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.     

Kinetics of oral and intravenous mexiletine: lack of effect of cimetidine and ranitidine

Summary The pharmacokinetics of mexiletine, a Class I antiarrhythmic drug, was investigated in 6 healthy volunteers after single oral doses and 15 min intravenous infusions of 3 mg/kg. Cimetidine and ranitidine are commonly used H₂-receptor antagonists, which interact adversely with many drugs, e.g. inhibition of the metabolism of Class I antiarrhythmics such as lidocaine and quinidine by cimetidine. To investigate the effects of the two drugs on the kinetics of mexiletine, cimetidine 800 mg·day^–1 or ranitidine 600 mg·day^–1 were administered orally for one week.Neither H₂-receptor antagonist altered the distribution and elimination of mexiletine, nor did they affect its overall kinetics, or excretion of the metabolites para- and 4-OH-methylmexiletine after oral and intravenous administration of mexiletine.     

Pharmacokinetics of intravenous and intraperitoneal ceftriaxone in chronic ambulatory peritoneal dialysis

Summary The kinetics of ceftriaxone was investigated in 8 patients without infection, who were receiving continuous ambulatory peritoneal dialysis (CAPD). Ceftriaxone 1 g was injected i.v. and 1 g was given intraperitoneally in the CAPD fluid during a 4-h dwell time. Ceftriaxone was assayed by HPLC. After intravenous administration, the kinetic parameters of ceftriaxone were: plasma t_1/2, 12.3 h, total plasma clearance, 14.0 ml/min, volume of distribution at steady state 0.18 l/kg, and peritoneal clearance 0.59 ml/min. Over 72 hours only 5.5% of the dose was eliminated by the peritoneal route. After intraperitoneal administration, ceftriaxone rapidly appeared in serum; the absorption t_1/2 was 1.1 h and the mean peak concentration was 38.8 µg/ml. The absorption of ceftriaxone from the peritoneal space was 39%. A single 1.0 g IP dose led to serum and dialysate concentrations of ceftriaxone above the minimum inhibitory concentration for susceptible pathogens for 24 hours.     

Effect of intravenous infusion of ranitidine on intragastric acidity in fasting subjects: comparison with bolus or Gastrojet (pH-stat-adjusted) infusion

This study was undertaken in nine fasting healthy volunteers to compare the effect of intravenous continuous infusion versus bolus injection of ranitidine on 12-h intragastric pH, and to compare the efficacy of these two modes of administration of pH-stat-adjusted infusion of ranitidine using the Gastrojet. Each volunteer had three study sessions with 12-h pH measurements. In the ranitidine infusion treatment arm (RAN-INF), ranitidine was continually infused intravenously using an IVAC-pump at a dose of 0.125 mg mg.kg over a 12-h period. In the ranitidine bolus treatment arm (RAN-BOL), ranitidine bolus 50 mg was given over 10 min, every 6 h. When ranitidine infusion was given by the pH stat method using the Gastrojet (RAN-JET), sufficient ranitidine was given to maintain a preset value of pH ≥ 5. The study was analysed with a 3 × 3 Latin square cross-over design with multiple measurements of each phase of the cross-over. No difference was found between RAN-INF and RAN-BOL in 12-h or in daytime (10.00–18.00 h) mean pH, median pH, or percentage of pH ≥ 5. Using RAN-JET, 89.5% of the pH values were ≥ 5, compared with 39.7% and 40.0% with RAN-INF or RAN-BOL. RAN-JET also gave higher (P < 0.05) mean and median 12-h or daytime pH values, as compared with RAN-INF or RAN-BOL. The mean doses of ranitidine given in the 12-h infusion periods were 100 mg, 109 mg and 112 mg (RAN-BOL, RAN-INF and RAN-JET, respectively). Thus, this superior inhibition of acid inhibition achieved with Gastrojet does not require higher mean doses of ranitidine. These findings cannot necessarily be applied to persons with duodenal ulcer disease or to patients in an intensive-care unit setting. However, the data do raise the possibility that much greater inhibition of acid inhibition can be achieved by individualizing the dose of ranitidine using the Gastrojet.     

