Therapeutic effects of cimetidine on acetaminophen-induced hepatotoxicity in rats

Acetaminophen is a widely used analgesic and antipyretic drug. An overdose can cause life-threatening hepatotoxicity in humans and experimental animals. In this study, 80 female Sprague–Dawley rats randomized into eight groups (three control and five test groups) were used. Three milligrams per kilogram acetaminophen was administered orally to induce liver necrosis. Cimetidine (12.5 mg/kg) was administered intraperitoneally at 0, 1, 2, 4, and 8 h after acetaminophen administration. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and extent of pathologic changes in liver were evaluated in all groups (1–8), and were found to be increased in group 2 (acetaminophen control), but not in groups 1 and 3 (control groups), and were decreased in some treatment groups. The decrease observed in groups 7 and 8 was more than that in group 6. However, in these groups, more animals died due to toxicity before blood sampling. It was concluded that injection of cimetidine 2 h after acetaminophen administration (group 6) can markedly decrease the serum levels of ALT, AST, and the extent of pathologic lesions in the liver with minimal toxicity and death.     

Therapeutic effect of cimetidine on acetaminophen-induced hepatotoxicity in rabbits

Acetaminophen is an analgesic and antipyretic drug that may cause hepatic toxicity in humans and experimental animals. Cimetidine is an H₂ blocker used for suppression of gastric acid secretion. One of the side effects of cimetidine is blockade of the cytochrome P-450 enzyme system which results in increased half-life of some drug. In this study, 120 female rabbits, randomized into 12 groups (three control and nine test groups), were used. Acetaminophen, 3.24 g/kg, in suspension form as the LD₅₀, was administered orally to induce liver necrosis. Cimetidine (40 mg/kg) was administered intravenously at 0, 2, and 4 h after administration of acetaminophen. Some treatment groups received cimetidine in two equal divided doses—20 mg/kg cimetidine was administered at 2 and 12 h, 2 and 24 h, 4 and 12 h, and 4 and 24 h after administration of acetaminophen. Blood samples were collected at 0, 12, 24, and 36 h after induction of acetaminophen toxicity. Alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, bilirubin, and arginase were measured in all groups and were found to be increased in acetaminophen control group and some treatment groups (p < 0.05). Results showed that the best treatment effect of cimetidine could be obtained with whole dose of cimetidine administration and 2 h after acetaminophen intake.     

Therapeutic effect of cimetidine on acetaminophen-induced nephrotoxicity in rabbits

Acetaminophen is an analgesic and antipyretic drug that can cause nephrotoxicity in humans and experimental animals. Cimetidine is an H₂ blocker used for suppression of gastric acid secretion. One of its side effects is blockade of the cytochrome P-450 enzyme system which results in an increased half-life of some drugs. In this study, 120 female rabbits were randomized into 12 groups (three control and nine test groups). The LD₅₀ of acetaminophen was calculated to be 3.24 g/kg, and a suspension at this concentration was administered orally to induce renal necrosis. Three treatment groups received a single dose of cimetidine (40 mg/kg) administered intravenously at 0, 2, or 4 h after administration of acetaminophen depending upon treatment group. The six remaining treatment groups received cimetidine in two equal doses of 20 mg/kg administered at 0 and 12 h, 0 and 24 h, 2 and 12 h, 2 and 24 h, 4 and 12 h, or 4 and 24 h after the administration of acetaminophen. Blood samples were collected at 0, 12, 24, and 36 h after the induction of acetaminophen toxicity. Blood urea nitrogen and creatinine levels were measured in all groups and were significantly raised in the acetaminophen control group and some treatment groups (p < 0.05). The results indicate that the most effective treatment with cimetidine was obtained with a single dose of cimetidine administered 2 h after acetaminophen intake.     

