The protective effects of ascorbic acid, cimetidine, and nifedipine on diethyldithiocarbamate-induced hepatic toxicity in albino rats.

The aim of the present work was to clarify the involvement of free radicals, cytochrome P450 toxic metabolites, and deregulation of calcium homeostasis in the mechanism of diethyldithiocarbamate (DDC) hepatotoxicity. This was elucidated through the preadministration of ascorbic acid (a free radical scavenger), cimetidine (an inhibitor of cytochrome P450 enzymes), or nifedipine (a calcium-blocking agent) before DDC treatment to male albino rats. DDC was administered either as a single dose [800 mg/kg body weight (b.w.), subcutaneously, s.c.] or daily repeated doses for 30 days (400 mg/kg b.w., s.c.). Oxidative stress indicators [e.g., malondialdehyde (MDA), reduced glutathione (GSH), and superoxide dismutase enzyme (SOD)] showed that single or repeated DDC doses induce an increase in MDA level and a decrease in SOD activity in the liver, whereas it causes depletion in hepatic GSH after a single dose and an elevation in its value after repeated doses. Severe histopathological changes were also observed in the livers of rats treated with single or repeated DDC doses. Ascorbic acid, cimetidine, and nifedipine pretreatments were found to induce highly protective effects against the evinced DDC hepatotoxicity, manifesting that free radical, cytochrome P450, and calcium-dependent processes contribute to DDC liver toxicity. Finally, although multiple mechanisms may be involved in the hepatotoxic changes induced by DDC, calcium disarrangement and free radical formation play a more critical role than cytochrome P450 in metabolic events leading to toxic effects of DDC.

Evaluation of antiulcer and antisecretory potential of Linum usitatissimum fixed oil and possible mechanism of action.

The aim of the study was to evaluate the antiulcer activity of Linum usitatissimum fixed oil against aspirin-, indomethacin-, ethanol-, reserpine-, serotonin- and stress-induced gastric ulceration in rats and histamine-induced gastric ulceration in guinea pigs. Attempts were also made to evaluate the in vitro anticholinergic and antihistaminic activity and in vivo antisecretary and antiulcer activity of oil following pylorus ligation in rats. L. usitatissimum fixed oil exhibited significant antiulcer activity against different ulcerogens in experimental animal models. The fixed oil significantly inhibited acetylcholine- and histamine-induced contraction of guinea pig and rat ileums, respectively, suggesting its anticholinergic and antihistaminic activity. The oil also exhibited significant inhibitory effect on gastric secretion/total acidity and aspirin-induced gastric ulceration in pylorus-ligated rats. The lipoxygenase inhibitory, histamine antagonistic and antisecretory (anticholinergic) effects of the oil could probably have contributed towards antiulcer activity. L. usitatissimum fixed oil may be considered to be a drug of natural origin which possesses significant antiulcer activity. The present observation is the first experimental data showing antiulcer activity of L. usitatissimum fixed oil.

Acute liver acetaminophen toxicity in rabbits and the use of antidotes: a metabonomic approach in serum.

The metabonomic approach has been widely used in toxicology to investigate mechanisms of toxicity. In the present study alterations in the metabolic profiles, monitored by (1)H-NMR spectroscopy, on serum samples in acetaminophen (APAP)-induced liver injury in rabbits were examined. Furthermore, the effect of the established antidote N-acetylcysteine (NAC) and the proposed antidotes silybinin (SIL), cimetidine (CIM) and SIL/CIM was also investigated. A single dose of APAP (2 g kg(-1) b.w., i.g.) was administered to rabbits and APAP combined with the antidotes SIL, CIM and NAC. Animals were sacrificed at 24 h post-APAP treatment. Healthy untreated animals served as controls. (1)H-NMR spectra of serum samples were acquired and underwent principal component analysis (PCA). Acute liver injury was verified by histopathological examination and the alterations of serum biochemical enzymes AST and ALT. (1)H-NMR spectroscopy revealed variations in the serum metabolic profile of APAP-intoxicated rabbits compared with controls. Co-administration of APAP with NAC, CIM and SIL + CIM seems to ameliorate the metabolic profile of animals compared with simply APAP-treated ones. In this study, the model of APAPinduced liver injury was successfully described using the (1)H-NMR based metabonomic approach in serum. Furthermore, the use of antidotes that reduced the toxic insult was also recorded using this technique. The combination of NMR spectroscopy and PCA is a rapid methodology, capable of detecting alterations in the metabolic profile, and produces adequate models that could be used for the characterization of unknown samples, both experimental and clinical, reinforcing its future use in clinical settings.