Effect of cimetidine and ranitidine on carbamazepine and sodium valproate pharmacokinetics

Summary The pharmacokinetics of a single oral dose (400 mg) of carbamazepine and sodium valproate were compared in peptic ulcer patients before and after four weeks of a therapeutic course of either cimetidine (1 g/day, n=6 subjects) or ranitidine (300 mg/day, n=6 subjects). There was a small (up to 20%) but statistically significant decrease in oral clearance of carbamazepine after cimetidine treatment. A similar fall in sodium valproate clearance in five cimetidine-treated patients was accompanied by a significantly prolonged elimination half-life. No such trends were demonstrated during ranitidine treatment. Since both anticonvulsants are partly metabolized by hepatic mixed function oxidases, an inhibition by cimetidine at this level may be responsible for the observed impairment of clearance. Thus a potentially important clinical interaction may occur in patients taking anticonvulsants and cimetidine concurrently.     

复方卡托普利片的药代动力学及生物等效性评价

目的：研究两种复方卡托普利片的药代动力学及生物等效性。方法：采用柱前衍生化高效液相色谱法测定１０名志愿受试者单剂量口服５０ｍｇ两种复方卡托普利片后血中卡托普利血药浓度的变化情况，数据经 ３ｐ８７药代动力学程序处理结果：两种片剂药时曲线下面积分别是（８６４．３０±１６９．９９）（ｎｇ／ｍＬ）×ｈ与（８５３．３８±１６５．７７）（ｎｇ／ｍＬ）×ｈ，达峰时间分别为（０．９１ ±０．２７）ｈ与（０．９１ ±０．２６）ｈ，峰浓度分别是（２８５．００±３７．３６）ｎｇ／ｍＬ与（２７９．８０± ３２．７７）ｎｇ／ｍＬ结论：配对ｔ检验与双单侧ｔ检验结果表明：二者药时曲线下面积、峰浓度及达峰时间均无显著性差异（Ｐ＞０．０５），为生物等效制剂。     

Effect of methyldopa on prolactin serum concentration

Summary In a group of ten hypertensive patients, the effects of methyldopa administration in two different formulations on serum prolactin (PRL) were studied. A single oral dose of normal release methyldopa significantly increased serum prolactin levels, peak concentrations occurring 3 to 6 h after drug administration. On the contrary, administration of sustained release methyldopa at the same dose was only followed by slight and not significant fluctuations in prolactin plasma levels. Both formulations produced a significant decrease of systolic and diastolic blood pressures, without significant differences between sustained and normal release methyldopa effects.     

Effect of cimetidine and ranitidine on pharmacokinetics and pharmacodynamics of a single dose of dofetilide

AIMS: The aim of this open-label, placebo-controlled, randomized, four-period crossover study was to determine the effects of cimetidine and ranitidine on the pharmacokinetics and pharmacodynamics of a single dose of dofetilide. METHODS: Twenty healthy male subjects received 100 or 400 mg twice daily of cimetidine, 150 mg twice daily of ranitidine, or placebo for 4 days. On the second day, a single oral 500 microg dose of dofetilide was administered immediately after the morning doses of cimetidine, ranitidine, or placebo. Treatment periods were separated by 1-2 weeks. Pharmacokinetic parameters were determined from plasma and urinary dofetilide concentrations; prolongation of the QTc interval was determined from three-lead electrocardiograms. RESULTS: Ranitidine did not significantly affect the pharmacokinetics or pharmacodynamics of dofetilide; however, a dose-dependent increase in exposure to dofetilide was observed with cimetidine. When dofetilide was administered with 100 and 400 mg of cimetidine, the area under the plasma concentration-time curve of dofetilide increased by 11% and 48% and the maximum plasma dofetilide concentration increased by 11% and 29%, respectively. The respective cimetidine doses reduced renal clearance of dofetilide by 13% and 33% and nonrenal clearance by 5% and 21%. Dofetilide-induced prolongation of the QTc interval was enhanced by cimetidine; the mean maximum change in QTc interval from baseline was increased by 22% and 33% with 100 and 400 mg of cimetidine, respectively. However, the relationship between the prolongation of the QTc interval and plasma dofetilide concentrations was unaffected by cimetidine or ranitidine; a 1 ng ml-1 increase in plasma dofetilide concentration produced a 17-19 ms prolongation of the QTc interval. Dofetilide was well tolerated, with no treatment-related adverse events or laboratory abnormalities. CONCLUSIONS: These results suggest that cimetidine increased dofetilide exposure by inhibiting renal tubular dofetilide secretion, whereas ranitidine did not. This effect is not an H2-receptor antagonist class effect but is specific to cimetidine. If therapy with an H2-receptor antagonist is required, it is recommended that cimetidine at all doses be avoided; since ranitidine has no effect on dofetilide pharmacokinetics or prolongation of the QTc interval, it can be seen as a suitable alternative.     

