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Biomedical subjects

W O Frank

Publications and source records attributed to W O Frank.

At least 19 recordsLinked to original sources
PubMed1991

Effects of various concomitant medications on gastric alcohol dehydrogenase and the first-pass metabolism of ethanol.

Inhibition of gastric alcohol dehydrogenase (ADH) has been shown to enhance alcohol absorption in man under certain circumstances. To determine whether various medications might affect alcohol absorption, we screened 18 compounds for an effect on ADH. Salicylic acid, acetaminophen, propranolol, ethacrynic acid, and three H2-receptor antagonists all inhibited rat gastric ADH in vitro, indicating that several commonly used medications have the potential to enhance alcohol absorption. Of these, cimetidine, ranitidine, and nizatidine were studied further to define their effect on alcohol absorption in man and to assess the clinical relevance of the effect. Both ranitidine and nizatidine enhanced the absorption of small doses of alcohol (0.15 g/kg) in the morning by 63% and 64% and increased Cmax by 48% and 54% respectively (p less than 0.001), effects similar to those reported by others for cimetidine. The effect of ranitidine given before dinner was greatly attenuated with increases in Cmax of 8% (NS) and AUC of 21% (p = 0.02). Cimetidine 800 mg hs did not affect the absorption of 0.15 g/kg alcohol given in the evening, and cimetidine 400 mg bid decreased absorption by 14% (p = 0.11). Cimetidine 300 mg qid had no effect on larger doses of alcohol given at dinner. We conclude that many commonly used medications affect gastric ADH, but that the increase in the actual amount of alcohol absorbed is quite small, and demonstrable only under special conditions.

Acetaminophen↗
PubMed1990

Cimetidine 800 mg twice daily for healing erosions and ulcers in gastroesophageal reflux disease.

Although H2-receptor antagonists have been the mainstay of therapy for gastroesophageal reflux disease (GERD), none of these agents has been approved by the FDA as effective in healing lesions. Since proton pump inhibitors may be associated with long-term disadvantages, a healing regimen with cimetidine would be useful clinically. This multicenter, randomized, double-blind study was conducted to evaluate the efficacy of cimetidine 800 mg b.i.d. in healing lesions and in providing symptomatic relief in patients with ulcerative or erosive esophagitis. Patients with greater than or equal to 8 heartburn episodes during a 1-week screening period, reflux confirmed by esophageal pH monitoring, and esophageal ulcers or erosions confirmed by endoscopy were randomized to treatment with placebo or cimetidine for 12 weeks. Cimetidine provided significantly greater (p less than 0.01) improvement (74% vs. 51%) and complete healing (67% vs. 36%) of esophageal lesions than did placebo. In these patients with erosive or ulcerative esophagitis, the median time to achieve 24 h without heartburn was 13 days with cimetidine and 30 days with placebo (p = 0.01). The mean heartburn severity score in the cimetidine group decreased rapidly during the first week and was consistently lower than in the placebo group. Cimetidine, 800 mg twice daily, is effective in promoting healing of esophageal ulcers and erosions and in providing heartburn relief in patients with symptomatic erosive/ulcerative GERD.

Adult↗
PubMed1990

Maintenance therapy of duodenal ulcer with H2-receptor antagonists--a meta-analysis.

A theoretical basis for similar recurrence rates among H2-receptor antagonists exists based on recent concepts of ulcer recurrence, ulcer healing and suppression of nocturnal gastric acidity. In order to compare H2-receptor antagonists in the maintenance therapy of duodenal ulcer, a meta-analysis was carried out using 29 studies in the literature that met strict criteria. When the results of the placebo-controlled studies were expressed as odds ratios, a technique used to minimize differences in protocol design and patient populations among studies, cimetidine, ranitidine, famotidine and nizatidine were all found to be superior to placebo to approximately the same extent. Odds ratios (and 95% confidence limits) for the recurrences in the pooled studies were cimetidine 0.22 (0.18-0.28), ranitidine 0.23 (0.18-0.30), famotidine 0.28-0.31 and nizatidine 0.36. These reflected similar 1-year recurrence rates of 24.9% (n = 530) for 400 mg cimetidine nocte, 22.4 (n = 508) for 150 mg ranitidine nocte, 28.0% (n = 371) for 20 mg or 40 mg famotidine nocte, and 21.8% (n = 261) for 150 mg nizatidine nocte. In studies to compare cimetidine and ranitidine directly, the odds ratio (and 95% confidence limits) was 0.64 (0.48-0.86). However, for two studies done by a single protocol, the odds ratio of 0.51 (0.35-0.75) tended to differ from the odds ratio of 0.85 (0.54-1.33) for six other studies (P = 0.09). These reflected recurrence rates for cimetidine and ranitidine of 28.3% and 16.8% (two studies) and 23.3% and 20.6% (six studies) respectively.

