Pharmacokinetics of famotidine,a new H2-receptor antagonist,in relation to renal function

Summary The pharmacokinetics of a new, potent H₂-receptor antagonist, famotidine, 20 mg i.v. was studied in 7 subjects with normal renal function and in 24 patients with varying degrees of renal impairment. The volume of distribution at steady state was 1.14 l/kg in normal subjects and was not altered in renal failure. The half-life of elimination was 2.59 h in normal subjects and was unchanged in mild renal failure (creatinine clearance, CL_CR 90–60 ml/min/1.48 m²) but was increased to 4.72 h in moderate renal failure (CL_CR 60–30 ml/min/1.48 m²), and to 12.07 h in severe renal failure (CL_CR below 30 ml/min/1.48 m²). The cumulative urinary excretion and renal clearance of famotidine were correspondingly reduced in patients with impaired kidney function. In normal subjects and in patients with mild to moderate renal failure, about 70% of famotidine was excreted through the kidney, mainly by tubular secretion. In patients with a CL_CR above 60 ml/min/1.48 m² the normal daily dose of famotidine can be employed, but in those with a CL_CR between 60 and 30 ml/min/1.48 m² the dose should be reduced by half, and in patients with a CL_CR below 30 ml/min/1.48 m² a reduction by three quarters of the normal dose is recommended.     

Removal of famotidine by haemodialysis in elderly anuric patients

Summary The effect of haemodialysis on the pharmacokinetics of oral famotidine has been studied in five elderly anuric patients. Famotidine 20 mg was administered in a cross-over design to patients on and not on haemodialysis.The elimination rate constant of haemodialysis (k) was 4.6-fold larger than the systemic elimination rate constant (k_e). Although the mean maximum serum concentration of famotidine during haemodialysis (141.5 ng·ml^–1) was not significantly lower than that without haemodialysis (195.6 ng·ml^–1), the AUC up to 5 h during haemodialysis was significantly decreased to 58.1% of the value without it.The data suggest that famotidine is dialysable by haemodialysis.     

Effects of loxtidine,a new histamine H2-receptor antagonist,on 24-hour gastric secretion in man

Summary The gastric inhibitory effects of loxtidine, a new histamine H₂-receptor antagonist, were studied in healthy volunteers. Doses of 20, 40 and 80 mg given in the evening reduced nocturnal acid secretion by 91, 97 and 95%, respectively, and nocturnal pepsin secretion by 86, 89 and 90%, respectively. The same doses also increased median 24-hour intragastric pH from 1.6 to 4.1, 5.4 and 5.5, respectively, but intragastric pH had returned to control values by the end of the 24-hour study period. Loxtidine at a dose of 40 mg twice daily rendered gastric contents virtually anacid throughout the 24-hour study period. The powerful gastric inhibitory effects of loxtidine denote a potential use in the treatment of peptic diseases.     

Blood level of cimetidine in relation to age

Summary The blood level versus time curve for unchanged cimetidine after a 200 mg oral dose has been determined in 20 apparently healthy subjects, ranging from 22 to 84 years of age. A significant relationship between the area under the curve (AUC) and age was found (r=0.81; P<0.001). The peak concentrations of cimetidine were significantly inversely related to body weight (r=–0.71; P<0.001). The age-related increase in bioavailability of oral cimetidine, as measured by AUC, was probably due to decreased total clearance of the drug, which resulted from the opposed changes (by themselves not significant) of distribution volume towards a decrease and of half-life towards an increase with age. Reduction in the standard oral dose of cimetidine by one third to one half should be feasible in the elderly without loss of efficacy, and it may be advisable in order to obviate extreme individual responses that may occur in this population.     

Famotidine,a new H2-receptor antagonist,does not affect hepatic elimination of diazepam or tubular secretion of procainamide

