Administration Of Cimetidine Research Articles

Two histamine H2 receptor antagonists, zolantidine and cimetidine, modulate nociception in cholestatic rats

Cholestasis is associated with analgesia. The histamine H(2) receptors control pain perception. The involvement of histamine H(2) receptors on modulation of nociception in a model of elevated endogenous opioid tone, cholestasis, was investigated in this study using zolantidine and cimetidine as two H(2) receptor antagonists and dimaprit as a selective H(2) receptor agonist. Cholestasis was induced by ligation of the main bile duct using two ligatures and transsection of the duct at the midpoint between them. A significant increase in tail-flick latencies was observed in cholestatic rats compared to non-cholestatic rats. Administration of zolantidine (10, 20 and 40 mg/kg) and cimetidine (25, 50 and 100 mg/kg) in the cholestatic group significantly increased tail-flick latencies while dimaprit (10 and 20 mg/kg) injection in the cholestatic group decreased tail-flick latencies compared to the saline treated cholestatic group. Antinociception produced by injection of zolantidine and cimetidine in cholestatic rats was attenuated by co-administration of naloxone. Drug injection in non-cholestatic rats did not alter tail-flick latencies compared to the saline treated rats at any of the doses. At the doses used here, none of the drugs impaired motor coordination as revealed by the rota rod test. These data show that the histamine H(2) receptor system may be involved in the regulation of nociception during cholestasis. According to the hypothesis that increasing the nociception threshold in cholestasis may lead to a decrease in the perception of pruritus, the provision of the drugs that increase the threshold to nociception may be a novel approach to the treatment of cholestatic pruritus.

Whole-body physiologically based pharmacokinetic population modelling of oral drug administration: inter-individual variability of cimetidine absorption

Abstract Objectives Inter-individual variability of gastrointestinal physiology and transit properties can greatly influence the pharmacokinetics of an orally administered drug in vivo. To predict the expected range of pharmacokinetic plasma concentrations after oral drug administration, a physiologically based pharmacokinetic population model for gastrointestinal transit and absorption was developed and evaluated. Methods Mean values and variability measures of model parameters affecting the rate and extent of cimetidine absorption, such as gastric emptying, intestinal transit times and effective surface area of the small intestine, were obtained from the literature. Various scenarios incorporating different extents of inter-individual physiological variability were simulated and the simulation results were compared with experimental human study data obtained after oral cimetidine administration of four different tablets with varying release kinetics. Key findings The inter-individual variability in effective surface area was the largest contributor to absorption variability. Based on in-vitro dissolution profiles, the mean plasma cimetidine concentration–time profiles as well as the inter-individual variability could be well described for three cimetidine formulations. In the case of the formulation with the slowest dissolution kinetic, model predictions on the basis of the in-vitro dissolution profile underestimated the plasma exposure. Conclusions The model facilitates predictions of the inter-individual pharmacokinetic variability after oral drug administration for immediate and extended-release formulations of cimetidine, given reasonable in-vitro dissolution kinetics.

Whole-body physiologically based pharmacokinetic population modelling of oral drug administration: inter-individual variability of cimetidine absorption

Inter-individual variability of gastrointestinal physiology and transit properties can greatly influence the pharmacokinetics of an orally administered drug in vivo. To predict the expected range of pharmacokinetic plasma concentrations after oral drug administration, a physiologically based pharmacokinetic population model for gastrointestinal transit and absorption was developed and evaluated. Mean values and variability measures of model parameters affecting the rate and extent of cimetidine absorption, such as gastric emptying, intestinal transit times and effective surface area of the small intestine, were obtained from the literature. Various scenarios incorporating different extents of inter-individual physiological variability were simulated and the simulation results were compared with experimental human study data obtained after oral cimetidine administration of four different tablets with varying release kinetics. The inter-individual variability in effective surface area was the largest contributor to absorption variability. Based on in-vitro dissolution profiles, the mean plasma cimetidine concentration-time profiles as well as the inter-individual variability could be well described for three cimetidine formulations. In the case of the formulation with the slowest dissolution kinetic, model predictions on the basis of the in-vitro dissolution profile underestimated the plasma exposure. The model facilitates predictions of the inter-individual pharmacokinetic variability after oral drug administration for immediate and extended-release formulations of cimetidine, given reasonable in-vitro dissolution kinetics.

