52.7% vs. 52.2%, P = 0.12). CONCLUSION: In non-fasting volunteers both low-dose H2-antagonists had comparable antisecretory effects and were superior to placebo over the first 8 h of therapy. Both drugs achieved a slightly higher antisecretory effect without food intake compared to with food intake.     

Interaction of ranitidine and famotidine with guinea pig-isolated parietal cells

The inhibitory effects of the histamine H2-receptor antagonists, ranitidine and famotidine on histamine-stimulated gastric acid secretion have been studied in guinea pig isolated, enriched parietal cells using the 14C-aminopyrine accumulation technique. The 14C-aminopyrine accumulation curves in response to histamine were shifted towards the right in a parallel fashion by ranitidine, and in a nonparallel fashion by famotidine. The inhibitory effect of ranitidine, but not that of famotidine, was readily reversed by washing the parietal cells. It is concluded that the histamine H2-receptors in guinea pig parietal cells are blocked competitively and reversibly by ranitidine, but noncompetitively and partially reversibly by famotidine.     

Implementing therapeutic interchange of intravenous famotidine for cimetidine and ranitidine

The steps taken to implement a therapeutic interchange program for i.v. histamine H2-receptor antagonists and to determine the potential cost savings are described. A literature review conducted by pharmacists at a 273-bed nonteaching community hospital showed that i.v. famotidine was as safe and effective as i.v. cimetidine or ranitidine and that it was feasible to add famotidine to total parenteral nutrition (TPN) solutions. Because of famotidine's cost advantage, it was proposed that i.v. famotidine be used in place of specific dosage regimens of i.v. ranitidine or cimetidine and in TPN solutions ordered for patients receiving concurrent H2-antagonist therapy. The approval of the hospital attorney and hospital gastroenterologists was secured, and a formal proposal was submitted. The pharmacy department distributed a memorandum describing the advantages of famotidine, conducted inservice education sessions, and sought the compliance of physicians by placing reminders on order forms and patient charts and by contacting physicians directly. The program was implemented in May 1989. During the first three months, only one physician insisted that patients receive i.v. ranitidine rather than famotidine. It was projected that the interchange of i.v. famotidine for cimetidine or ranitidine would result in a total savings of $37,565 during the first year due to reductions in the cost of drugs, supplies, and nursing labor. The acceptance of a therapeutic interchange program for H2 antagonists was excellent, and the projected savings are substantial.     

A single night-time dose of famotidine is equivalent to ranitidine in decreasing 24-hour gastric acidity in asymptomatic duodenal ulcer subjects

Six asymptomatic, non-smoking men with endoscopically proven duodenal ulcer disease received single nocturnal doses of placebo, 40 mg famotidine and 300 mg ranitidine each for 1 week prior to serial measurement of pH, peptic activity and serum gastrin concentrations over 24 h and of acid output. The intragastric pH fluctuated between 1.53 and 5.07 when subjects were given placebo but within 2 h of taking famotidine or ranitidine it rose to 5.57 or higher; the effect lasted for 12 h from midnight. Peptic activity fell during famotidine and ranitidine treatment and the decline was somewhat greater 8-15 h after using famotidine. Serum gastrin levels did not change materially with any treatment. The study shows the equivalent effect of standard bed-time doses of famotidine and ranitidine on intragastric pH, acid output and serum gastrin concentrations in asymptomatic men with duodenal ulcer disease.     

Comparison of the effect of the antacid Rennie versus low-dose H2-receptor antagonists (ranitidine, famotidine) on intragastric acidity

Background:

Symptoms of functional dyspepsia are common and patients often self-medicate with antacids, or with low-dose H₂-antagonists which are available as over-the-counter medications. To date, there has been limited information available comparing the effects on intragastric acidity of these two types of over-the-counter medication. Therefore we studied the effect of the antacid Rennie and two H₂-antagonists on the intragastric pH of fasting volunteers.

Methods:

Sixteen healthy, fasting volunteers were randomized into a double-blind, placebo-controlled, four-way crossover study comparing Rennie (calcium-magnesium carbonate) 1360 mg, ranitidine 75 mg, famotidine 10 mg and placebo. Their effect on gastric pH was monitored by a 4-h gastric pH-metry. The primary efficacy parameter was the time lag before an intragastric pH > 3.0 was reached after drug administration.