The effect of cimetidine on parathyroid function and histopathology in primary hyperparathyroidism

Recent evidence suggests that cimetidine given pre-operatively in primary hyperparathyroidism (1 degree HPT) might cause structural changes in parathyroid glands, while its suppressive effects on the disease are disputable. To determine these possible changes we studied 38 patients with 1 degree HPT who underwent parathyroidectomy. In 14 of these (group I) cimetidine was given pre-operatively (1000 mg orally daily for 4 weeks). The remaining 24 patients (group II) did not take any drug. Parathyroid function was estimated by nephrogenous cAMP (NcAMP) and serum immunoreactive parathyroid hormone (iPTH) measurements. Histological examination of the parathyroids was made by conventional techniques. In group I at the end of cimetidine treatment, the only change observed was a small but significant (p less than 0.05) decrease of plasma calcium (-0.77 mg/dl). Histologically, the glands of group I--compared with those of group II--showed the following findings: increased gland mass: mean increase 1050 mg (adenomas) and 700 mg (hyperplasias); central oedema in all the cases of group I only; increased (about 50 per cent) cellular size and intranuclear 'inclusions' in 10 out of 14 cases of group I only. It is concluded that treatment with cimetidine in 1 degree HPT is followed by histopathologic alterations leading to increased size of the diseased parathyroids.     

Dietary composition alters gentamicin-induced nephrotoxicity in rats

Previous studies have shown temporal variations in gentamicin-induced renal toxicity characterized by a peak when administered during the resting period and a trough during the active period. This time-dependent toxicity was also altered according to the macronutrient composition of dietary regimens offered to female rats. In the present study, adult female Sprague-Dawley rats were adapted to semipurified isocaloric diets containing 20% casein or soy-protein (10% fat each) or to a standard chow diet (18.1% mixed proteins; 4.5% fat). The animals were then chronically treated for 10 days with a nephrotoxic dose of gentamicin sulfate (40 mg/kg/day ip) or a saline solution administered in the middle of their resting period (1200 h) or in the middle of their activity period (0000 h). Body weights of rats injected in the middle of their resting period decreased over the last 6 days of gentamicin treatment. Total 12-h light and 12-h dark food intakes were decreased in gentamicin-treated rats. Rats fed the standard chow diet had significantly lower corticocellular regeneration, serum creatinine and blood urea nitrogen compared to those fed the casein- and soy-containing diets. The present study demonstrates that chronic gentamicin-induced renal toxicity varies temporally according to the time of administration and that a mixed protein diet containing a lower fat level can protect against gentamicin-induced nephrotoxicity.     

西咪替丁对小儿轮状病毒肠炎的临床疗效分析

目的 探讨西咪替丁对小儿轮状病毒肠炎的临床疗效分析.方法 选择2012年1月-2015年12月收治的150例轮状病毒感染的肠炎患儿,根据随机数字表法,将所有患儿分为观察组与对照组.两组均给予常规治疗,对照组在常规治疗基础上给予利巴韦林用药,观察组在常规治疗基础上给予西咪替丁用药,观察两组患儿平均退热时间、平均止泻时间、平均止吐时间、疗效及不良反应.观察两组治疗前后的IL-2、IL-6及TNF-α水平.结果 观察组的平均退热时间、平均止泻时间、平均止吐时间明显低于对照组,观察组的总有效率明显高于对照组,治疗后两组患儿的IL-6、TNF-α均显著降低,组内对比差异明显,组间对比发现观察组明显低于对照组(P＜0.05);治疗后两组的IL-2均明显升高,组内对比差异明显,组间对比观察组明显高于对照组(P＜0.05).观察组的不良反应率低于对照组,但组间对比无统计学差异(P＞0.05).结论 西咪替丁可通过调节轮状病毒引起的炎症反应,提高治疗总有效率,加快患儿临床症状的恢复,治疗小儿轮状病毒肠炎安全有效,值得临床推广应用.     

Immunomodulation of cimetidine in healthy volunteers

Summary The effect of cimetidine, a histamine H2-receptor antagonist, on the immune system in man was investigated in 11 healthy volunteers. Cimetidine was administered orally in daily doses of 800 mg for a period of 7 days. At the end of the administration period the number of peripheral CD8+ (cytotoxic/suppressor) cells had diminished significantly (P<0.05) along with a corresponding increase in the CD4+ (helper/inducer): CD8+ (cytotoxic/suppressor) cell ratio (P<0.01). Compared with pretreatment values, a significant in vitro blastogenic response to mitogen stimulation with concanavalin A (P<0.005), phytohemagglutinin (P<0.01), and pokeweed mitogen (P<0.05) was observed in lymphocytes of volunteers after cimetidine intake. The cell-mediated hypersensitivity as assessed by skin testing of seven recall antigens was also enhanced significantly (P<0.001). Using Spearman's coefficient of correlation to compare mitogen-stimulation tests and skin tests of delayed hypersensitivity to the CD4+:CD8+ ratio, yielded a positive correlation (r=0.89;r=0.85, respectively). These effects were reversible 96 h after the last cimetidine dose. In contrast, leukocytes, total T lymphocytes (CD2+, CD3+), CD4+ (helper/inducer) cells, natural killer cells (Leu7+), immunoglobulins, and total complement, C3, C4 were unaffected by cimetidine administration.Abbreviations Con A concanavalin A - NK natural killer - PHA phytohemagglutinin - PWM pokeweed mitogen This work is dedicated to the memory of Professor Dr. med. E.E. Ohnhaus, a stimulating teacher and a great person, who passed away in 1988     