Comparative treatment of alpha-amanitin poisoning with N-acetylcysteine, benzylpenicillin, cimetidine, thioctic acid, and silybin in a murine model.

STUDY OBJECTIVE: The foraging of wild mushrooms can be complicated by toxicity from several mushroom types. Amatoxin, a peptide contained in several mushroom species, accounts for the majority of severe mushroom poisonings by binding to RNA polymerase II irreversibly, leading to severe hepatonecrosis. There is no effective antidote for severe amatoxin poisoning. We compare the effectiveness of 5 potential antidotal therapies in limiting the degree of hepatonecrosis in a randomized, controlled, murine model of amatoxin-induced hepatotoxicity. METHODS: One hundred eighty male Institute of Cancer Research mice were randomized into 6 equal groups. Within each group, 21 mice were intraperitoneally injected with 0.6 mg/kg of alpha-amanitin (amatoxin); the remaining 9 were injected with 0.9% normal saline solution. Four hours postinjection, each group of 30 mice was randomized to 1 of 5 intraperitoneal treatments (N-acetylcysteine, benzylpenicillin, cimetidine, thioctic acid, or silybin) or normal saline solution. Repeated dosing was administered intraperitoneally every 4 to 6 hours for 48 hours. After 48 hours of treatment, each subject was killed, cardiac blood was aspirated for hepatic aminotransferase measurements (alanine transaminase and aspartate transaminase), and liver specimens were harvested to evaluate the extent of hepatonecrosis. The degree of hepatonecrosis was determined by a pathologist blinded to the treatment group and divided into 5 categories according to percentage of hepatonecrosis. RESULTS: Amanitin significantly increased aspartate transaminase in treated mice compared with normal saline solution-treated controls (mean [SD] 2,441 [2,818] IU/L versus 310 [252]; P=.03). None of the antidotal therapies were found to significantly decrease the increase in aminotransferases compared with controls. Further, none of the antidotal therapies demonstrated an important decrease in hepatonecrosis compared with controls when a histologic grading scale was used. CONCLUSION: In this murine model, N-acetylcysteine, benzylpenicillin, cimetidine, thioctic acid, and silybin were not effective in limiting hepatic injury after alpha-amanitin poisoning. Increases of aminotransferases and degrees of histologic hepatonecrosis were not attenuated by these antidotal therapies.

Role of intravenous omeprazole in patients with high-risk peptic ulcer bleeding after successful endoscopic epinephrine injection: a prospective randomized comparative trial.

BACKGROUND: Epinephrine injection is the most common endoscopic therapy for peptic ulcer bleeding. Controversy exists concerning the optimal dose of proton pump inhibitors (PPI) for patients with bleeding peptic ulcers after successful endoscopic therapy. The objective of this study was to determine the optimal dose of PPI after successful endoscopic epinephrine injection in patients with bleeding peptic ulcers. METHODS: A total of 200 peptic ulcer patients with active bleeding or nonbleeding visible vessels (NBVV) who had obtained initial hemostasis with endoscopic injection of epinephrine were randomized to receive omeprazole 40 mg infusion every 6 h, omeprazole 40 mg infusion every 12 h or cimetidine (CIM) 400 mg infusion every 12 h. Outcomes were checked at 14 days after enrollment. RESULTS: Rebleeding episodes were fewer in the group with omeprazole 40 mg infusion every 6 h (6/67, 9%) as compared with that of the CIM infusion group (22/67, 32.8%, p < 0.01). The volume of blood transfusion was less in the group with omeprazole 40 mg every 6 h than in those groups with omepraole 40 mg infusion every 12 h (p= 0.001) and CIM 400 mg infusion every 12 h (p < 0.001). The hospital stay, number of patients requiring urgent operation, and death rate were not statistically different among the three groups. CONCLUSION: A combination of endoscopic epinephrine injection and a large dose of omeprazole infusion is superior to combined endoscopic epinephrine injection with CIM infusion for preventing recurrent bleeding from peptic ulcers with active bleeding or NBVV.

