Comparison of antiproliferative effects of 1-histamine-2 receptor antagonists,cimetidine, ranitidine,and famotidine,in gastric cancer cells

In the immune system, histamine is known to suppress cytotoxic T-lymphocytes and mitogen induced lymphocyte thymidine uptake, down-regulate some cytokines, and activate suppressor T-lymphocytes, and in the gastrointestinal system, histamine was reported to have trophic effects on gastrointestinal epithelial cells. Enhanced rates of cell proliferation by histamine are implicated in the pathogenesis of carcinogenesis. This study was designed since there is a lack of comparative data about the cell proliferations of histamine-2 receptor antagonist (H2-RA), cimetidine, ranitidine, and famotidine, in gastric cancer. KATO-III and AGS cell lines were used in this experiment. The concentrations of the histamine and cimetidine were 10⁻⁵, 10⁻⁸M, respectively and those of ranitidine and famotidine were 10⁻⁶-10⁻⁹M, respectively. Cell proliferation after drug treatment was evaluated by direct cell counting, [³H]thymidine incorporation, and MTT assay. Activities of ornithine decarboxylase (ODC), a rate limiting enzyme in polyamine synthesis, were measured after each drug treatment. Protein kinase A, a cAMP-dependent protein kinase system, was assayed using [α-³²p]ATP. Histamine showed statistically significant cell proliferating effects in a dose-dependent manner (P < 0.01), the maximal effect in 10⁻⁵M concentration. ODC activities were increased in accordance with the increment of cell numbers after histamine treatment. Cimetidine reversed the histamine-stimulated cell proliferation significantly, the maximal effect in 10⁻⁵M concentration (P < 0.01). Although ranitidine showed the tendency to attenuate the cell proliferation dose-dependently, but without statistical significance, famotidine did not show such an effect at all. cAMP-dependent protein kinase activities were significantly increased following 10⁻⁵M histamine treatment, also reversed significantly by cimetidine co-administration (P < 0.01). Beneficial clinical outcomes could be anticipated from cimetidine treatment in patients with gastric cancer by anti-proliferating effects against gastric cancer cells. These effects of H2-RA are likely to be mediated by specific interactions at the H2-receptor.     

Pharmacology of the novel H2 antagonist famotidine: In vitro studies

The novel antiulcer drug famotidine was found to be a potent and selective inhibitor of histamine H2 receptors. Its activity on different parameters involving H2 receptors was higher than that of other compounds of the family: pA₂ values were 8.33, 7.86 and 7.83 in the guinea pig atria, guinea pig papillary muscle and isolated rat gastric secretion, respectively. Apart from quantitative differences, famotidine differred from the other compounds, since it caused a competitive antagonism only at low concentrations and an unsurmountable antagonism at higher concentrations. The duration of the inhibitory action on the in vitro gastric secretion resembled that of cimetidine and ranitidine. Famotidine was highly effective (approximately 10 times as potent as ranitidine) also on the rat uterus (unsurmountable antagonism) and on the guinea pig gallbladder (pA₂value=7.71). Famotidine was apparently devoid of non-specific effects converning the gastrointestinal motility even at very high concentrations (10^–4 M). In this respect, famotidine appeared to be more selective than cimetidine and ranitidine at the H2 receptor level. The high potency, the peculiarity of the antagonism and the lack of side-effects on a number of isolated preparations, indicate this H2 antagonist as a very peculiar member of the group.     

Two cases of h(2)-receptor antagonist hypersensitivity and cross-reactivity

H(2)-receptor antagonists, such as cimetidine, ranitidine and famotidine, are some of the most commonly prescribed medications for gastric acid-related disorders. These compounds are generally well-tolerated and anaphylactic reactions to them are rare. Here, we report two cases of H(2)-receptor antagonist-induced anaphylactic reactions: the first presented with sudden dyspnea, sneezing, urticaria, and swelling of the eyelids after ranitidine intake. The second presented with sudden severe urticaria, facial swelling, chest discomfort, dizziness, and hypotension. Possible cross-reactivity with other H(2)-receptor antagonists was assessed by oral challenge and skin tests. To date, only a few reports addressing cross-reactivity among H(2)-receptor antagonists have been published. We review the literature and summarize the data available on drug cross-reactivity in H(2)-receptor antagonist hypersensitivity.     