Pharmacokinetics of cimetidine in dogs after oral administration of cimetidine tablets

Long-term oral treatment with cimetidine is recommended to reduce vomiting in dogs with chronic gastritis. Despite this, few studies have specifically examined the plasma disposition and pharmacokinetics of cimetidine in dogs, particularly following repeated oral administration. The pharmacokinetics of cimetidine following oral administration as tablets was investigated in healthy dogs. Cimetidine was absorbed rapidly post-treatment (t(max) = 0.5 h). A mean absolute bioavailability of 75% was calculated following a single oral administration of 5 mg cimetidine/kg body weight. After intravenous administration, a plasma half-life of 1.6 h was calculated. Repeated oral administration at the recommended dose rate and regime (5 mg/kg body weight three times daily) for 30 consecutive days did not lead to any accumulation of cimetidine in plasma. Food intake concomitant with oral administration of cimetidine delayed (t(max) = 2.25 h) and decreased the rate and extent of absorption (AUC) by about 40%. Cimetidine was well absorbed in fasted dogs. Administration of food decreased the bioavailability of cimetidine by 40%. Cimetidine does not accumulate over time in plasma when administered long term to dogs.

Rapid correction of metabolic alkalosis in hypertrophic pyloric stenosis with intravenous cimetidine: preliminary results

Pyloromyotomy has been the treatment of choice for hypertrophic pyloric stenosis (HPS) for the past century. In most HPS cases, there is mild metabolic alkalosis, which requires intravenous fluid resuscitation with 5% dextrose/normal saline for 1-2 days. However, in some cases, due to a delay in diagnosis, alkalosis becomes severe and a much longer resuscitation period (5-10 days) is required to normalize serum pH. Metabolic alkalosis of HPS results from excessive vomiting of hydrochloric acid; and therefore if its production is reduced, serum pH can be normalized faster. In this study, the use of intravenous cimetidine (CM) in a small number of infants with HPS is presented. Over a 28-month period, 32 HPS cases, including a sub-group of 17 infants (aged 7-9 weeks) with arterial pH >7.60, were admitted to a tertiary referral unit. Four infants in this sub-group were treated with standard resuscitation fluids for 4 days prior to intravenous CM, while 12 infants received CM immediately. Intravenous CM (10 mg/kg) was given at twice daily until arterial pH was less than 7.50. In one case, intravenous omeprazole at 0.1 mg/kg was given instead of CM. In all 17 cases, CM treatment or omeprazole therapy (for 12-48 h) reduced pH to less than 7.50, thus allowing for Ramstedt pyloromyotomy the same day. These patients were allowed oral feeding on the following day and were discharged at 1-3 post-operative days. No complications due to CM (or omperazole) treatment were observed. Intravenous CM administration can rapidly normalize severe metabolic alkalosis in HPS patients. As a result, pyloromyotomy can be performed sooner reducing both hospital stay and costs.

Creatinine reabsorption by the aged kidney

The handling of renal creatinine in human beings has classically been described as the result of two particular physiological processes: glomerular filtration and proximal tubular secretion. However, there are particular physiological situations in which tubular creatinine reabsorption has been documented, such as in the case of healthy newborns and premature babies. We performed a prospective study in order to evaluate if there is tubular creatinine reabsorption in healthy elderly people. We studied prospectively nine healthy volunteers, four of them young (20-33 years old) and the remaining five, old (65-73 years old). Since creatinine is secreted in the proximal tubules, and its secretion can be completely blocked by cimetidine administration, a creatinine clearance with cimetidine reliably represents the glomerular filtration rate. Therefore, if the ratio creatinine clearance (Ccr)/creatinine clearance with cimetidine (CcrWC) is higher than one, this would indicate net creatinine secretion, whereas a ratio lower than one would indicate a net renal creatinine tubular reabsorption; a ratio equal to one indicates creatinine filtration. Finally, the Ccr, CcrWC, and Ccr/CcrWC ratios were compared between the young and old group. Mann-Whitney and Wilcoxon tests were used. As expected, creatinine clearance in the elderly was significantly lower than in the young [Ccr: 74.4 ml/min (47.9-100.9) (old) vs. 153.8 ml/min (108.3-199.2) (young), p = 0.014]. Similarly, the creatinine clearance with cimetidine (CcrWC) was significantly lower in the elderly compared to the young [CcrWC: 81.8 ml/min (69.2-94.5) (old) vs. 122.5 ml/min (82.6-162.4) (young), p = 0.028]. The ratio of Ccr/CcrWC was 0.9 in the elderly vs. 1.26 in the young (p = 0.014), indicating net creatinine reabsorption in the elderly and net creatinine secretion in the young. Our findings indicate that there seems to be a net reabsorption of creatinine in the renal tubules of healthy old persons.