Summary In 8 healthy male volunteers the pharmacodynamic responses to a single dose of diazepam and a single dose of procainamide were assessed before and after pre-treatment with the H₂-receptor antagonist famotidine in a randomized crossover study. The pharmacokinetics of diazepam and procainamide were also studied, and the binding of famotidine to human liver microsomes was also measured. Cimetidine induced binding changes with a spectral dissociation constant (K_s) of 0.87 mM, whereas famotidine produced no measurable spectral alteration in concentrations up to 4 mM. The elimination half-life (t_1/2: 45.6 h) and total plasma clearance (CL: 0.28 ml/min/kg) of diazepam were not significantly altered by famotidine (t_1/2=39.0±11.4 h; CL =0.31±0.08 ml/min/kg). Similarly, there was no enhancement of the sedative effect of diazepam by famotidine. The pharmacodynamics and pharmacokinetics of procainamide and N-acetylprocainamide (NAPA), too, were not significantly changed by famotidine: procainamide t_1/2 2.9 vs 3.0 h under famotidine and renal clearance (CL_R) 436 vs 443 ml/min; and NAPA CL_R 195 vs 212 ml/min under famotidine. The data suggest that famotidine, in contrast to cimetidine, does not affect the pharmacokinetics of diazepam (hepatic elimination) or procainamide (tubular secretion). This new H₂-receptor antagonist appears to be devoid of an interaction potential for either type of drug elimination.     

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.     

Ranitidine pharmacokinetics in continuous ambulatory peritoneal dialysis

Summary Ranitidine kinetics in renal failure were evaluated in six patients undergoing continuous ambulatory peritoneal dialysis (CAPD). On separate occasions each patient received either 50 mg intravenously (i.v.) or 150 mg orally of ranitidine HCl. Following i.v. administration, the plasma concentration vs time curve was best described by a two compartment model with firstorder elimination. The mean ± SD distribution and elimination rate constants were 2.47±0.78 and 0.098±0.013 h, respectively. The area under the serum concentration vs time curve after the i.v. dose was 5979±2870 μg·h· 1⁻¹, resulting in a mean volume of distribution of 76.81 and a total body clearance of 126 ml·min⁻¹. Following oral administration the observed maximum plasma concentration was 904±483 μg·l⁻¹ at 4.2±1.8 h, and the bioavailability was 69.7±35.6%. The peritoneal clerance of ranitidine was 3.2±0.7 and 2.6±0.6 ml·min⁻¹ for the i.v. and oral groups, respectively. The amount of drug removed by dialysis was 561.2±336.2 μg for the i.v. and 1197.1±602.3 μg for the oral group. Four patients in the i.v. group had urine output during the study period with renal ranitidine clearance values of 9.9±9.9 ml· min⁻¹. Two patients in the oral group had urine output and corresponding renal ranitidine clearance values of 5.1 and 20.1 ml·min⁻¹. A dosage regimen for ranitidine is proposed based on ranitidine kinetics in patients undergoing CAPD.     

Effect of Cimetidine on the Pharmacokinetics and Pharmacodynamics of Chlorpheniramine and Diphenhydramine in Rabbits

Purpose. The effects of concomitant administration of the H₂-receptor antagonist cimetidine on the pharmacokinetics and pharmacodynamics of the H₁-receptor antagonists chlorpheniramine and diphenhydramine were studied in rabbits. Methods. A single dose of chlorpheniramine 10 mg (Group A) or diphenhydramine 10 mg (Group B) was given intravenously on three different study days as follows: 2 weeks before cimetidine administration, after giving cimetidine 100 mg/kg intravenously every 12 hours for one week, and two weeks after discontinuing the cimetidine. Serum chlorpheniramine and diphenhydramine concentrations were measured by HPLC. Histamine H₁-blockade was assessed by measuring suppression of the histamine-induced wheals in the skin. Results. The chlorpheniramine and diphenhydramine terminal elimination half-life values and area under the curve values were significantly increased, and the systemic clearance rates were significantly decreased, during concomitant administration of cimetidine. For each H₁-receptor antagonist, pharmacokinetic parameters were similar before cimetidine was co-administered and two weeks after cimetidine was discontinued. Wheal suppression produced by chlorpheniramine or diphenhydramine was increased and prolonged when cimetidine was administered concomitantly. Conclusions. Any enhanced peripheral H₁-blockade observed could be attributed, at least in part, to a pharmacokinetic interaction.     