Gastric mucosal cell proliferation in ethanol-induced chronic mucosal injury is related to oxidative stress and lipid peroxidation in rats

The oxygen free radicals-induced lipid peroxidation (LP) has been implicated in the pathogenesis of acute ethanol-induced gastric mucosal lesions. However, the role of LP in the generation of chronic gastric mucosal injury is unknown. We have developed a model of chronic mucosal injury induced by continuous ethanol ingestion for 5 days and characterized by marked alterations in plasma membranes from gastric mucosa. Therefore, LP was evaluated in this experimental model. Indicators of peroxidative activity, mucosal glutathione content, thymidine kinase activity (an index of cell proliferation), and histamine H2-receptor (H2R) binding constants were quantified in animals undergoing gastric mucosal damage. The effect of famotidine, a H2R antagonist that readily ameliorates the chronic mucosal injury, was also tested. Increased free radicals and LP levels were detected during gastritis; however, a second, higher peak of LP was noted in mucosal plasma membranes after ethanol withdrawal (recovery period). This further increase of LP coincided with active cell proliferation, decreased mucosal glutathione levels, and diminished specific cimetidine binding by H2R. Administration of famotidine accelerated the mucosal proliferative process, inducing the second lipoperoxidative episode sooner, and preserved the content of glutathione. In addition, LP correlated directly with cell proliferation and inversely with mucosal membrane cimetidine binding. In conclusion, LP seems to be involved in chronic ethanol-induced gastric mucosal injury. However, a further enhancement of plasma membrane LP occurred, associated with increased DNA synthesis and diminished cimetidine binding by membrane H2R. Therefore, increased LP could also participate in the compensatory mucosal proliferation initiated after ethanol withdrawal.     

Mechanism of action of H2-antagonists on histamine-or dimaprit-stimulated H2-receptors of spontaneously beating guinea-pig atrium

Cimetidine, ranitidine and famotidine are antagonists of the histamine H₂-receptors on the spontaneously beating right atrium of the guinea pig. When analyzed by the classical Schild method theirpA ₂-values are respectively: 6.3, 6.8 and 7.7 with dimaprit as agonist and 5.8, 6.5 and 7.7 with histamine as agonist. Radiolignad-displacement studies with [³H]-tiotidine as radioligand resulted inpK _d values for cimetidine, ranitidine and famotidine of 6.3; 6.9 and 8.2 respectively.In dimaprit-stimulated atria all antagonists added at concentrations above theirK _d values depressed the maximal increase in frequency. In the presence of histamine this effect was much less pronounced and only visible at concentrations of ranitidine and famotidine around 10 ·K _d.The rightward shift of the curves as well as the decrease inE _max are reversible but the dissociation constants of the antagonists are small (less than 10^–3 s^–1).The spontaneously beating right atrium showed receptor reserve for histamine and virtually no receptor reserve for dimaprit.The results have been interpreted in a model in which H₂-antagonists act mainly by competing with the agonist for the histamine receptor site but have in addition a distinct affinity for a secondary site on the receptor. Occupation of this site by the antagonist prevents building up of the stimulus elicited by the agonist and thus decreases theE _max. In systems with receptor reserve (histamine) the effect of antagonist binding to the secondary binding site is seen only at high concentration of antagonist while in absence of receptor reserve (dimaprit) the depression ofE _max is directly visible.Simulations of the model show that the affinity of this secondary binding site is 50- (famotidine) to 100-(cimetidine and ranitidine) fold lower than for the agonist binding site.     

The effect of ranitidine on gastric acid secretory response curves to histamine,pentagastrin or bethanechol in the dog with a heidenhain pouch

The H₂-receptor antagonists ranitidine and cimetidine were tested against gastric secretory dose-response curves to histamine, pentagastrin and bethanechol in the Heidenhainpouch dog. Histamine-induced gastric secretion was antagonized in a competitive manner by both ranitidine and cimetidine, but ranitidine was approximately 8 times more potent than cimetidine. Pentagastrin-induced secretion was markedly reduced by ranitidine and cimetidine but this antagonism was not competitive in nature. Bethanechol-induced gastric secretion was slightly reduced by both drugs. These findings are discussed in relation to he physiological control of gastric secretion.     

The role of interleukin 2 (IL-2) and serum-soluble IL-2 receptor cells in idiopathic IgA nephropathy.