Cimetidine inhibits salivary gland tumor cell adhesion to neural cells and induces apoptosis by blocking NCAM expression

BackgroundCimetidine, a histamine type-2 receptor antagonist, has been reported to inhibit the growth of glandular tumors such as colorectal cancer, however the mechanism of action underlying this effect is unknown. Adenoid cystic carcinoma is well known as a malignant salivary gland tumor which preferentially invades neural tissues. We demonstrated previously that human salivary gland tumor (HSG) cells spontaneously express neural cell adhesion molecule (NCAM), that HSG cell proliferation may be controlled via a homophilic (NCAM-NCAM) binding mechanism and that NCAM may be associated with perineural invasion by malignant salivary gland tumors. We further demonstrated that cimetidine inhibited NCAM expression and induced apoptosis in HSG cells. Here, we investigated the effects of cimetidine on growth and perineural/neural invasion of salivary gland tumor cells.MethodsIn this study, we have examined the effect of cimetidine on cancer cell adhesion to neural cells in vitro, one of the critical steps of cancer invasion and metastasis. We have also used an in vivo carcinogenesis model to confirm the effect of cimetidine.ResultsWe have demonstrated for the first time that cimetidine can block the adhesion of HSG cells to neural cell monolayers and that it can also induce significant apoptosis in the tumor mass in a nude mouse model. We also demonstrated that these apoptotic effects of cimetidine might occur through down-regulation of the cell surface expression of NCAM on HSG cells. Cimetidine-mediated down-regulation of NCAM involved suppression of the nuclear translocation of NF-κB, a transcriptional activator of NCAM gene expression.ConclusionThese findings suggest that growth and perineural/neural invasion of salivary gland tumors can be blocked by administration of cimetidine via induction of apoptosis and in which NCAM plays a role.

Cimetidine does not appear to influence the distribution of metformin into human milk

Cimetidine does not appear to influence the distribution of metformin into human milk

Treatment failure of cimetidine in duodenal ulcer (author's transl)

Acid secretion was measured after a six-week standard treatment with cimetidine in ten patients each with healed or non-healed duodenal ulcer, and the drug's pharmacokinetics studied. There was no difference between the two groups with respect to fasting concentration of cimetidine (compliance), the area under the plasma-level curve, as well as renal excretion (bioavailability) and the period of effective plasma concentration. Maximal secretion during cimetidine treatment was also identical in the two groups. On the other hand, basal secretion in the group of treatment failure was significantly increased (P less than 0.05). Basal secretion during administration of cimetidine can be used as a prognostic criterion for the healing of duodenal ulcer.

Choledochoscope manometry about different drugs on the Sphincter of Oddi

To assess the effects of H(2)-receptor blocking pharmacon, protease inhibitor, and gastro kinetic agents on the human Sphincter of Oddi (SO) motility by choledochoscope manometry. One hundred and seventy-five patients with T tube installed after cholecystectomy and choledochotomy were assessed by choledochoscope manometry. They were randomly assigned into groups of H(2)-receptor blocking pharmacon, protease inhibitor, and gastro kinetic agents. The Sphincter of Oddi basal pressure (SOBP), amplitude (SOCA), frequency of contractions (SOF), duodenal pressure (DP), and common bile duct pressure (CBDP) were scored and analyzed. SOBP and SOCA were significantly decreased after cimetidine administration, and no statistical difference was seen in the famotidine group. In the gabexate mesilate group, SOBP had decreased significantly. In the ulinastatin group, SOCA decreased when ulinastatin was given at the rate of 2500 U/min; when ulinastatin administration was raised to 5000 U/min, SOBP, SOF and SOCA all experienced a fall. SOBP and SOCA for domperidone and SOCA for mosapride groups all decreased distinctly after administration. The regular dosage of cimetidine showed an inhibitory effect on the motility of SO, while famotidine had no obvious effects otherwise. Gabnexata mesilate, ulinastatin and gastro kinetic agents also showed inhibitory effects on the SO motility.