Cimetidine↗
PubMed1989

Parenteral antisecretory drug therapy in patients with Zollinger-Ellison syndrome.

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.

Administration, Oral↗
PubMed1989

Determining the optimal dosage regimen for H2-receptor antagonist therapy--a dose validation approach.

A large number of clinical studies have been performed to establish the safety and efficacy of H2-receptor antagonist therapy. Few if any of these studies have attempted to address the rationale for the dosage and/or dosage regimens being studied. This study is the first large-scale clinical trial, the purpose of which is to validate the chosen regimen and to address the issue of an optimal therapy for a specific patient population. A regimen of a single nightly dosage is generally acknowledged to offer the potential for improved patient compliance. Furthermore, recent research had suggested that suppression of nocturnal acid secretion is all that is required to heal duodenal ulcers. Hence such a regimen offered the potential for an effective lowered dosage of cimetidine with minimal interference with gastric physiology, increased safety and substantial efficacy. This multicentre, double-blind, placebo-controlled trial therefore evaluated a 4-week course of single night-time dosage of cimetidine. After 4 weeks of treatment the cumulative, endoscopically proven, ulcer healing rate with an 800 mg regimen was 73%, which was statistically higher and significantly superior to the 41% healing seen with placebo (P less than 0.001). The 400 mg nocte dosage regimen of cimetidine normally used as maintenance therapy was significantly inferior to the 800 mg nocte regimen (P = 0.01), and increasing the dosage to 1600 mg nocte for 4 weeks failed to provide a significant improvement in healing over the 800 mg nocte regimen. This 800 mg nocte regimen provided rapid pain relief, with 75% of the patients being free of night-time pain and 65% free of day-time pain, by the end of the first week. The 400 mg 'maintenance dosage' was unable to provide this degree of rapid, complete and early relief to patients with a duodenal ulcer. Furthermore, increasing the dosage to 1600 mg nocte failed to increase the level of early pain relief significantly, perhaps because the extensive response of duodenal ulcer patients to the 800 mg nocte regimen leaves little room for improvement. Based both on the early symptom relief and the ulcer healing rate during 4 weeks of treatment, it is concluded that an 800 mg night-time dosage of cimetidine may be an optimal regimen for many duodenal ulcer patients, particularly those who in the physician's opinion will benefit from a once-daily regimen.

Adolescent↗
PubMed1989

Acute treatment of benign gastric ulcer with once-daily bedtime dosing of cimetidine compared with placebo.

This multicentre, double-blind study evaluated the efficacy of cimetidine 800 mg nocte compared to placebo for ulcer healing and pain relief in patients with endoscopically confirmed, benign gastric ulcers treated for up to 8 weeks. Cimetidine accelerated ulcer healing throughout the study. More cimetidine-treated patients (35 of 82, 43%) than placebo-treated patients (26 of 79, 33%) had healed ulcers after 4 weeks of therapy. Similarly, after 6 and 8 weeks of treatment, cimetidine continued to have superior healing rates, 76% (59 of 78, P = 0.02) and 91% (69 of 76, P = 0.02) heal rates for cimetidine recipients compared with 58% (42 of 73) and 74% (52 of 70) for placebo. For every week of the study except the second, a greater proportion of cimetidine-treated patients were free of daytime and night-time pain than placebo-treated patients; the differences were statistically significant for night-time pain. Adverse reaction profiles were similar for the cimetidine and placebo groups. In conclusion, cimetidine 800 mg nocte was comparably safe and significantly more effective than placebo in accelerating healing and relieving pain in the treatment of acute, benign gastric ulcer.

Adult↗
PubMed1989

Reduction of indomethacin induced gastroduodenal mucosal injury and gastrointestinal symptoms with cimetidine in normal subjects.

A study was performed in 57 healthy volunteers to determine the effectiveness of cimetidine on reducing gastrointestinal (GI) mucosal lesions and symptoms induced by indomethacin. Endoscopic evidence of gastroduodenal injury and various GI symptoms appeared within 4 days after initiation of indomethacin therapy (50 mg TID) alone. Concomitant therapy with cimetidine, either 200 mg QID or 400 mg BID reduced the incidence of gastric erosions by up to 25% and duodenal erosions by up to 44% (gastric erosions from 81 to 61 and 78%, and duodenal erosions from 90 to 50 and 61%). The incidence of gastric ulcers was reduced from 24 to 0 and 6%, and of duodenal ulcers from 14 to 0 and 11%). The occurrence of moderate or severe pain was also significantly less with coadministration of cimetidine. Results from our study suggest that cimetidine may provide an effective prophylactic therapy against both NSAID related symptoms and gastroduodenal mucosal lesions.

Adolescent↗
PubMed1986

The effect of single intravenous doses of cimetidine or ranitidine on gastric secretion.