Human gastric mucosal adenylate cyclase: Activation by histamine-H2-receptor stimulation and inhibition by cimetidine in vitro and in peptic ulcer patients

Summary Biopsy specimens of human fundic mucosa from 96 subjects were assayed for adenylate cyclase activity to characterize specificity of the histamine receptor with selective agonists and antagonists in vitro, and to study the effect of cimetidine therapy. Histamine and the selective histamine H₂-receptor agonist dimaprit were almost equally potent throughout the concentration-response curve (10^–7–10^–3 mol/l); maximal stimulation was obtained with concentrations of 10^–4–10^–3 mol/l, and half maximal stimulation with about 10^–5 mol/l. The selective H₁-receptor agonist PEA 10^–5 and 10^–3 mol/l failed to stimulate adenylate cyclase. Mepyramine 10^–6 mol/l, a selective H₁-receptor antagonist, and cimetidine 10^–6 mol/l, a selective H₂-receptor antagonist, did not affect basal adenylate cyclase activity. Histamine-stimulated adenylate cyclase was inhibited in a concentration dependent manner by cimetidine 10^–7 and 10^–5 mol/l, but not by the same concentrations of mepyramine. Almost identical basal adenylate cyclase activities of about 150 pmol cAMP/mg protein/20 min were found in gastric mucosal biopsies from controls and from peptic ulcer patients, whether or not treated with cimetidine. Histamine 10^–5 mol/l doubled adenylate cyclase activity in the controls and the untreated ulcer group, but was completely ineffective in specimens from the cimetidine-treated peptic ulcer patients. The data underline the concept that the effects of histamine on acid secretion and on adenylate cyclase activity are linked together and that the therapeutic effect of cimetidine in ulcer treatment is related to histamine H₂-receptor blockade followed by inhibition of adenylate cyclase.     

Safety and pharmacokinetics of mifentidine after increasing oral doses in healthy subjects

Summary Eight healthy men were each given single oral doses of mifentidine 20, 40 and 80 mg, a new H₂-receptor antagonist, in a four-way, double-blind, placebo-controlled, cross-over, dose-proportionality study.No significant objective or subjective effects were noted. Mifentidine showed unusual pharmacokinetic behaviour, producing a significant secondary peak in the drug concentration profile. The plasma AUC of mifentidine increased linearly with dose (r=0.983). The apparent plasma clearance was 38.11·h^–1, 31.01·h^–1, and 47.41·h^–1 for the 20, 40 and 80 mg doses, respectively, and the corresponding terminal plasma half-lives were 10.3 h, 12.0 h, and 8.6 h. About 20% of the parent drug was excreted in urine over 24 h. The renal clearance (9.41/h for 20 mg, 9.5 l/h for 40 mg, and 12.8 l/h for 80 mg mifentidine) indicates that some of the drug was excreted by active tubular secretion.The results indicate that mifentidine is safe after single oral doses up to 80 mg. The pharmacokinetics of the 20 and 40 mg doses were similar, but after 80 mg the total body and renal clearances were significantly greater than after the two lower doses. As the terminal plasma half-life of mifentidine is longer than of other available H₂-receptor antagonists, it may have clinical implications for once-a-day therapy of peptic ulcer diseases.     

Effect of some new histamine H2-receptor antagonists on the guinea-pig papillary muscle

Summary Several histamine H₂-receptor antagonists (cimetidine, ranitidine, oxmetidine and tiotidine) were tested for their activity on the papillary muscle of the guinea pig stimulated by histamine. All of the compounds exerted a competitive antagonism against histamine the order of potency being tiotidine > oxmetidine > ranitidine > cimetidine. Oxmetidine was the only drug which at high concentrations (10^–6 M) decreased the maximum response of histamine probably because of non specific effects of the molecule already described in the literature. As it was expected, the H₁-receptor antagonist, mepyramine, exerted a non-competitive antagonism.     

Inhibition of pentagastrin-stimulated gastric acid secretion and plasma levels of the new histamine H2-receptor antagonist ramixotidine dihydrochloride (CM 57755) in human volunteers