Interleukin 2 (IL-2) plays a central role in the immune response and may be involved in the derangement of cellular immunoregulation of idiopathic IgA nephropathy (IgAN). The aim of this study was to investigate the serum levels and production of IL-2 from peripheral blood mononuclear cells (PBMC) and the distribution of IL-2 receptor cells and serum-soluble IL-2 receptor cells (sIL-2R) in patients with IgAN. Twenty-four patients with IgA nephropathy and 11 healthy controls (age and sex matched) were studied during an infection-free period without signs of clinical activity at the moment of the study. Serum IL-2 concentrations did not differ between patients and controls. The supernatant levels of IL-2 taken from 24-hr cultures of PBMC stimulated with phytohemagglutinin or tumor necrosis factor increased significantly in the patients but not in the controls. The percentage of IL-2R positive cells (CD25+) was increased in patients compared with controls. Moreover, IgAN patients had increased activated CD4+ lymphocytes when compared with the controls. Serum levels of sIL-2R were significantly higher in patients than in controls. There were no correlations among renal function, serum IgA levels, and urinary findings with cellular subsets or with IL-2 levels. However, sIL-2R was higher in the subgroup of patients with episodic macrohematuria and was closely related with the presence of red blood cells in the urinary sediment. We conclude that PBMC of IgA nephropathy patients have an overproduction of IL-2 after mitogenic stimulation, an increased helper T cell activity, increased IL-2R+ cells, and elevated serum levels of sIL-2R. These alterations are present in periods of apparent clinical inactivity. Finally, sIL-2R is closely related with hematuria, providing a good marker for disease activity. Our results suggest a pivotal role of IL-2 in cellular immune responses with regard to T cell activation in patients with IgAN.     

Inhibitory effect of famotidine on cat gastric secretion

The inhibitory effect of the novel H2 receptor antagonist famotidine was studied in conscious gastric fistula cats against dimaprit-induced hypersecretion, in comparison with ranitidine. On the secretory plateau induced by dimaprit (2 mol kg^–1 h^–1) famotidine (0.05–0.2 mol kg^–1 i.v.) exerted a dose-dependent inhibitory effect, being approximately 4.5 times as potent as ranitidine (ID₅₀ values were 0.067±0.015 and 0.30±0.025 mol kg^–1 for famotidine and ranitidine, respectively). No significant differences were found between the two drugs, as for the time-course of the inhibitory effect. Famotidine (0.01–0.32 mol kg^–1 h^–1) caused a parallel displacement of the dose-response curve to dimaprit to the right, without reducing the maximum response to the stimulant, thus behaving as a competitive antagonist, like ranitidine. pA₂ values for famotidine and ranitidine were 7.95 and 6.92, respectively. In the same range of doses famotidine dose-dependently reduced also the secretory response to histamine. From these data it was concluded that famotidine is a potent histamine H2 receptor antagonist in the cat gastric mucosa; moreover, conversely from in vitro data, the antagonism was surmountable even at the highest doses tested. In vivo experiment, therefore, did not reveal any particular feature of this compound, apart from the undoubtedly high potency, in comparison with other members of the family.     

Cytotoxicity in patients with different clinical forms of Chagas' disease

There are few studies on cell-mediated cytotoxicity in human Chagas' disease. In the present study, we evaluated peripheral blood mononuclear cell (PBMC) cytotoxicity activity from chagasic patients with different clinical forms of disease. To verify the cytotoxic response, we performed cell lysis assays using ⁵¹Cr-labelled K562 cells as targets. Results are reported as lytic units (LU=number of cells required for 30% lysis) per million PBMC. Exposure of patients’ PBMC to Trypanosoma cruzi antigen led to an increase in cytotoxic activity compared with unstimulated patient cells against K562. Asymptomatic cardiomyopathy patients had higher responses (37.8±5.0 LU/10⁶ PBMC; mean±s.d.) than indeterminate (11.5±3.6 LU/10⁶) and symptomatic cardiomyopathy (7.8±2.5 LU/10⁶). Normal control PBMC stimulated with T. cruzi antigen had 4.36±1.31 LU/10⁶ PBMC against K562. Addition of recombinant interferon-gamma (IFN-γ) did not lead to significant increase in cytotoxicity in any group of patients. On the other hand, recombinant human IL-12 significantly increased cytotoxic responses from symptomatic cardiomyopathy patients and normal controls who presented low levels of cytotoxicity induced by T. cruzi antigen. The combined use of IL-12 and a neutralizing anti-IFN-γ antibody did not change IL-12-induced cytotoxic responses, showing the direct role of this cytokine on natural killer (NK) cells. NK cells were the main cells responsible for the lysis of K562 target cells as evidenced by testing cell subsets following magnetic cell sorting. These data demonstrate that chagasic patients with different clinical forms of disease have PBMC which respond to T. cruzi antigen with a cytotoxic response, and this response is up-regulated by IL-12.     