Results:

The median time lag before pH > 3.0 was reached after drug administration was 5.8 min for Rennie, 64.9 min for ranitidine, 70.1 min for famotidine and 240.0 min for placebo. The percentage of time with values of pH > 3.0 was 10.4% for Rennie, 61.4% for ranitidine, 56.6% for famotidine and 1.4% for placebo.

Conclusion:

The onset of action in fasting volunteers was significantly faster with the antacid than with the two H₂-antagonists. The duration of action was significantly longer with an H₂-antagonist than with the antacid. This suggests that the two products should be used for different indications: antacids are superior for rapid pain relief, whereas H₂-antagonists might be better for symptom prophylaxis—for example for nocturnal dyspepsia.

     

Changes in the effects of nizatidine and famotidine on cardiac performance after pretreatment with ranitidine

Summary This was an open, randomized study of the cardiovascular effects of the histamine H₂ receptor antagonists ranitidine, famotidine, and nizatidine after single oral doses alone or in combination in healthy volunteers.When compared with placebo ranitidine (450 mg) did not have any haemodynamic effects. Nizatidine (300 mg) caused significant falls in heart rate and cardiac output. Famotidine (40 mg) caused significant falls in stroke volume and cardiac output and an increase in pre-ejection period.Pretreatment with ranitidine abolished the haemodynamic effects of nizatidine and caused a time-shift of 2 h in the onset of the cardiovascular effects of famotidine.The difference in the results for nizatidine and famotidine can be explained by the longer half-life of famotidine. Vascular effects are assumed to be responsible for impairment of cardiac performance by famotidine.     

Effect of ranitidine and indomethacin on nocturnal gastric acidity in normal subjects

To assess the effect of indomethacin on gastric acidity and to identify a potential pharmacodynamic interaction between indomethacin and ranitidine, we measured nocturnal acidity on half-hourly aliquots of gastric contents from 10 volunteers on the seventh day of four dosing regimens given in a randomized double-blind manner. These were indomethacin (50 mg t.d.s.) and ranitidine (300 mg in the evening) together or alone with matching placebos. Median nocturnal acidity on placebo was 41.7 mmol/L (range 67.6-25.1 mmol/L) and was 39.8 mmol/L (63.1-24.0 mmol/L) on indomethacin (N.S.). During ranitidine dosing it was 0.4 mmol/L (21.3-0.0 mmol/L) without and 0.8 mmol/L (43.7-0.0 mmol/L) with concurrent indomethacin, representing 99 and 98% decreases in gastric acidity (P less than 0.01) compared with placebo. Indomethacin did not increase overnight gastric acidity and did not influence the suppression of acidity produced by ranitidine. It is unlikely that the ulcerogenic potential of indomethacin is explicable by an effect on gastric acidity.     

The effect of ranitidine, cimetidine or famotidine on low-dose post-prandial alcohol absorption

Plasma alcohol concentration following oral ingestion of 0.3 g/kg of alcohol (ethyl alcohol), one hour after an evening meal, was measured in four groups of 12 healthy subjects. Each group had a control study and a repeat study after 7 days dosing with either placebo or an H2-receptor antagonist (300 mg ranitidine nocte, 800 mg cimetidine nocte, or 40 mg famotidine nocte). There was no significant difference between the control and post-dosing studies in the integrated 4-h plasma alcohol concentration, peak plasma alcohol concentration, or time to reach peak alcohol concentration. This study shows that post-prandial alcohol absorption after 0.3 g/kg of alcohol is not affected by ranitidine, cimetidine or famotidine.     

The antisecretory profile of action of the H2-receptor antagonists, famotidine, loxtidine, ranitidine and L-643,441 on the rat isolated gastric mucosa

Four H2-receptor antagonists, famotidine, loxtidine, ranitidine and L-643,441 were tested against gastric secretory concentration-response curves to histamine, methacholine and dibutyryl cyclic AMP (dbcAMP) on the rat isolated gastric mucosa. All four drugs inhibited the secretory response to histamine, but the nature of this H2-receptor antagonism differed according to the drug. Ranitidine and famotidine were competitive, fully surmountable antagonists of histamine, but loxtidine and L-643,441 were unsurmountable antagonists. At high concentrations, the H2-receptor antagonists caused a small inhibition of the secretory response to methacholine but had no effect on the secretory response to dbcAMP. The rat isolated gastric mucosa is a useful preparation for characterisation of the antisecretory effects of H2-receptor antagonists.     