Summary The new competitive histamine H₂-receptor antagonist, ramixotidine 2 HCl (CM 57755), has been tested in healthy male volunteers for its ability to inhibit pentagastrin-stimulated gastric acid secretion. In the first study, in 8 subjects, pentagastrin 6 µg·kg^–1 was injected s.c., 90 min after the following 4 oral treatments given in random order at weekly intervals: placebo, 100, 200 and 400 mg CM 57755. Gastric contents were collected over 15-min periods during the 2 h after pentagastrin stimulation. In a second, similar study, 8 subjects received placebo, 0.5 and 1.0 g CM 57755 and 800 mg cimetidine, 120 min before a 2 h i.v. infusion of 6 µg·kg^–1·h^–1 pentagastrin. Cumulative gastric secretion in placebo-treated subjects was 46±14 and 62±11 mmol H⁺·2 h^–1 (mean±SD), respectively, in the first and second studies. It was significantly reduced only after 400 mg CM 57755 in the first study. In the second study either dose of CM 57755 and cimetidine caused a significant reduction in gastric acid secretion. Average plasma levels of ramixotidine were dose-related after 0.2 and 1.0 g and ranged from 0.3 and 1.6 µg/ml, respectively, at 60 min to 0.5 and 3.7 µg/ml at 180 min. The peak cimetidine level averaged 3.6 µg/ml at 150 min. Individual CM 57755 plasma levels throughout the test period were fairly consistent with the inhibition of cumulative gastric acid secretion scored concurrently in each subject. No subjective side-effects attributable to the treatments were reported, and no abnormal findings were seen in the ECG or in laboratory tests.     

硫糖铝与抑酸剂联用与单用比较的Meta分析

目的 系统评价硫糖铝与抑酸剂联用的有效性和安全性。方法 计算机检索Cochrane图书馆临床对照试验资料库(2011年第4期)、MEDLINE、EMbase、中国生物医学文献数据库和中国期刊全文数据库(从建库至2011年11月)。由两位研究者按纳入与排除标准选择随机对照研究评价质量及提取资料后,采用RevMan 4.2软件对数据进行Meta分析。结果 初检出11篇文献,经筛选最终纳入7篇文献共7个随机对照研究,包括595例患者。Meta分析结果显示,硫糖铝与抑酸剂联用与单药相比,临床症状有效率[OR 1.6,95%CI(0.87,2.93),P=0.13]、胃镜治愈率[OR 1.36,95%CI(0.87,2.12),P=0.17]、不良反应发生率[OR 1.36,95%CI(0.64,2.90),P=0.42],均无统计学差异。结论 现有研究结果表明,硫糖铝与抑酸剂联用与单药相比,未能显著增加疗效和减少不良反应,不优于两者单用。     

Analysis of the histamine H2-receptor in human monocytes

Histamine receptors are G-protein-coupled receptors (GPCRs). Canonically, the histamine H₂-receptor (H₂R) couples to G_s-proteins and activates adenylyl cyclases (ACs) with subsequent adenosine-3′,5′-cyclic monophosphate (cAMP) generation. Recently, the classic two-state model describing GPCR activation has been extended to a multiple-state model implying that any ligand stabilizes a ligand-specific receptor conformation, also referred to as functional selectivity. In our present study we pharmacologically characterized the H₂R in human monocytes. We found dissociations in the effects of histamine (HA) and H₂R agonists on cAMP accumulation and inhibition of formyl peptide-induced production of reactive oxygen species (ROS). In addition, we excluded participation of protein kinase A (PKA) in HA-induced ROS inhibition. Comparison of the potencies and efficacies of H₂R agonists in monocytes, neutrophils and eosinophils unmasked cell type-specific pharmacological profiles of individual ligands. Taken together, our data extend the concept of functional selectivity to the H₂R in human monocytes and demonstrate striking cell-type specificity in the pharmacological profile of the H₂R.     

Influence of cigarette smoking on melatonin levels in man

Objective Polycyclic aromatic hydrocarbons in cigarette smoke induce cytochrome P₄₅₀(CYP)1A2, which is involved in the hepatic metabolism of melatonin (MT). This suggests that habitual smokers may have low serum MT levels during smoking compared with a non-smoking period. We decided to investigate whether this suggestion is correct.Methods Eight habitual smokers were tested on two occasions. They had smoked prior to the first occasion but had not smoked for 7 days prior to the second. Each test was divided into two parts. The first part spanned the night between 2000 hours and 0800 hours. Venous blood samples were collected every second hour during this period for analysis of endogenous serum MT. The second part was performed the subsequent day. At 0930 hours, 25 mg MT was ingested orally, and blood samples for exogenous serum MT analysis were collected every hour between 1000 hours and 1600 hours. Endogenous and exogenous areas under the serum MT–time curve (MT-AUCs) were calculated.Results Endogenous serum MT-AUCs were similar during the two periods. Oral administration of MT induced supraphysiological levels of serum MT. Moreover, exogenous serum MT-AUCs were significantly smaller before than after smoking abstinence (7.34±1.85 versus 21.07±7.28 nmol/l×h; P<0.02; means±SEM).Conclusion This investigation shows that exogenous, but not endogenous (at night), serum MT levels are influenced by cigarette smoking. When the MT levels are low, the influence of CYP1A2 levels appears to be less pronounced than when they are high, and the enzyme capacity hugely utilized. These findings implicate that interactions between exogenous MT, and substrates metabolized by CYP1A2, may differ in individuals before and after smoking abstinence.     