Oral sustained delivery of theophylline and cimetidine from in situ gelling pectin formulations in rabbits.

The aim of this study was to evaluate the potential of an in situ gelling pectin formulation as a vehicle for the oral sustained delivery of theophylline and cimetidine. In vitro studies demonstrated diffusion-controlled release of theophylline from 1, 1.5, and 2% w/v pectin gels. Release of this drug from 1.5% w/v pectin gels formed in situ in rabbit stomach was sustained over a period of 12 hours giving a theophylline bioavailability some seven fold higher than when administered from a commercial syrup. In contrast, interactions between cimetidine and pectin led to weak gelation of the pectin sols that prevented any meaningful determination of in vitro release characteristics. Similarly, in vivo release profiles from pectin formulations containing cimetidine were similar to that from a solution of this drug in buffer, indicative of weak gelation. Examination of the content of the rabbit stomach 5 hours after administration of 1.5% w/v pectin sols containing drug confirmed gel formation, but gels containing cimetidine were noticeably softer than those containing theophylline.

[Effect of cimetidine with chemotherapy on stage IV colorectal cancer].

We herein report the result of a prospective study to investigate the efficacy of cimetidine administration in conjunction with chemotherapy for stage IV colorectal cancer. Sixty-two patients treated with Leucovorin/5-fluorouracil therapy were enrolled from 1996 to 2000. Both groups were well matched for pre-treatment characteristics. There was no difference in survival in cur B patients. However, the cimetidine group had significantly prolonged survival in the patients with cur C or non-resectable carcinoma. This study suggests that cimetidine treatment may improve the survival of patients with non-curative surgery for stage IV colorectal cancer.

Intravenous proton-pump inhibitors versus H2-antagonists for treatment of GI bleeding.

OBJECTIVE: To evaluate the evidence supporting the use of intravenous proton-pump inhibitors in the treatment of gastrointestinal (GI) hemorrhage in comparison with histamine(2) (H(2))-receptor antagonists. DATA SOURCES: Clinical literature was accessed through a MEDLINE search (1966-October 2002). Data from abstracts and fully published articles were retrieved for analysis. Key search terms included pantoprazole, omeprazole, proton-pump inhibitors, gastrointestinal hemorrhage, histamine(2)-receptor antagonists, ranitidine, and cimetidine. DATA SYNTHESIS: There are limited published clinical outcome data evaluating the use of intravenous pantoprazole in patients with upper GI hemorrhage. However, there are several gastric pH studies suggesting that intravenous pantoprazole is effective in quickly obtaining and maintaining a pH >6. When considering the results from studies of high-dose intravenous omeprazole, in addition to the pantoprazole data, the relative efficacy of intravenous proton-pump inhibitors appears to be superior to that of intravenous H(2)-receptor antagonists in providing a more predictable and sustained pH control. CONCLUSIONS: Intravenous proton-pump inhibitors are suitable, possibly superior, alternatives to intravenous H(2)-receptor antagonists in treatment of upper GI bleeding.

Cimetidine increases survival of colorectal cancer patients with high levels of sialyl Lewis-X and sialyl Lewis-A epitope expression on tumour cells.