Differential effects of histamine receptor antagonists on human natural killer cell activity

In this study we investigated the modulation of natural killer (NK) cell activity by various histamine receptor antagonists in vitro. The histamine H2-receptor antagonists cimetidine, ranitidine and tiotidine suppressed NK cell cytotoxicity (NKCC) at a high concentration (10(-3) M). Cimetidine enhanced NKCC of Ficoll-Hypaque-separated lymphocytes and of lymphocytes enriched for NKCC by Percoll density gradient centrifugation. The enhancing effect of cimetidine was dose-dependent at final concentrations of 10(-4)-10(-7) M and did not require the presence of adherent cells/monocytes. Ranitidine did not affect NKCC over a wide range of concentrations. Tiotidine strongly enhanced NKCC of low-density, large granular lymphocyte-enriched mononuclear cells (MNC) in the presence of adherent cells/monocytes, but was ineffective in nonadherent effector cells. All H2-receptor antagonists clearly antagonized histamine-induced NKCC enhancement in monocyte-containing effector cells. Clemastin, a specific H1-receptor antagonist, effectively suppressed NKCC. This effect was mimicked by a clemastin isomer with very low affinity for H1-receptors. We conclude that (1) cimetidine enhances NKCC in vitro by a mechanism of action that is not specifically related to antagonism of H2-receptors, (2) tiotidine displays mixed agonist/antagonist properties for MNC H2-receptors and (3) NK-suppressive properties of clemastin are unrelated to H1-receptor antagonism.     

IL-2 regulation of soluble IL-2 receptor levels following thermal injury.

In the immunosuppressed burn patient serum levels of both IL-2 and a soluble form of IL-2 receptor alpha (sIL-2R alpha) are significantly elevated. Strikingly, the production of these markers by the in vitro activated patients' cells is decreased. This study examines the role of IL-2 in the decreased production of the sIL-2R alpha in vitro in patients with major burns (n = 18, 30 to greater than 70% total body surface area). Peripheral blood mononuclear cell (PBMC) cultures from patients with highly elevated serum sIL-2R alpha, and from healthy controls (n = 12) were activated with concanavalin A (Con A) at initiation. In patients' cultures mitogen-induced increments of sIL-2R alpha levels were significantly lower. There was a significant negative correlation (r = 0.64, P less than 0.001) between a high serum sIL-2R alpha level and a decreased lectin-induced sIL-2R alpha release in vitro. Low levels of sIL-2R alpha in patients' samples were not normalized by increasing the number of T lymphocytes. Also exogenous rIL-1 was without effect, whereas rIL-3 increased sIL-2R alpha release in some cultures. However, sIL-2R alpha levels were significantly increased in patients' cultures by (i) addition of exogenous IL-2; (ii) removal of adherent cells; (iii) addition of cyclooxygenase inhibitor, indomethacin; (iv) bypassing cell surface activation by the combination of the calcium ionophore A23187 and the phorbol ester 12-o-tetradecanoyl acetate. The cyclic AMP-elevating drug, forskolin, abrogated the ability of exogenous IL-2 to increase sIL-2R alpha production. Thus, in the burn patient, the reduced in vitro sIL-2R alpha release appears to relate to abnormalities in IL-2 production and action mediated through its functional surface receptor. Elevated levels of sIL-2R alpha in vivo may, therefore, reflect systemic activation of T lymphocytes in response to biologically active IL-2.     

The significance of serum soluble IL-2 receptor as a marker for active visceral leishmaniasis in Sicilian patients.

Sera from nine Sicilian patients with confirmed visceral leishmaniasis (Leishmania donovani infantum; VL), at the moment of the diagnosis, during the course of the disease and after clinical recovery, were analysed for the concentration of soluble IL-2 receptor (sIL-2R). The results show that sIL-2R is a marker of disease activity, since it is in high concentration at the beginning of infection and returns to the normal range following successful chemotherapy. At the same time of serum analysis for sIL-2R, peripheral blood mononuclear cells (PBMC) of VL patients were stimulated with phytohaemagglutinin (PHA) or antigen and supernatant tested for IL-2 and interferon-gamma (IFN-gamma) production. Data demonstrate that there is an inverse relation between concentration of IL-2 and IFN-gamma in the supernatants and sIL-2R secretion in the sera.     