Effects of famotidine at the mouse neuromuscular junction compared with those of cimetidine and ranitidine

The effects of some histamine H2-receptor antagonists on the cholinergic system have been evaluated at the mouse end-plate. Previous data revealed interactions at both pre- and postsynaptic sites for cimetidine and ranitidine. The present work shows the effects of the same two drugs, and of famotidine, on some parameters related to the neuromuscular transmission. Ranitidine potentiates the amplitude of the spontaneously occurring miniature end-plate potentials. Famotidine reduces the same parameter. A common effect achieved with higher concentrations of the three drugs is the reduction of the quantal content. The kinetic parameters of the quantal conductance change is lengthened, in a different manner, by all the assayed drugs too. These results, besides strengthening the hypothesis of an inhibitory action of ranitidine on acetylcholinesterase, indicate a collateral inhibitory effect at presynaptic levels of cimetidine, ranitidine and famotidine.     

The effects of cimetidine, ranitidine and famotidine on rat hepatic microsomal cytochrome P-450 activities

It has been questioned whether the interaction of H2-antagonists with cytochrome P-450 that is observed in vitro is also relevant for the in vivo situation. Until now the possibility that cytochrome P-450 may function with different modes of action has been neglected in this respect. We studied the effect of cimetidine, ranitidine and famotidine on the monoxygenase, the oxidase and the peroxidase action of cytochrome P-450. Biotransformation catalyzed by the monoxygenase and oxidase action of cytochrome P-450 was affected by cimetidine (probably via its ligand interaction with cytochrome P-450), whereas metabolism by the peroxidase mode of action of cytochrome P-450 was hardly influenced. Ranitidine and famotidine (both pharmacodynamically more potent than cimetidine) only slightly affected cytochrome P-450 activities.     

Effects of short- and long-term administrations of famotidine and ranitidine on some pituitary, sexual and thyroid hormones

The endocrine effects of short-term (4 weeks) and long-term (6 months) oral administration of famotidine (40 and 20 mg nocte, respectively) and ranitidine (300 and 150 mg nocte, respectively), were investigated in 20 male patients with duodenal ulcers. Basal PRL, LH, FSH and TSH serum levels were evaluated and their response to specific releasing factors, and basal blood levels of some sexual (E2, P, T) and thyroid (T3, T4) hormones. None of the treatments modified basal and RH-stimulated levels of PRL, LH, FSH and TSH, nor basal levels of sexual hormones. Regarding the thyroid hormones, no effect was observed during the administration of famotidine. On the contrary, short-term treatment with ranitidine induced a significant decrease in thyroxine serum levels, while no effect was observed during maintenance treatment.     

The effects of low doses of ranitidine on intragastric acidity in healthy men

Background:

H₂-receptor antagonists are becoming widely available as over-the-counter medications for the treatment of heartburn and excess gastric acidity.

Aim:

To determine the effects of single low doses of ranitidine on intragastric acidity.

Methods:

Intragastric pH was measured for 9 h after lunch in five studies involving 24 healthy male volunteers. Antacid was given to all subjects on day 1. They then received single oral doses of a study drug 45 min after lunch on four separate occasions: placebo and either ranitidine 25 mg, 75 mg or 125 mg were given double-blind according to a predetermined randomization schedule.

Results:

During both of the post-dosing time periods (0–5 h and 5–9 h) there were significant decreases in integrated intragastric acidity for each ranitidine dose compared with placebo (P < 0.0001). There was a significant linear relationship between dose and integrated intragastric acidity with a greater decrease in acidity with increasing ranitidine doses (P < 0.0001). Compared with placebo, time with pH > 3 was significantly greater for ranitidine 75 mg and 125 mg (P < 0.001), but not ranitidine 25 mg. Results with the antacid were similar to placebo.

Conclusions:

Using low doses of ranitidine (25, 75 or 125 mg) there was a dose-related decrease in intragastric acidity for 9 h after dosing. A single dose of antacid did not decrease intragastric acidity significantly.

     

Direct determination of ranitidine and famotidine by CE in serum,urine and pharmaceutical formulations

A simple and sensitive capillary electrophoresis method using UV detection has been developed for the direct determination of ranitidine (RANT) and famotidine (FAMT) in serum, urine and pharmaceutical formulations. A buffer consisting of 60 mM phosphate buffer adjusted to pH 6.5 was found to provide a very efficient and stable electrophoretic system for the analysis of both drugs. The detection limits obtained were 0.088 microgram ml(-1) for RANT and 0.16 microgram ml(-1) for FAMT.