Cimetidine and dapsone‐mediated methaemoglobinaemia

I read with interest the case report from Choi et al. [1] relating to dapsone-mediated methaemoglobinaemia. The role of cimetidine in partially attenuating the haematological side-effects of dapsone does not appear to have been discussed in the anaesthesia literature. I wish to suggest the possible therapeutic benefit of peri-operative administration of cimetidine in patients receiving dapsone. The oxidative metabolism of dapsone leads to its toxicity. The majority of dapsone undergoes reversible acetylation in liver followed by elimination as N-hydroxylamine and to a lesser degree monoacetylated hydroxylamine. Dapsone N- hydroxylation is responsible for the haematological side-effects such as methaemoglobinaemia and haemolysis. Dapsone hydroxylamine depletes glutathione within glucose-6-phosphate dehydrogenase (G6PD)-deficient cells. The nitroso derivative then causes peroxidation reactions, leading to rapid haemolysis. Doses of 100 mg or less in normal healthy persons and 50 mg or less in G6PD-deficient individuals do not cause haemolysis [2]. A maximum dose of 150–300 mg a day, in divided doses, is recommended to minimise the risk of methaemoglobinaemia [3]. Cimetidine, an H2-recector antagonist, competes with dapsone for cytochrome P 450 enzymes. Thus cimetidine may be used as a selective inhibitor of N-hydroxylation and decrease the quantity of methaemoglobinaemia produced by dapsone [3, 4]. Cimetidine 400 mg three times daily has been shown to lead to a significant (> 25%) and sustained fall in methaemoglobin in patients on chronic dapsone therapy [5]. This dose appears to be well tolerated and not associated with adverse effects. The peri-operative use of cimetidine is likely to benefit patients by increasing the clinical safety margin, minimising the incidence and severity of methaemoglobinaemia and, possibly, avoiding the complications associated with treatment modalities such as methylene blue or ascorbic acid [6]. The mean elimination half-life of dapsone is about 20–30 h. Sulphones are retained in the circulation for long periods because of intestinal re-absorption from bile, requiring periodic interruption of treatment in dermatological diseases [2]. It is imperative to discontinue dapsone at least 4–7 days pre-operatively in patients listed for elective surgery. Furthermore, the G6PD level should be checked in all patients receiving dapsone therapy to identify patients at risk of peri-operative methaemoglobinaemia.

Cimetidine induces apoptosis of human salivary gland tumor cells

It has been reported that cimetidine, a histamine type-2 receptor (H2R) antagonist, inhibits the growth of glandular tumors such as colorectal cancer. However, its effects against salivary gland tumors are still unknown. We demonstrated previously that human salivary gland tumor (HSG) cells spontaneously express the neural cell adhesion molecule (NCAM) and also that HSG cell proliferation could be controlled via a homophilic (NCAM-NCAM) binding mechanism and that NCAM may be associated with perineural invasion by malignant salivary gland tumors. In the present study, we investigated the effects of cimetidine via the expression of NCAM on tumor growth and perineural/neural invasion in salivary gland tumor cells. Expression of both NCAM mRNA and protein was found to decrease in a dose-dependent manner upon treatment with cimetidine for 24 h. The MTT assay and confocal laser microscopy clearly showed that HSG cells underwent apoptosis after treatment with cimetidine. Activation of caspases 3, 7, 8 and 9 was observed in HSG cells after cimetidine treatment, thus confirming that the apoptosis was induced by the activated caspases. Apaf-1 activity was also detected in HSG cells in a dose-dependent manner after treatment with cimetidine. We also found that the cimetidine-mediated down-regulation of NCAM expression in HSG cells did not occur via blocking of the histamine receptor, even though H2R expression was observed on HSG cells, as two other H2R antagonists, famotidine and ranitidine, did not show similar effects. We demonstrated for the first time that cimetidine can induce significant apoptosis of salivary gland tumor cells, which express NCAM, at least in part by down-regulation of NCAM expression on the cells. These findings suggest that the growth, development and perineural/neural invasion of salivary gland tumor cells can be blocked by cimetidine administration through down-regulation of NCAM expression, as well as induction of apoptosis.

Creatinine Clearance after Cimetidine Administration—Is It Useful in the Monitoring of the Function of Transplanted Kidney?