Soluble plasma IL-2 receptors and malaria.

Plasma levels of soluble IL-2 receptor (sIL-2R) were measured by immunoassay in 180 individuals, aged 1-70 years, living in a malaria-endemic community in West Africa. sIL-2R levels were compared with age, malaria parasitaemia, malaria-associated morbidity and cellular immune responses to Plasmodium falciparum antigens. Plasma levels of sIL-2R were independently associated with both age and patent malaria parasitaemia. No significant association was observed between IL-2R levels and concurrent malaria morbidity (i.e. fever associated with malaria), but the number of individuals with clinical malaria at the time of sampling was small. Although there was no association between plasma sIL-2R levels and in vitro proliferative responses of peripheral blood mononuclear cells (PBMC) to a number of defined malaria antigens, we did find a significant negative association between sIL-2R and in vitro proliferation of unstimulated PBMC. High levels of sIL-2R (up to 5500 U/ml) were detected in the plasma of malaria-infected individuals; this is indicative of a vigorous cellular immune response to malaria antigens in vivo and does not support the notion that malaria infections are generally immunosuppressive. Indeed, we found that, at the low levels of parasitaemia present in study subjects, there was no significant difference in the mean proliferative response to malaria antigens in infected subjects when compared with uninfected subjects.     

Soluble interleukin-2 receptor and soluble CD8 antigen in active rheumatoid arthritis

Concentrations of soluble interleukin-2 receptor (sIL-2R) and of soluble CD8 antigen (sCD8) in sera and in supernatants of phytohemagglutinin (PHA)-stimulated peripheral blood mononuclear cells (PBMC) derived from patients with active rheumatoid arthritis (RA) were studied. sIL-2R concentrations in sera derived from patients with RA (1484 +/- 382 U/ml) were significantly higher than in sera derived from healthy controls (380 +/- 110 U/ml; P less than 0.0005). In contrast, supernatants of PHA-stimulated PBMC derived from patients with RA contained similar amounts of sIL-2R (727 +/- 467 U/ml) as those derived from healthy control individuals (833 +/- 508 U/ml; P greater than 0.1). When investigated for the presence of sCD8 antigen, sera derived from patients with RA contained significantly lower amounts (30 +/- 28 U/ml) than sera derived from healthy controls (405 +/- 136 U/ml; P less than 0.0005). Similarly, PHA stimulation of PBMC derived from patients with RA resulted in a significantly lower production of sCD8 (35 +/- 46 U/ml) as compared to the one obtained by PHA stimulation of PBMC derived from healthy controls (177 +/- 59 U/ml; P less than 0.0005). This difference could not be explained by a lower proliferative response to PHA by PBMC derived from patients with RA (21,474 +/- 14,022 cpm) as compared to healthy controls (29,549 +/- 11,188 cpm; P greater than 0.05). Our data demonstrate that PBMC derived from patients with active RA differ from PBMC derived from healthy individuals concerning their ability to produce sIL-2R and sCD8.     

IL-2 responsiveness of lectin-induced lymphoblasts: soluble IL-2 receptor release and differential in vitro effects of immunosuppressants.

We examined the mode of action of different immunosuppressants on the responsiveness of phytohemagglutinin (PHA)-induced lymphoblasts further stimulated by recombinant interleukin-2 (rIL-2). The stimulation of PHA blasts with rIL-2 resulted in an enhancement of tritiated thymidine ([3H]TdR) incorporation and of soluble interleukin-2 receptor (sIL-2R) release. Cyclosporin A (CsA) and prednisolone inhibited in different ways the responsiveness of PHA pre-stimulated blood mononuclear cells (PBMC) to rIL-2, as measured by [3H]TdR incorporation. The addition of CsA resulted in considerable enhancement of the release of sIL-2R, whereas the addition of prednisolone was associated with a similar enhancement only when the higher concentrations of rIL-2 were employed. EGTA, a calcium (Ca2+) chelator, and verapamil, a Ca2+ channel blocker, inhibited [3H]TdR incorporation in a concentration-dependent manner. EGTA inhibited sIL-2R release in the same manner when used alone, and reversed the CsA- and prednisolone-induced enhancement of sIL-2R release by rIL-2 induced lymphoblasts, when used in combination with CsA or prednisolone. Verapamil had a similar but less striking effect. The effects of CsA and prednisolone were also studied in PHA-induced blasts originating from purified CD4+ or CD8+ lymphocytes. Stimulation of these blasts with rIL-2 resulted in higher [3H]TdR incorporation by CD8+ blasts than by CD4+ blasts: however, no sIL-2R release was detected in supernatants of either CD4+ or of CD8+ blasts. Both CsA and prednisolone inhibited the rIL-2-induced enhancement of [3H]TdR incorporation by both T-cell subsets.(ABSTRACT TRUNCATED AT 250 WORDS)     