Cimetidine has been shown to have beneficial effects in colorectal cancer patients. In this study, a total of 64 colorectal cancer patients who received curative operation were examined for the effects of cimetidine treatment on survival and recurrence. The cimetidine group was given 800 mg day(-1) of cimetidine orally together with 200 mg day(-1) of 5-fluorouracil, while the control group received 5-fluorouracil alone. The treatment was initiated 2 weeks after the operation and terminated after 1 year. Robust beneficial effects of cimetidine were noted: the 10-year survival rate of the cimetidine group was 84.6% whereas that of control group was 49.8% (P<0.0001). According to our previous observations that cimetidine blocked the expression of E-selectin on vascular endothelium and inhibited the adhesion of cancer cells to the endothelium, we have further stratified the patients according to the expression levels of sialyl Lewis antigens X (sL(x)) and A (sL(a)). We found that cimetidine treatment was particularly effective in patients whose tumour had higher sL(x) and sL(a) antigen levels. For example, the 10-year cumulative survival rate of the cimetidine group with higher CSLEX staining, recognizing sL(x), of tumours was 95.5%, whereas that of control group was 35.1% (P=0.0001). In contrast, in the group of patients with no or low levels CSLEX staining, cimetidine did not show significant beneficial effect (the 10-year survival rate of the cimetidine group was 70.0% and that of control group was 85.7% (P=n.s.)). These results clearly indicate that cimetidine treatment dramatically improved survival in colorectal cancer patients with tumour cells expressing high levels of sL(x) and sL(a).

Histaminergic and catecholaminergic interactions in the central regulation of vasopressin and oxytocin secretion.

Activation of histaminergic and noradrenergic/adrenergic neurons in the brain stimulates the release of the neurohypophysial hormones arginine vasopressin (AVP) and oxytocin (OT) and are involved the mediation of the hormone responses to physiological stimuli such as dehydration and suckling. We therefore investigated whether the two neuronal systems interact in their regulation of AVP and OT secretion in conscious male rats. When administered intracerebroventricularly (i.c.v.), histamine (HA) as well as the H1 receptor agonist 2-thiazolylethylamine or the H2 receptor agonist 4-methylHA stimulated AVP and OT secretion. Prior i.c.v. infusion of antagonists specific to alpha or beta adrenergic receptors or their subtypes did not significantly affect the hormone response to HA or the histaminergic agonists. Infused i.c.v. norepinephrine (NE) or epinephrine (E) increased AVP and OT secretion. Prior i.c.v. infusion of the H1 receptor antagonist mepyramine or the H2 receptor antagonist cimetidine significantly inhibited the AVP and OT responses to NE and the AVP response to E, whereas only cimetidine inhibited the OT response to E significantly. Systemic pretreatment with imetit, which by activation of presynaptic H3 receptors inhibits neuronal synthesis and release of HA, decreased the AVP and OT responses to NE and E significantly. In the doses used, HA and E had no significant effect on mean arterial blood pressure. NE increased mean arterial blood pressure 10% at 1 and 2.5 min, whereafter the blood pressure returned to basal level within 10 min. The results indicate that noradrenergic and adrenergic neurons stimulate AVP and OT secretion via an involvement of histaminergic neurons, which may occur at magnocellular neurons in the supraoptic and paraventricular nuclei of the hypothalamus. The stimulatory effect of the amines on neurohypophysial hormone secretion seems to be independent of a central action on blood pressure. In contrast, a functionally intact noradrenergic and adrenergic neuronal system seems not to be a prerequisite for a HA-induced release of AVP and OT. The present findings further substantiate the role of histaminergic neurons in the central regulation of neurohypophysial hormone secretion.

Antiulcer drug prescribing in hospital successfully influenced by "immediate concurrent feedback".

OBJECTIVE: To determine whether immediate concurrent feedback (ICF) focused on inpatient omeprazole prescribing achieved more rational and cost-effective antiulcer drug prescribing and usage. METHODS: In a 1400-bed teaching hospital, an audit (by specially trained personnel) was conducted to monitor inpatient prescribing of omeprazole (1) in preference to H2-antagonists and other drugs according to agreed criteria (Helicobacter pylori eradication, severe reflux esophagitis, rapid ulcer healing deemed urgent because of severe symptoms or complications, high-dose steroid therapy of > or =30 mg/day prednisolone) and (2) appropriateness of intravenous dosing (oral route not feasible or contraindicated). After baseline monitoring for 1 month, followed by relevant antiulcer drug therapy education, ICF was instituted for 1 year. This entailed explanatory memoranda requesting a change in prescribing issued to the respective medical teams of patients whose omeprazole prescription did not "conform." The main outcomes of the study were omeprazole prescription numbers per month and the proportion conforming, defined daily doses of antiulcer drugs used and corresponding expenditures, and pertinent antiulcer drug utilization data from 9 other local hospitals. RESULTS: Baseline omeprazole prescribing conformed in 32 of 173 (18%) of the patients compared with 451 of 546 (83%) during institution of ICF (P < 0001; chi2 test). Correspondingly, average overall omeprazole and ranitidine usage (inpatient and outpatient) and expenditure decreased (44% and 45%, respectively); collectively, use of less expensive alternatives increased about 61%. Estimated savings averaged about HK$150,000 ($20,000) per month. No comparable changes in usage were noted in 9 other local hospitals. CONCLUSION: Regarding hospital antiulcer drugs, this ICF strategy was associated with more rational prescribing and usage, and an important saving of resources.