Background. Determination of clearance of endogenous creatinine using its plasma and urinary concentration (standard clearance), Cockroft and Gault formula, or MDRD formula (estimated clearance) is commonly performed for assessment of glomerular filtration rate. Although the evaluation of renal function in this way is useful, it is biased with an error resulting from secretion of creatinine in tubules. This error can be reduced by determining the clearance after administration of cimetidine, which competitively blocks creatinine tubular transport. Methods. The study was performed in the group of 87 patients after renal transplantation. In this group, estimated clearance and creatinine clearance after cimetidine administration (1000 mg in 75 patients and then 1600 mg in 12 patients with plasma creatinine above 3 mg/dL) were determined. Results. Analysis of mean percentage differences between clearance values after cimetidine administration and estimated clearance shows increasing contribution of creatinine tubular secretion along with plasma creatinine increase in renal transplant recipients. A higher dose of cimetidine resulted in lower clearance values in renal transplant recipients with plasma creatinine above 3 mg/dL. Conclusions. Creatinine clearance after administration of 1000 mg cimetidine seems to be a useful measure of glomerular filtration rate in renal graft recipients with plasma creatinine concentration below 2.5 mg/L. Higher dose of cimetidine would be needed to effectively block tubular excretion at higher concentrations of creatinine. Establishing an efficient but safe dose of cimetidine for such patients needs further investigations. As we have noticed that creatinine clearance calculated according to MDRD formula was similar to the clearance after administration of cimetidine, we propose a strategy of one GFR measurement at baseline using 24h urine collection after cimetidine administration and follow-up with creatinine clearance calculated from MDRD formula during standard check-up visits.

The Clinical Pharmacokinetics of Escitalopram

Escitalopram is the (S)-enantiomer of the racemic selective serotonin reuptake inhibitor antidepressant citalopram. Clinical studies have shown that escitalopram is effective and well tolerated in the treatment of depression and anxiety disorders. Following oral administration, escitalopram is rapidly absorbed and reaches maximum plasma concentrations in approximately 3-4 hours after either single- or multiple-dose administration. The absorption of escitalopram is not affected by food. The elimination half-life of escitalopram is about 27-33 hours and is consistent with once-daily administration. Steady-state concentrations are achieved within 7-10 days of administration. Escitalopram has low protein binding (56%) and is not likely to cause interactions with highly protein-bound drugs. It is widely distributed throughout tissues, with an apparent volume of distribution during the terminal phase after oral administration (V(z)/F) of about 1100L. Unmetabolised escitalopram is the major compound in plasma. S-demethylcitalopram (S-DCT), the principal metabolite, is present at approximately one-third the level of escitalopram; however, S-DCT is a weak inhibitor of serotonin reuptake and does not contribute appreciably to the therapeutic activity of escitalopram. The didemethyl metabolite of escitalopram (S-DDCT) is typically present at or below quantifiable concentrations. Escitalopram and S-DCT exhibit linear and dose-proportional pharmacokinetics following single or multiple doses in the 10-30 mg/day dose range. Adolescents, elderly individuals and patients with hepatic impairment do not have clinically relevant differences in pharmacokinetics compared with healthy young adults, implying that adjustment of the dosage is not necessary in these patient groups. Escitalopram is metabolised by the cytochrome P450 (CYP) isoenzymes CYP2C19, CYP2D6 and CYP3A4. However, ritonavir, a potent inhibitor of CYP3A4, does not affect the pharmacokinetics of escitalopram. Coadministration of escitalopram 20mg following steady-state administration of cimetidine or omeprazole led to a 72% and 51% increase, respectively, in escitalopram exposure compared with administration alone. These changes were not considered clinically relevant. In vitro studies have shown that escitalopram has negligible inhibitory effects on CYP isoenzymes and P-glycoprotein, suggesting that escitalopram is unlikely to cause clinically significant drug-drug interactions. The favourable pharmacokinetic profile of escitalopram suggests clinical utility in a broad range of patients.

Cimetidine improves the therapeutic/toxic ratio of dapsone in patients on chronic dapsone therapy.