Histaminwirkungen am Herzen unter besonderer Berücksichtigung kardialer Nebenwirkungen von H2-Rezeptor-Antagonisten

Summary The existence of cardiac h₁- and h₂-receptors is evidenced by pharmacologic studies. Despite of the relatively high content of cardiac histamine it is not clarified whether histamine actually plays a physiologic role — apart from pharmacologic effects — in the regulation of myocardial function and coronary blood flow. Under pathophysiologic conditions (during anaphylaxis, surgical procedures, accidents, stress etc.), however, when a local or systemic histamine release occurs both hemodynamic and arrhythmogenic effects are evident. Numerous studies in animal models conclusively demonstrated a role of cardiac histamine as a major mediator of serious arrhythmias. Consequently, a combination of h₁- and h₂-receptor antagonists (f.e. Dimetinden/Cimetidin) was recommended as a prophylactic treatment against severe anaphylaxis including life-threatening arrhythmias for cardiac patients at risk.There is pharmacologic evidence of both a positive inotropic and chronotropic effect in the human heart via h₂-receptor and stimulation of adenylate cyclase. Histamine-induced coronary effects such as vasoconstriction via h₁-receptor and coronary dilatation via h₂-receptor are not yet sufficiently validated. Studies on the human heart in vitro using coronary strips from explanted hearts and in vivo investigations on the intact coronary system yielded conflicting results.H₂-receptor blocking agents cimetidine, ranitidine and famotidine have qualitatively a different pharmocodynamic spectrum of side effects due to differences in chemical structure. Data on cardiac arrhythmias are mostly associated to cimetidine. Symptomatic bradycardia were reported for both ranitidine and cimetidine. A possible negative inotropic effect of famotidine, although presently not validated, requires further studies.— Causative and adverse side effects of cimetidine on the cardiovascular system, however, are to be expected extremely seldom due to easily reversible competetive h₂-receptor binding. For prophylaxis rapid intravenous injections of h₂-blockers, particularly in elder patients with cardiac diseases, should be avoided. Compared to cimetidine, a tendency of explainable difference seems to become apparent for ranitidine and famotidine due to higher receptor affinity.

---

Abkürzungsverzeichnis A Atrium - AVN AV-Knoten - HF Herzfrequenz - V Ventrikel     

Indomethacin induced changes in mucosal lysosomal enzyme activity: Effect of H2 antagonists

Indomethacin induced gastric damage in rats was accompanied by a decrease in mucosal activities of three lysosomal enzymes tested, with serum levels remaining unchanged. Petreatments with cimetidine (100 mg/kg b.w.) and ranitidine (30 mg/kg b.w.) were found partially to prevent the decrease ofN-acetylglucosaminidase and acid phosphatase, as well as of beta-glucuronidase, while the latter was also prevented by famotidine (10 mg/kg b.w.). All the H₂ antagonists tested reduced dose-dependently the extent of gastric injury induced by indomethacin and reversed the changes in protein levels. The stabilisation of lysosomal membranes and thus the prevention of lysosomal leakage may be one of the favourable additional mechanisms of antiulcer activity of H₂ antagonists.

     

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 observedin vitro is also relevant for thein 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.     

Different effects of cimetidine and ranitidine on gastric emptying in rats and man

Cimetidine and ranitidine were tested for their effect on gastric emptying in the rat. At low doses, cimetidine was inactive, whereas it significantly delayed emptying rate when administered at higher doses. Ranitidine always accelerated gastric emptying. At variance with rats, ranitidine delayed human gastric emptying whereas cimetidine was completely inactive. All these data are consistent with the idea that these effects of H₂-antagonists are independent of H₂-receptor blockade.