Effect of food and gastric acidity on absorption of orally administered ketoconazole

Effects of food and gastric acidity on the bioavailability of ketoconazole tablets were investigated in 12 volunteers using a six-treatment, randomized, Latin-square crossover design. All volunteers received all treatments, as follows: (A) ketoconazole 200 mg administered after a fast; (B) ketoconazole 200 mg with a standardized high-fat meal; (C) ketoconazole 200 mg with a standardized high-carbohydrate meal; (D) ketoconazole 200 mg after pretreatment with glutamic acid hydrochloride 680 mg as capsules; (E) ketoconazole 200 mg in a simulated achlorhydric state induced with cimetidine and sodium bicarbonate; and (F) ketoconazole 200 mg administered with glutamic acid hydrochloride in a simulated achlorhydric state. Ketoconazole concentrations were measured by high-performance liquid chromatography in plasma samples drawn immediately before and at various times over 24 hours after drug administration. Bioavailability variables, including natural logarithm transformation for area under the concentration-time curve (AUC), were subjected to analysis of variance followed by Duncan's Multiple Range testing. Treatments B and C significantly prolonged the times required to achieve the peak plasma ketoconazole concentration, and treatment C also significantly reduced the peak plasma ketoconazole concentration (Cmax) compared with treatment A. There was a trend toward increased AUC values with treatment B and decreased AUC values with treatment C. Treatment D produced a higher Cmax compared with treatment A, and treatment E produced large, significant reductions in Cmax and AUC values compared with treatment A. Treatment F significantly increased AUC values and Cmax compared with treatment E.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of food and ranitidine on saquinavir pharmacokinetics and gastric pH in healthy volunteers

STUDY OBJECTIVES: To assess the relative bioavailability of saquinavir after administration with ranitidine alone, ranitidine and food, and food alone; and to investigate the mechanism underlying the effects of pH and food on saquinavir absorption. DESIGN: Single-center, open-label, randomized, three-part crossover, pharmacokinetic pilot study. SETTING: General clinical research center in Scotland. SUBJECTS: Twelve healthy male volunteers. INTERVENTION: Each subject was given a single dose of saquinavir mesylate 600 mg with one of three randomly assigned treatments: ranitidine 150 mg on the evening before and 150 mg on the day of study drug administration, without food (treatment A); ranitidine 150 mg on the evening before and 150 mg on the day of study drug administration, with food (treatment B); and with food alone (treatment C, control). After a 7-day washout period between each of the interventions, subjects received the other two treatments. MEASUREMENTS AND MAIN RESULTS: Blood samples were taken serially for 24 hours after each saquinavir dose, and gastric pH was measured during the 8 hours after dosing. Adverse events were monitored throughout the study. Single doses of saquinavir were well tolerated with or without ranitidine. Of the three treatments, the highest mean maximum plasma concentration (C(max)) and area under the plasma concentration-time curve (AUC) for saquinavir occurred with treatment B; the lowest C(max) and AUC occurred with treatment A. Compared with treatment C (control), saquinavir's bioavailability was 15.9% (90% confidence interval [CI] 10-25%) after treatment A and 167% (90% CI 106-265%) after treatment B. Interindividual variability in both C(max) and AUC was slightly greater after treatments A and B than after treatment C. No correlation was found between pharmacokinetic parameters (C(max) and AUC) and gastric pH parameters, including maximum pH and pH at the time of drug delivery. CONCLUSION: Plasma concentrations of saquinavir were significantly higher when the drug was administered with food and ranitidine than when it was given with food alone. However, these increases were not related to changes in gastric pH caused by ranitidine. It can be postulated that food does not increase the bioavailability of saquinavir through its effect on gastric pH.     

