Plasma clearance of neostigmine and pyridostigmine in the dog

1 The pharmacokinetics of neostigmine and pyridostigmine was studied in conscious dogs by the use of a cross-over design. 2 Both neostigmine and pyridostigmine were cleared from plasma in a biexponential manner. 3 The apparent volume of distribution of pyridostigmine was invariably greater than that of neostigmine, and its fast disposition half-life was approximately three times longer. 4 The whole body clearance and the urinary elimination of pyridostigmine was approximately twice that of neostigmine. 5 The slow disposition half-life of pyridostigmine was approximately three times longer than that of neostigmine, suggesting that the longer duration of action of pyridostigmine is related to the differential clearance of the two quarternary amines from plasma.     

The effect of combined therapy with ranitidine and pirenzepine in the treatment of reflux oesophagitis

The combination of a histamine H2-receptor antagonist and a muscarinic receptor antagonist has been reported to result in greater suppression of intragastric acidity than either agent alone. The present randomized, double-blind, multicentre trial compared the effects of the oral combination of 150 mg ranitidine b.d. plus 50 mg pirenzepine b.d. with 150 mg ranitidine b.d. plus placebo pirenzepine b.d. in the treatment of patients with reflux oesophagitis. All 157 patients had symptoms of gastro-oesophageal reflux with endoscopically confirmed oesophageal erosions (Savary and Miller grades I-III). After four weeks of treatment, healing rates were 32/75 (43%) in the combined treatment group and 34/76 (45%) in the group receiving ranitidine alone. After eight weeks, the cumulative healing rates had increased to 48/72 (67%) and 51/75 (68%), respectively. More patients receiving ranitidine plus pirenzepine had complete relief of day- and night-time heartburn after four weeks compared with those receiving ranitidine alone (day: 59% vs. 38%, P = 0.02; night: 69% vs. 52%, P = 0.04). After eight weeks, symptom relief was comparable in both groups. Clinical adverse effects were reported by nine patients receiving ranitidine and by 19 patients receiving the combination. It is concluded that combining ranitidine with pirenzepine does not aid the healing of reflux oesophagitis but does improve symptom relief at four weeks.     

盐酸雷尼替丁微丸胶囊在健康志愿者的生物等效性研究

目的:研究盐酸雷尼替丁微丸胶囊和善胃得(盐酸雷尼替丁片,葛兰素史克)的人体药代动力学和生物等效性。方法:20名健康志愿者按双周期随机交叉试验设计口服受试制剂盐酸雷尼替丁微丸胶囊和参比制剂盐酸雷尼替丁片,用高效液相色谱(HPLC)法测定血浆中雷尼替丁的浓度。结果:单剂量口服盐酸雷尼替丁微丸胶囊和盐酸雷尼替丁片后Cmax分别为1.62±0.56和1.78±0.69μg.ml-1,tmax分别为2.8±1.1和2.6±0.8 h,AUC0-τ分别为6.69±1.46和6.67±1.86μg.h.ml-1,AUC0-∞分别为7.06±1.56和7.06±1.86μg.h.ml-1。受试制剂盐酸雷尼替丁微丸胶囊的相对生物利用度为103.8%±19.1%。结论:盐酸雷尼替丁微丸胶囊和善胃得两种制剂生物等效。     

Plasma clearance of neostigmine and pyridostigmine in rats with ligated renal pedicles

The elimination of equimolar doses of ¹⁴C-neostigmine and ¹⁴C-pyridostigmine was studied in rats with ligated renal pedicles. Although both drugs were eliminated from plasma in a bi-exponential manner, there were statistically significant differences in their plasma half-lives. It was considered that this phenomenon might be related to qualitative differences in hepatic metabolism. The results of the experiments suggest that the metabolism of pyridostigmine is slower than neostigmine and that cumulation of pyridostigmine may occur in renal failure.     