Intravenous cimetidine, 300 mg or 400 mg, or ranitidine, 50 mg, was administered as a single dose to 36 volunteers in a randomized, crossover fashion. Aspirates of gastric juice were obtained after dosing, and the pH, titratable acidity, gastric fluid volume, and gastric acid output were determined from baseline through 71/2 hours for each subject. Each intervention significantly increased pH and suppressed hydrogen ion concentration, gastric fluid volume, and gastric acid output. Both the magnitudes of the changes when compared with baseline and the time of the mean maximum effects were similar in all three drug regimens. The effect of all three interventions on gastric fluid volume and gastric acid output diminished sharply after 6 hours. The data indicate that the gastric secretory response to all three interventions did not differ substantially.

Adolescent↗
PubMed1986

The effect of age on theophylline clearance in normal subjects.

Dose-interval AUC and clearance of theophylline at steady-state were determined in healthy male subjects in each of three age groups (18-35, 36-54 and 55-70 years old). Mean AUC in the oldest group was significantly higher than in the youngest and clearance in both the middle and oldest groups was significantly lower than in the youngest. Though clearance was significantly correlated with age, age alone accounted for only 31% of the variability in clearance.

Adult↗
PubMed1986

Safety: cimetidine and concomitant theophylline or warfarin--drug interactions and their implications.

Theophylline and warfarin are two drugs whose interactions with cimetidine may have clinically significant effects. Therefore, recent efficacy studies comparing cimetidine 800 mg at bedtime (HS) with 300 mg QID included studies of interactions between cimetidine and these agents. Thirty healthy men were stratified into three age groups: 18 to 35, 36 to 53, and 54 to 70 years and were given 300 mg QID of anhydrous theophylline sustained-action tablets. When steady state was reached (nine days), cimetidine was begun concomitantly in a dosage of 300 mg QID or 800 mg HS for ten days. Three days after cimetidine was started, morning and evening trough theophylline serum levels were monitored. The area under the theophylline serum level-time curve (AUC) was determined on days 5 and 10 of the cimetidine regimen. Upon discontinuation of cimetidine, morning and evening trough serum theophylline levels were measured to determine when all subjects had returned to precimetidine steady-state conditions. A new baseline AUC was then obtained and concomitant administration of the alternate cimetidine regimen was started. Serum theophylline levels were measured as with the first cimetidine regimen. Theophylline was continued for an additional ten days with monitoring of trough levels, after the second cimetidine regimen was completed. AUC was measured after precimetidine steady-state conditions were reached. Steady-state theophylline levels were increased less by the 800-mg HS cimetidine regimen than by the 300-mg QID regimen. Although both regimens significantly (P less than 0.05) increased the theophylline AUC and maximum serum concentration (Cmax) in all age groups, the effect of cimetidine 800 mg HS was significantly less for all subject data combined and particularly for the oldest groups of subjects, indicating that the theophylline-cimetidine interaction is age-related. New theophylline steady-state levels were achieved by day 5 of concomitant cimetidine administration, and precimetidine theophylline serum trough levels, Cmax, and AUC were observed five days after discontinuation of both cimetidine regimens. The effects of the same two cimetidine regimens on the pharmacodynamics and pharmacokinetics of warfarin were also evaluated in 25 patients stabilized on anticoagulant therapy. The preliminary data indicate that patients with a baseline prothrombin time ratio (PTR) of less than 2.0 would not be expected to exceed a PTR greater than 2.5 after two weeks of concomitant administration of cimetidine at either dosage.(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗
PubMed1986

Gastric acid secretion and mucosal defense mechanisms with special reference to the role of cimetidine in critically ill patients.

The gastromucosal barrier (GMB) can be disrupted by a number of aggressive factors or by a decrease in mucosal defense factors. If there is back diffusion of hydrogen ions into the mucosa, mucosal damage ranging from an erythematous gastro-duodenitis to erosive and ulcerative gastritis or life-threatening hemorrhage may ensue. The pathogenesis of stress-related mucosal damage seen in critically ill patients suffering from burns, sepsis, head trauma, respiratory insufficiency, or multisystem disease is also related to a decrease in mucosal resistance. Early studies of cimetidine in animals and in humans demonstrated its ability to increase gastric transmucosal potential difference, indicating an enhancement of the integrity of the GMB. Several studies show that cimetidine protects the stomach from aspirin-induced mucosal damage; increases gastric mucus production and mucus glycoprotein content, which contributes to the protective action of mucus; increases mucosal secretion of bicarbonate; increases gastric mucosal blood flow, which prevents mucosal hypoxia seen in patients in shock or otherwise critically ill patients; increases endogenous mucosal prostaglandin synthesis; and increases the rate of epithelial cell renewal, a factor important to mucosal healing. Since cimetidine suppresses acid secretion and enhances mucosal defense, it is an important therapeutic tool in the management of acid-related disorders, particularly stress-related mucosal damage.

Animals↗