We have previously shown that cimetidine, given concurrently for 2 weeks to patients on chronic dapsone therapy, reduced methaemoglobinaemia by inhibiting the formation of the toxic hydroxylamine metabolite of dapsone. The aim of the present study was to examine the effect of this combination on the benefit/toxic ratio of dapsone over a longer period. Eight patients (six dermatitis herpetiformis, one linear IgA disease, one folliculitis decalvans) on long-term dapsone 50-100 mg daily, took cimetidine 1.6 g daily concurrently for 3 months. At 3-weekly intervals, a clinical assessment was made, plasma dapsone and methaemoglobin were measured, and parameters of oxidative haemolysis were monitored. The dapsone level rose from 2298 +/- 849 ng/ml (mean +/- SD) at baseline to 3006 +/- 1131 ng/ml at week 3 of cimetidine (P < 0.01). This rise in plasma dapsone was sustained during cimetidine administration, falling to 2446 +/- 954 ng/ml when cimetidine was stopped (P < 0.02). The methaemoglobin fell from 5.5 +/- 2.2% (mean +/- SD) at baseline to 3.9 +/- 1.1% at week 3 (P < 0.01), and remained low until week 12, when there was a return to baseline values (P < 0.01). The haemoglobin did not change from the baseline of 12.7 +/- 0.3 g/dl (mean +/- SD), and other parameters of haemolysis were unaltered. There was a fall in the visual analogue score for headache (P < 0.05), but this was not associated with any deterioration in control of the skin disorders. Hence, long-term concurrent cimetidine results in increased plasma dapsone levels without increased haemolysis, and is accompanied by reduced methaemoglobinaemia for more than 2 months.(ABSTRACT TRUNCATED AT 250 WORDS)

Preventive and curative effects of curcumin on the development of gastric inflammatory diseases in rats.

Preventive and curative effects of curcumin on experimental acute and chronic gastric ulcers were investigated to validate its clinical application on a remedy for peptic ulcer. Intraduodenal administration of curcumin, 5-20mg/kg, inhibited gastric acid secretion in pylorus-ligated rats, and oral administration prevented ethanol-induced acute gastric mucosal lesions. Curcumin (20-80mg/kg, p.o.) dose-dependently prevented both serotonin-induced gastric mucosal lesions and compound 48/80-induced gastric mucosal lesions in rats. Furthermore, oral administration of curcumin, 10-80mg/kg, twice daily for 10days, significantly accelerated the healing of acetic acid-induced chronic gastric ulcer and promoted mucosal regeneration in the ulcerated portion in a dose-related manner. Cimetidine prevented the formation of ethanol-induced gastric mucosal lesions, but not of serotonin-induced and compound 48/80-induced gastric mucosal lesions. Consecutive administration of cimetidine showed a marked acceleration in the healing of acetic acid-induced ulcer. Aminoguanidine, an inducible nitric oxide synthase (iNOS) inhibitor, showed anti-ulcerogenic effects similar to those oberved for curcumin. The present results indicate that curcumin exhibits gastric cytoprotection in the acute lesion models and ulcer healing promotion in the chronic ulcer model. The preventive and curative effects of curcumin might be due to an increase in the mucosal defensive mechanism through its antioxidant property and inhibition of NO or cytokine-mediated inflammation.

Blockade of histamine H2 receptors protects the heart against ischemia and reperfusion injury in dogs

We have previously reported that histamine H(2) blockers may be cardioprotective in patients with chronic heart failure. Since both endogenous histamine and histamine H(2) receptors are present in heart tissue, we tested the hypothesis that the blockade of histamine H(2) receptors mediates protection against reversible or irreversible ischemia and reperfusion injury. In open-chest dogs, the left anterior descending coronary artery was occluded for 90 minutes, followed by reperfusion for 6 hours. Administration of famotidine and cimetidine from 10 minutes before occlusion until after 1 hour of reperfusion reduced infarct size (17.0 +/- 4.1% and 17.8 +/- 2.9% vs. 36.9 +/- 5.9% of the solvent group, respectively) Famotidine administration only during the reperfusion period for 1 hour also attenuated infarct size (22.5 +/- 3.5%). There were no differences in either area at risk or collateral flow among the groups. In another set of experiments, we decreased coronary perfusion pressure in dogs so that the coronary blood flow decreased to 50% of the non-ischemic level. In such conditions, we observed the increases in histamine release compared with non-ischemic conditions (0.04 +/- 0.03 to 0.28 +/- 0.13 ng/ml, p < 0.05). Famotidine improved anaerobic myocardial metabolism gauged by both lactate extraction ratio and myocardial oxygen consumption. We conclude that the blockade of histamine H(2) receptors mediates improvements in the anaerobic myocardial metabolism, and thus protects against ischemia and reperfusion injury.