盐酸雷尼替丁咀嚼片剂的人体药动学及相对生物利用度

目的:研究盐酸雷尼替丁咀嚼片剂的人体药动学和生物等效性.方法:20名健康受试者采用双周期随机交叉、单剂量口服盐酸雷尼替丁咀嚼片剂与盐酸雷尼替丁片剂,服药剂量均为150mg.用HPLC法测定血浆中雷尼替丁经时过程的血药浓度,使用3P97软件对试验数据进行处理.结果:盐酸雷尼替丁咀嚼片剂和盐酸雷尼替丁片剂的雷尼替丁Cmax分别为(425.5±119.1),(479.6±135.1)μg·L-1;Tmax分别为(3.0±1.0),(2.9±1.2)h;AUC0-12分别为(2707.0±572.1),(2699.7±544.5)μg·h·L-1,AUG0～∞分别为(3155.2±700.8),(3026.4±612.0)μg·h·L-1,盐酸雷尼替丁咀嚼片剂相对于盐酸雷尼替丁片剂的生物利用度为(102.0±20.6)%.结论:盐酸雷尼替丁咀嚼片剂和盐酸雷尼替丁片剂具有生物等效性.     

The effects of cimetidine and ranitidine on psychomotor function in healthy volunteers

Single oral doses of cimetidine (400 mg), ranitidine (150 mg), promethazine (25 mg) or placebo were administered to 8 healthy volunteers in a double-blind study. Cimetidine and ranitidine did not cause any significant change in critical flicker frequency (c.f.f.), reaction time, pursuit rotor of the visual analogue scale scores for sedation. Promethazine significantly lowered c.f.f., prolonged reaction time and increased sedation when compared with placebo. It is concluded that in this study cimetidine and ranitidine had little, if any, effect on psychomotor function.     

Physiological and performance effects of pyridostigmine bromide in healthy volunteers: a dose-response study

RATIONALE: Questions have been raised about the role pyridostigmine bromide (PB) plays in the etiology of Gulf War veterans' illnesses. There is a need to understand better the physiological and behavioral effects of this drug, particularly at the 30-mg/8-h regimen recommended by the US Military. OBJECTIVE. To perform a double-blind, cross-over, dose-response study of PB in 67 healthy, young volunteers (31 women, 36 men). METHODS: Volunteers were initially trained on a standardized test battery. Supervised administration of placebo (PL) and PB (every 8 h/5 days) occurred in each of two dosing weeks, separated by a non-dosing week. One group received 30 mg PB and PL, and the other 60 mg PB and PL. In each dosing week, the battery was performed after the first pill and again when steady-state plasma PB levels were achieved. RESULTS: PB was associated with an overall improvement in reaction time on tests of memory and attention, and with a reduction in RMS error on a tracking task. PB slowed heart rate and decreased the high frequency component of heart rate variability (HF HRV). Dose-response effects were found only for HF HRV, and RMS error. The extent of cholinesterase inhibition was directly related to the magnitude of the HF HRV decrease, and was predicted by the weight-normalized PB dose. Cholinesterase inhibition was not related to the extent or severity of reported drug side effects. CONCLUSIONS: PB does not appear to have detrimental physiological or performance consequences at the recommended 30-mg dose, or at twice that dose, when evaluated under non-stressful laboratory conditions.     

The effects of cimetidine and ranitidine on psychomotor function in healthy volunteers

Summary

Single oral doses of cimetidine (400?mg), ranitidine (150?mg), promethazine (25?mg) or placebo were administered to 8 healthy volunteers in a double-blind study. Cimetidine and ranitidine did not cause any significant change in critical flicker frequency (c.f.f.), reaction time, pursuit rotor or the visual analogue scale scores for sedation. Promethazine significantly lowered c.f.f., prolonged reaction time and increased sedation when compared with placebo. It is concluded that in this study cimetidine and ranitidine had little, if any, effect on psychomotor function.     