The effect of ranitidine and cimetidine on imipramine disposition

Summary The pharmacokinetic characteristics of imipramine were studied after a single, oral, 100 mg dose was taken by 12 healthy male subjects following 3 days of pretreatment with placebo, cimetidine (300 mg every 6 h), and ranitidine (150 mg every 12 h) in a randomized, double blind, crossover trial. After each imipramine dose plasma samples were collected for 72 h and assayed for imipramine, desipramine, 2-hydroxyimipramine and 2-hydroxydesipramine by HPLC. Cimetidine preadministration statistically prolonged imipramine t_1/2 compared to ranitidine (22.7 vs. 13.0 h) or placebo (10.8 h). Mean imipramine area under the curve (AUC) following cimetidine pretreatment was more than double that following placebo (2.633 vs. 0.966 µg·h·ml^–1) or ranitidine (1.14 µg·h·ml^–1) pretreatment. Imipramine apparent oral clearance was reduced in all 12 subjects after cimetidine. Compared to ranitidine or placebo, cimetidine pretreatment was associated with an increased imipramine/desipramine AUC ratio, suggesting cimetidine-induced impairment of demethylation of imipramine. Ranitidine was not observed to alter imipramine pharmacokinetics.     

Effect of concomitant administration of cimetidine and ranitidine on the pharmacokinetics and electrocardiographic effects of terfenadine

Summary Terfenadine is a widely prescribed non-sedating antihistamine which undergoes rapid and almost complete first pass biotransformation to an active carboxylic acid metabolite. It is unusual to find unmetabolised terfenadine in the plasma of patients taking the drug. Terfenadine in vitro is a potent blocker of the myocardial potassium channel. Overdose, hepatic compromise and the coadministration of ketoconazole and erythromycin result in the accumulation of terfenadine, which is thought to be responsible of QT prolongation and Torsades de Pointes ventricular arrhythmia in susceptible individuals. Cimetidine and ranitidine are two popular H₂ antagonists which are often taken with terfenadine. The effects of cimetidine and ranitidine on terfenadine metabolism were studied in two cohorts of 6 normal volunteers given the recommended dose of terfenadine (60 mg every 12 h) for 1 week prior to initiation of cimetidine 600 mg every 12 h or ranitidine 150 mg every 12 h. Pharmacokinetic profiles and morning pre-dose electrocardiograms were obtained whilst the patients were on terfenadine alone and after the addition of cimetidine or rantidine.One of the subjects in each cohort had a detectable plasma level of parent compound after 1 week of terfenadine therapy alone; it did not accumulate further after addition of the H₂ antagonist. The pharmacokinetics of the carboxylic acid metabolite of terfenadine (C_max, t_max, AUC) were not significantly changed after co-administration of either H₂ antagonist. None of the remaining 5 subjects in either cohort demonstrated accumulation of unmetabolised terfenadine after addition of the respective H₂ antagonist and electrocardiographic QT intervals and T-U morphology in them was not changed during the course of the study.We conclude that cimetidine and ranitidine in the dosages used in this study did not affect the metabolism of terfenadine, and that patients exposed to these drug combinations are not at increased risk of altered cardiac repolarisation.The views expressed in this article are those of the authors and do not reflect the official policy of the Uniformed Services University, Walter Reed Army Medical Center, Department of Defense or the Food and Drug Administration     

老年人静滴庆大霉素的血药浓度测定及临床意义

本文对老年和非老年人静滴庆大霉素240mg/d进行了血药浓度测定。结果老年人伴有肾功能不全或心衰者,最高血药浓度明显增高(12.41±1.1μg/ml),药物在体内消除缓慢,T_(1/2)明显延长,易发生毒性反应。因此我们认为对于老年人或(和)心、肾功能不全者不宜静滴240mg/d,应予减量,可采用部分量静滴、部分量夜间肌注的方法。     

Radioimmunoassay of plasma lisuride in man following intravenous and oral administration of lisuride hydrogen maleate; effect on plasma prolactin level