[Reduction of cardiovascular disorders by preventive perioperative antihistamine administration in general surgery: are the drugs interchangeable?]. / Verminderung kardiovaskulärer Störungen durch perioperative Antihistaminikaprophylaxe in der Allgemeinchirurgie: Sind die Medikamente austauschbar?

In clinical reality the drugs used for H1/H2-prophylaxis are not restricted to the combination of dimetinden/cimetidine, also only for this combination the effectiveness for preventing severe cardiorespiratory disturbances is proven in a randomised controlled clinical trial. However, it is almost impossible to conduct such an extended clinical trial in order to check all possible combinations. Instead of this, we developed a complex animal model featuring clinical variability and the principles of a well conducted randomised controlled clinical trial (CMRT = clinic modelling randomised trials), to evaluate different H1/H2 combinations. In this CMRT in pigs (four groups of 15 animals), the H1/H2 combination of dimetinden/cimetidine and dimetinden/famotidine showed an effectiveness similar to the randomised clinical trial. With dimetinden/ranitidine no significant prophylactic effect was observed. Two conclusions can be drawn: (1) CMRTs in animals are able to answer relevant clinical and research questions that otherwise only could be solved by clinical studies and may be a successful intermediate between basic research and clinical trials. (2) Drugs, even of the same substance class, may not be simply exchangeable. Hence, before changing a proven medication, trials in an adequate complex animal model (CMRT) should be mandatory.

A randomized, placebo-controlled study of oral cimetidine as an immunopotentiator of parenteral immunization with a group B meningococcal vaccine.

Cimetidine (CIM) is an H2-receptor antagonist with a long history of clinical use in peptic ulcer disease. In addition to its inhibitory effect upon gastric acid secretion, CIM can also block histamine-mediated immunosuppression by inhibiting H2 receptors on suppressor T cells. CIM results in immunoaugmentation of both cellular and humoral immunity by this mechanism and has been used clinically in the treatment of chronic infectious and neoplastic diseases. We postulated that orally administered CIM, like an adjuvant, could augment the immunologic response to a parenteral vaccine. To test this hypothesis, a randomized placebo (PLB)-controlled, double-blinded study in 14 healthy volunteers was performed using a Group B meningococcal outer membrane protein (OMP) vaccine administered twice, 6 weeks apart. Volunteers were randomized within pairs defined by their screening OMP antibody titers to receive either CIM or PLB which was administered for 5 days, beginning 2 days before each of the two immunizations. All 14 volunteers completed the study with excellent compliance. Sera were tested for anti-OMP and bactericidal antibodies. The groups were comparable in terms of gender distribution, age and baseline anti-OMP titers. Reactogenicity to the vaccine was mild and comparable between groups. There was little effect of CIM (over PLB) on anti-OMP or functional bactericidal antibody levels over time. Geometric means of maximum OMP antibody increase over baseline was 3.3-fold (95% CI: 1.8-6.3) for CIM and 2.4 for PLB (CI: 1.6-3.7). CIM had a corresponding 3.9-fold increase (CI: 1.9-8.3) in bactericidal antibody level compared to 2.2 for PLB (CI: 1.4-3.4). We conclude that oral CIM was not effective as an immunopotentiator of immunization with this group B meningococcal vaccine.

Histamine H2 receptor antagonist-refractory oesophagitis: the efficacy of long-term omeprazole maintenance treatment.