Effect of silymarin on the oral bioavailability of ranitidine in healthy human volunteers

The effect of silymarin pretreatment on the pharmacokinetics of ranitidine was investigated in 12 healthy male human volunteers aged 19-26 years. After an overnight fast, ranitidine 150 mg was administered to the volunteers either alone or after 7 days pretreatment with thrice daily dose of 140 mg silymarin. The wash-out period between each treatment was 7 days. Serum levels of ranitidine were determined by HPLC. Pharmacokinetic parameters were determined based on non-compartmental model analysis using the computer program KINETICA. There was no influence of silymarin on the pharmacokinetics of ranitidine. Concomitant administration of silymarin at this dosage did not alter ranitidine C(max) and AUC(0-infinity). There was a significant difference in area under the first moment curve (AUMC) and mean residence time. This result is useful in predicting the interaction of silymarin with other cytochrome 3A4 and P-glycoprotein substrates at normal dosage.     

Renal clearance of sulphinpyrazone in man

Summary Six healthy young volunteers received a single dose of sulphinpyrazone 200 mg p.o. Plasma concentration and urinary excretion rate curves showed large intersubject variation for sulphinpyrazone and its metabolites. The sulphide metabolite could only be detected in plasma and not before 3–7 h after ingestion. The total recovery in urine of all compounds varied from 30–56% of the dose.In two subjects the mean residence time of sulphinpyrazone was twice as long as in the other subjects (10.4 h compared with 4.6 h), but the area under the plasma concentration-time curve was comparable to that in the others (mean: 3.0 mg·ml^–1·min), indicating that drug absorption was quantitatively similar but delayed.The renal clearance of sulphinpyrazone varied from 14–40 ml·min^–1 (mean: 28 ml·min^–1).In view of the very high plasma protein binding of sulphinpyrazone, active tubular secretion is the predominant mechanism in its renal clearance. The same holds for the sulphone metabolite, which has a mean renal clearance of 24 ml·min^–1, and even more for the p-hydroxysulphinpyrazone metabolite, which has a renal clearance of 118 ml·min^–1.No unambiguous evidence was found in favour of concentration-dependent renal clearance of sulphinpyrazone or its metabolites over the concentration range studied. The renal clearance, especially of sulphinpyrazone, appeared to be dependent on urine pH and not on urine flow rate.     

The effect of ranitidine on the plasma clearance and hepatic extraction of indocyanine green in patients with chronic liver disease.

Since hepatic clearance of ICG is reduced by H2-receptor antagonists in normal subjects, it has been suggested that they reduce liver blood flow. We have studied the effect of intravenous ranitidine on ICG clearance in twelve patients with chronic liver disease. Wedged and free hepatic venous pressure were measured before and after intravenous ranitidine in nine of the patients, and the hepatic extraction of ICG was determined in six patients. ICG clearance fell by 22 +/- 11% (s.e. mean) 60 min after ranitidine. In patients in whom ICG clearance fell after intravenous ranitidine the hepatic extraction of ICG was also reduced. There was no significant change in the gradient between wedged and free hepatic venous pressure after ranitidine. It is therefore unlikely that ranitidine lowers liver blood flow.     

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 influence of cimetidine and ranitidine on basophil histamine release and bronchial reactivity in asthmatic patients

Anti-IgE induced histamine release from isolated basophils after Cimetidine and Ranitidine administration was evaluated in 22 patients with atopic bronchial asthma. The histamine provocation test after Ranitidine treatment in 10 patients with atopic bronchial asthma and 10 patients with peptic ulcer was also performed. Investigations in vitro revealed that Cimetidine and Ranitidine in low concentrations had an inhibitory effect whereas in concentrations of over 10(-6) M and 10(-4) M, respectively, they enhanced histamine release. Investigations in vivo after administration of Ranitidine showed that it does not cause marked changes in the bronchial reactivity in patients with bronchial asthma and any change in patients with peptic ulcer. These preliminary studies seem to suggest that in patients with atopic bronchial asthma and concomitant peptic ulcer Ranitidine is preferable to Cimetidine in the treatment of digestive tract disorders.     