Summary The development of a sensitive radioimmunoassay for the determination of lisuride in plasma is described. The antiserum against lisuride-4-hemisuccinate-BSA was raised in rabbits. Using this method the plasma levels of lisuride were monitored following one intravenous (25 μg) and two oral (100 μg and 300 μg) doses of lisuride hydrogen maleate in three female and three male volunteers (intraindividual comparison). The plasma prolactin was also determined by radioimmunoassay. Following i. v. injection, the concentration of lisuride declined in three phases, with half-lives of 5 min, 25 min and 2 h. The total plasma clearance of 800±250 ml × min⁻¹ was in the range of “plasma flow” through the liver. In agreement with the high rate of biotransformation, the bioavailability of lisuride administered orally was 10%±7% of the 100-μg dose, and 22%±7% of the 300-μg dose. The plasma prolactin was lowered to 3%–18% of its pretreatment value depending on the route of administration and the dose. The reduction appeared to be short-lived and to be directly dependent on the plasma concentration of lisuride. Following intravenous injection, the prolactin level declined after a so far unexplained lagtime of 0.5 h.     

Effect of splitting the dose of esomeprazole on gastric acidity and nocturnal acid breakthrough

BACKGROUND: Twice-daily dosing is increasingly used to improve gastric acid control, although not all proton-pump inhibitors are more effective when doses are split. Standard dose esomeprazole provides better gastric acid control than other standard dose proton-pump inhibitors. AIMS: To compare the effect of standard dose esomeprazole (1 x 40 mg) with 20 mg b.d. on gastric acidity. METHODS: Thirteen healthy subjects participated in this crossover study, receiving esomeprazole 2 x 20 mg and 1 x 40 mg for 7 days in random order with a washout period of at least 7 days. Gastric 24-h pH was measured on days 1, 2 and 6. RESULTS: Median gastric 24-h pH was higher during 2 x 20 mg esomeprazole on day 2 (P < 0.01), no differences were detected on day 6. Night-time gastric acid suppression was significantly improved by 2 x 20 mg esomeprazole on all study days (P < 0.05). Nocturnal acid breakthrough was observed on all study days in subjects receiving 1 x 40 mg, but in only 85% (first night), 64% (second night), and 45% of subjects (sixth night) with 2 x 20 mg (P < 0.05). CONCLUSION: Splitting the esomeprazole dose improves initial acid suppression, this effect starts at the first night. Maximal benefit is achieved on day 2, while the effect on night-time acid control is detectable during the entire first week of treatment.     

Effect of pentacaine and ranitidine on gastric mucus changes induced by cold-restraint stress in rats

The potential involvement of increased mucus secretion in the antiulcer activity of a cytoprotective agent, pentacaine, and of the H2-antagonist ranitidine was studied in stressed rats. Cold-restraint stress decreased the gastric mucus content and induced haemorrhagic erosions in the stomach. Pretreatment with pentacaine and ranitidine dose-dependently diminished the extent of stress-induced gastric damage. Pentacaine prevented the depletion of mucus after stress, while ranitidine failed to affect it. In non-stressed rats only pentacaine was able to enhance mucus secretion. The stimulating effect of pentacaine on gastric mucus secretion may account for some of its antiulcer properties.     

麻醉药物对硬膜外阻滞利多卡因药动学的影响

目的：麻醉药物对硬膜外阻滞利多卡因药动学影响进行研究。方法：分别对12例腹部及下肢手术患者硬膜外阻滞加全麻和腰麻-硬膜外联合阻滞麻醉后的药动学参数进行研究和评价，采用荧光偏振免疫方法（FPIA）测定血中利多卡因浓度，3P97程序进行药动学参数线性拟合，t检验比较组间差异。结果：硬膜外阻滞加全麻和腰麻-硬膜外联合阻滞注药后，血药浓度达峰时间分别为（8．4±0．6）min和（9．0±0．6）min（P〉0．05），血药峰值分别为（2．16±0．25）mg·L^-1和（2．02±0．20）mg·L^-1（P〉0．05），吸收速率常数分别为（19．3±4．4）h^-1和（19．4±4．8）h^-1（P〉0.05），消徐半衰期分别为（3．3±1．7）h和（2．6±0．6）h（P〉0．05）。结论：麻醉药物对硬膜外阻滞利多卡因药动学无显著影响，可以安全使用。