Resposta cronotrópica ao teste cardiopulmonar após o uso de cimetidina

To test the hypothesis that the administration of cimetidine will modify the chronotropic response to exercise testing through a random clinical trial. The study selected 24 eligible healthy subjects, ages between 20 and 68 years, not athletes, who agreed to undergo cardiopulmonary exercise testing after the administration of placebo and 400 mg of cimetidine twice a day for one week. The tests were performed on a treadmill using a ramp protocol and direct analysis of the expired gases. Peak, resting and anaerobic threshold heart rate were recorded. The twenty subjects studied were equally distributed across sex with mean (+/- SD) age 43 +/- 11 years. Tests on placebo and on cimetidine presented similar duration (578 +/- 90 sec vs 603 +/- 131 sec) and similar peak oxygen uptake (35 +/- 8 ml/kg.min vs 35 +/- 8 ml/kg.min). Cimetidine administration had no significant effect on resting heart rate (75 +/- 10 bpm vs 74 +/- 8 bpm), heart rate at peak exercise (176 +/- 12 bpm vs 176 +/- 11 bpm), and on the difference between the peak and the resting heart rates--delta HR (101 +/- 14 bpm vs 101 +/- 13 bpm). The administration of cimetidine for 7 days has no significant effect on the chronotropic response to exercise testing.

Perioperative Cimetidine Administration Enhances Tumor Infiltration Lymphocytes and HLA-DR Expression in Colorectal Cancer

Objective: It has been shown in our previous study that cimetidine (CIM) can boost the hosts' cellular immunity in patients with gastrointestinal cancer. This study was conducted to evaluate CIM's effects on tumor infiltrating lymphocytes (TIL) and HLA-DR expression in tumor stroma in colorectal cancer (CRC), so as to investigate its role in local immune response at the tumor site in CRC. Methods: Forty-nine CRC patients were randomized into treatment group of 25 patients who took CIM 7 days before curative surgery till the operation day, and control group of 24 patients who received similar treatment except for CIM intervention. TIL responses and HLA-DR expression were studied on tumor tissues taken before and after surgical resection. Results: The percentage of significant TIL response was increased from 32% (8/25) to 76% (19/25) (P<0.005) in the CIM treatment group, whereas there were no significant changes in TIL response in the control group [25% (6/24) at recruitment vs. 33% (8/24) at operation, P>0.50]. Moreover, the percentages of HLA-DR expression were increased from 36% (9/25) to 72% (18/25) in the CIM treatment group, but there were no significant differences in HLA-DR expression in the control group [41.7% (10/24) before resection vs 45.8% (11/24) after resection, P>0.50]. Conclusion: CIM used before surgery might promote TIL responses and increase the HLA-DR expression in stroma cells in CRC patients, leading to enhanced host immunity against tumor.

Cimetidine-induced tubulointerstitial nephritis with both MPO-ANCA and PR3-ANCA

We describe a 75-year-old man with tubulointerstitial nephritis (TIN) with myeloperoxidase (MPO)-antineutrophil antibody (ANCA) and proteinase-3 (PR3)-ANCA. He had a slight fever and eruption with itching after taking cimetidine (prescribed after gastrectomy for gastric cancer) and he was admitted to a nearby hospital. There, he showed proteinuria, serum creatinine (sCr) of 2.9 mg/dl, and creatinine clearance (Ccr) of 44 ml/min per 1.73 m2. His MPO-ANCA titer was 267 EU, and PR3-ANCA titer was 112 EU. Abnormal concentrations in bilateral kidneys were found by gallium scintigraphy. For these reasons, he was transferred to our hospital. Percutaneous renal biopsy was performed after admission. Severe tubular atrophy, mild interstitial fibrosis, and severe mononuclear cell infiltration of the interstitium were noted. Drug-induced renal impairment was suspected, and cimetidine administration was withdrawn. Lymphocyte stimulation tests (DLSTs) were performed. The cimetidine titer was positive, at 2,537 cpm. After the withdrawal of cimetidine, the PR3-ANCA titer was reduced gradually, and, next, the MPO-ANCA titer was also reduced. The sCr level was reduced to 1.2 mg/dl. In summary, we report herein the first case of cimetidine-induced TIN associated with both MPO-ANCA and PR3-ANCA.