Comparison of the effects of ranitidine, cimetidine and thioridazine on psychomotor functions in healthy volunteers

Eight healthy male volunteers participated in four experimental sessions in which they ingested one of the following drugs: ranitidine hydrochloride (150 mg), cimetidine hydrochloride (400 mg), thioridazine hydrochloride (50 mg), placebo (lactose). Drugs were allocated to subjects and sessions in a double-blind fashion, according to a balanced cross-over design. The subjects' mood state and psychomotor performance were assessed 1 and 3 h after drug taking. Mood state was measured using a battery of visual analogue scales, and psychomotor performance using pencil-and-paper tests, critical flicker fusion frequency, wire-maze tracing and tapping. Ranitidine and cimetidine had no significant effect on subjectively rated alertness, whereas thioridazine caused a significant decrease in alertness. Ranitidine and cimetidine had no significant effect on performance on the pencil-and-paper tests (digit cancellation, digit symbol substitution, symbol copying), whereas thioridazine caused a significant decrement on these tests. Ranitidine and cimetidine had no significant effect on critical flicker fusion frequency, wire-maze tracing, and tapping rate. Thioridazine caused a significant impairment of psychomotor performance as evidenced by all the instrumental tests. It is concluded that, in contrast to thioridazine and similarly to cimetidine, ranitidine has little effect on subjectively rated alertness and psychomotor performance in healthy volunteers.     

Absolute bioavailability of pirenzepine in intensive care patients

Summary The absolute bioavailability (f) of pirenzepine was determined in 27 intensive care patients receiving the drug for prophylaxis and therapy of upper gastrointestinal tract bleeding. A multiple oral and intravenous dosage regimen and the times of blood sampling were adapted to individual conditions and treatment.Mean fin the patients was 0.28, which was significantly higher than in 12 normal subjects (0.14). It showed no dependence on age (range 20–82 y), nor on the risk factors cardiac insufficiency, renal and hepatic dysfunction, gastrectomy (Billroth II) and bleeding gastrointestinal ulcers, nor on concomitant administration of metoclopramide or antacids.Due to the wide therapeutic index of pirenzepine, it is concluded that individualization of therapy is not necessary for patients in intensive care.Dedicated to Professor Ellen Weber on the occasion of her 60th birthday     

A placebo controlled comparison of the effects of pirenzepine and amitriptyline on the tyramine pressor test in healthy volunteers.

The possibility of an interaction between pirenzepine, an antimuscarinic drug structurally similar to the tricyclic antidepressants, and sympathomimetic agents was investigated in a group of healthy volunteers. The effect of pirenzepine on response to intravenous tyramine was compared with that of placebo and amitriptyline. The mean dose of tyramine required to elevate systolic blood pressure by 30 mm Hg was 5.0 mg (+/- s.d. 0.8) after placebo, 5.1 mg (+/- 1.0) after pirenzepine and 11.3 mg (+/- 1.8) after amitriptyline. These results suggest that pirenzepine will not potentiate the effects of concurrently administered sympathomimetic drugs.     

Influence of the H2-receptor antagonists cimetidine and ranitidine on the pharmacokinetics of nimodipine in healthy volunteers

Summary A possible interaction between the calcium antagonist nimodipine and the H₂-receptor antagonists cimetidine and ranitidine has been investigated in two separate studies in healthy subjects.In eight young volunteers the concomitant administration of nimodipine 30 mg t.i.d. and cimetidine 1000 mg/d for 7 days led to a significant increase of the relative bioavailability of nimodipine. The changes in the pharmacokinetic parameters were not accompanied by discernible haemodynamic effects or any change in the tolerability of nimodipine.There was no evidence of any significant change in the steady-state pharmacokinetics of nimodipine during five days of combined treatment with 30 mg t.i.d. nimodipine and ranitidine 300 mg/d given as single morning dose to twelve healthy, elderly subjects. Analysis of haemodynamics, clinical chemistry and tolerance also did not reveal any difference between the two treatment periods.Presented in part at the IVth World Conference on Clinical Pharmacology and Therapeutics, Mannheim-Heidelberg, 23–28 July, 1989