BACKGROUND: Erosive oesophagitis refractory to high dose histamine H2 receptor antagonists (definition: failure to heal fully after > or = 3 months' treatment with cimetidine 3.2 g or ranitidine 0.9 g) responds well to omeprazole 40 mg daily but frequently relapses when the patients are put back on maintenance H2 receptor antagonists at medium or even high dose (e.g. cimetidine 1.6 g and 3.2 g, respectively). AIM: To investigate the efficacy of maintenance omeprazole 20 mg daily in refractory erosive oesophagitis. PATIENTS & METHODS: In this open, sequential study, patients with H2 receptor antagonist-refractory oesophagitis were healed on omeprazole 40 mg daily and then put on maintenance H2 receptor antagonists (cimetidine 1.6 g or 3.2 g). Relapses were re-treated with omeprazole 40 mg; upon rehealing, patients were put on maintenance omeprazole 20 mg daily for up to 4.5 years. RESULTS: Healing on omeprazole occurred in 38 out of 39 patients (97%) at 12 weeks. Only six of the 38 patients (16%) relapsed (asymptomatic in half) during subsequent maintenance treatment, whereas all had relapsed earlier on high dose H2 receptor antagonists. CONCLUSION: Within the limits of interpretation of an open study, omeprazole 20 mg daily seems effective in maintaining prolonged remission in this group of patients with H2 receptor antagonist-refractory oesophagitis.

A randomized trial of cimetidine with 5-fluorouracil and folinic acid in metastatic colorectal cancer.

Cimetidine has demonstrated a survival benefit in a randomized trial as adjuvant therapy for gastric cancer. We have demonstrated expression of histamine receptors on colon cancer cell lines and inhibition of their growth with cimetidine. Cimetidine also activates suppressor T cells and stimulates cell-mediated immunity. We therefore performed a randomized controlled clinical trial to determine the effect of cimetidine 400 mg given twice daily in conjunction with chemotherapy vs chemotherapy alone. Thirty-eight patients were randomized and 35 patients were eligible for further analysis. Both groups were well matched for pre-treatment characteristics. There was no difference in overall response. There was, however, a significantly increased rate of CEA response in the cimetidine group. Four of 11 patients (36%) in the cimetidine group had a CEA response compared to none of eight in the control. Meaningful comparisons of overall survival cannot yet be made. This study demonstrates that cimetidine has encouraging activity in increasing CEA response in patients with metastatic colorectal cancer treated with chemotherapy. This observation needs to be extended in a larger randomized study, which is currently underway.

Central nervous system activity of Rhazya stricta (Decne) in mice.

1. The effects of orally administered aqueous lyophilized extract of the leaves of Rhazya stricta (2, 4 & 8 g/kg) on aspects of nervous system function were investigated in mice. 2. In three antinociceptive tests (hot plate, abdominal constriction, and warm water tail flick tests), the extract exhibited dose-dependent and significant antinociceptive activity. Naloxone was ineffective in antagonizing the analgesic effect of Rhazya stricta on tail-flick and abdominal constriction tests, possibly indicating that this effect occurs via non-opiate pathways. 3.Pretreatment of mice with the xenobiotic metabolizing enzymes inhibitor cimetidine (50 mg/kg) did not significantly alter the antinociceptive action of the extract, indicating that the effect is probably due to the parent compound(s) present in the extract and not to metabolites thereof. 4. Rhazya stricta produce dose-dependent sedation, decreased motor activity, and impaired motor control. Time spent on a rotarod treadmill was significantly decreased after treatment with the extract. 5. Rhazya stricta extract (8 g/kg) produced a degree of sedation comparable to that produced by diazepam (5-10 mg/kg), and also significantly increased the reaction time of the tail-flick test, an action which was not produced by diazepam. 6. Administration of R. stricta extract potentiated pentobarbitone sleeping time in a dose dependent manner. The extract did not significantly antagonize picrotoxin induced convulsions. The extract (4 and 8 g/kg) significantly decreased the rectal temperature of normothermic and hyperthermic mice. 7. Pretreatment with R. stricta extract (8 g/kg) completely prevented the occurrence of aggressive behaviour in male mice. 8. It is concluded that the crude extract of R. stricta has central nervous system depressant properties.