Effect of cimetidine and ranitidine on the hepatic and renal elimination of nicotine in humans

Summary In a randomized, double-blind, cross-over experiment, 6 healthy consenting male subjects were administered cimetidine 600 mg or ranitidine 300 mg or placebo p.o. q12h×2 days. Nicotine bitartrate was administered i.v. on day 2 (1 ug/kg/min)×30 min.After cimetidine mean nicotine total and metabolic clearances were decreased by 30% and 27% while after ranitidine the clearances were decreased by 10% and 7% respectively.Since smokers regulate their smoke intake based in large part on their nicotine blood levels these results suggest that the diminished nicotine total clearance in the presence of cimetidine could be important in assisting smoking reduction or cessation.The views expressed in this publication are those of the authors and do not necessarily reflect those of the Addiction Research Foundation     

Histamine regulates growth of malignant melanoma implants via H2 receptors in mice

The present study examined the effect of histamine H₂-receptor antagonists and exogenous histamine on growth of malignant melanoma implant in mice. Drugs were administered to B16BL6 malignant-melanoma-implanted syngeneic mice, and the tumor volume was measured throughout the experiments. Cell proliferation was assessed by MTT assay and mRNA expression was determined by RT-PCR. Both roxatidine and cimetidine significantly suppressed growth of B16BL6 implant compared with vehicle. On the other hand, systemically administered histamine significantly stimulated growth of B16BL6 implants. In addition, the histamine-stimulated B16BL6 implant growth was markedly suppressed by co-administration of cimetidine in a dose-dependent manner. H₂-receptor antagonists, however, failed to affect in vitro proliferation of B16BL6 cells. H₂-receptor mRNA was detected in B16BL6 implants but not in the cell line. These results indicated that both endogenous and exogenous histamine have ability to stimulate growth of malignant melanoma implants via H₂ receptors expressed in host cells.     

Temporal responses of cutaneous blood flow and plasma catecholamine concentrations to histamine H1- or H2-receptor stimulation in man

Summary We have studied the effect of histamine and H₁- or H₂-receptor antagonists on cutaneous blood flow and catecholamine release in man.Histamine was infused alone or in combination with mepyramine, an H₁-antagonist or cimetidine, an H₂-antagonist for 2 h. Cutaneous blood flow was measured continously with a laser Doppler flowmeter, and noradrenaline and adrenaline concentrations were determined in blood samples drawn every 15 min.The infusion of histamine caused an immediate and sustained vasodilatation. The Concomitant infusion of mepyramine prevented the immediate vasodilatation, but had no effect on the sustained response. The Concomitant infusion of cimetidine was without effect on the immediate vasodilatation, but abolished the sustained response. Infusion of the antagonists alone had no effect on cutaneous blood flow.Histamine caused a rapid and sustained increase in plasma noradrenaline, while the increase during concomitant H₁-receptor blockade was delayed but achieved the level observed during the histamine infusion. The response to histamine during H₂-receptor blockade was small and transient. The rise in plasma adrenaline was not significant.These findings suggest that histamine causes an immediate cutaneous vasodilatation through H₁-receptors and a more sustained response through H₂-receptors. The vasodilatation is accompanied by an increase in plasma catecholamine concentrations. Despite the continuous infusion of histamine, blood flow decreased during the last hour of histamine infusion, while the plasma noradrenaline concentration was still elevated.     

Gastric inhibitory effects of CM57755

Summary The gastric inhibitory effects of CM57755, a new histamine H₂ receptor antagonist, have been compared in ten healthy male volunteers with the actions of an equal dose of cimetidine and with placebo. The inhibitory effect of CM57755 was virtually identical with, and not significantly different from the effects of cimetidine on nocturnal gastric secretion of acid, while neither drug influenced the secretion of pepsin. Neither drug, administered in the evening, influenced the intragastric pH and acidity during the following day, from breakfast onwards. The therapeutic impact of the new drug is likely to resemble that of cimetidine and clinical application will depend on the safety profile.