Resveratrol reduces light and electron microscopic changes in acetaminophen-induced hepatotoxicity in rats: Role of iNOS expression

Introduction: Hepatotoxicity is a major complication of acetaminophen (APAP), a widely used analgesic and antipyretic drug. Resveratrol (RSV) is a naturally occurring diphenol and it has anticancer, antioxidant, and anti-inflammatory properties. Objectives: In this study, the beneficial effects of RSV on APAP-induced hepatotoxicity was investigated in rats. Materials and methods: Group 1: Ethanol, Group 2: Saline, Group 3: RSV (10 mg/kg/ip), Group 4: APAP (1000 mg/kg/ip/single dose), Group 5: APAP+RSV (20 min after administration of APAP). The rats were sacrificed 24 h after administration of APAP. Light and electron microscopic changes were evaluated. Levels of malondialdehyde (MDA) and glutathione (GSH), catalase (CAT), and superoxide dismutase (SOD) activities were determined in liver tissue. Results: Rats of the ethanol, saline, and RSV groups did not present any histopathological alterations. In the APAP group, we observed vascular congestion, necrosis, inflammation, sinusoidal dilatation, and loss of glycogen content. In the APAP+RSV group, these changes were markedly reduced. iNOS immunostaining showed very weak positive stained hepatocytes the sections of control, saline, and RSV groups. However, in the APAP group, iNOS immunostaining was most evident in pericentral hepatocytes. In the same areas in APAP+RSV group, intensity of iNOS immunostaining decreased. A significant increase in MDA and decreases in GSH level, CAT, and SOD activity indicated that APAP-induced hepatotoxicity was mediated through oxidative stress. Significant beneficial changes were noted in tissue oxidative stress indicators in rats treated with RSV. Conclusion: These biochemical, histopathological, and ultrastructural findings revealed that RSV reduced the severity of APAP-induced alterations in liver.     

Cimetidine and stress ulcer in aged rats

Male Sprague-Dawley rats, 2, 6, 11, 18, and 26 months old, were subdivided into four drug treatment groups and received either 25, 50, 100 mg/kg of cimetidine or a placebo control before being exposed to restraint plus cold stress for 3 hr. Cimetidine, at all dose levels, significantly reduced ulcer severity in all age groups except the 18- and 26-month-old rats. Senescent rats were not more susceptible to restraint ulcer and cimetidine had the least anti-ulcer effect with the senescent 26-month-old rats.     

西咪替丁对血小板功能及血栓形成的影响

目的:观察西咪替丁(Cim)对血小板功能及血栓形成的影响。方法:在体外,Cim与血小板温育后,测量血小板聚集、血小板生成丙二醛(MDA)、血小板内游离钙[Ca²⁺]_i及血栓素B₂(TXB₂)含量。用电刺激大鼠颈动脉诱导血栓形成并观察Cim的促进作用。结果:Cim使ADP诱导的血小板聚集增加,凝血酶诱导的血小板[Ca²⁺]_i、MDA升高,TXB₂下降,使电刺激大鼠颈动脉闭塞时间(OT)缩短。结论:Cim增强血小板功能,促进血栓形成。     

Antiprostatic effect of cimetidine in rats

Administration of large doses of cimetidine for 45 days to rats decreases the weight of the prostate and seminal vesicles without affecting the testicles. The decrease in weight is due to a marked regression in the prostate of both epithelial and stromal tissue.Treatment with cimetidine also causes an increase in the plasma testosterone level without modifying the plasma values of LH and prolactin. The mechanism of action of cimetidine is discussed. In presence of high levels of testosterone, cimetidine depresses structures such as the prostate and seminal vesicles, which are sensitive to androgens, but does not depress the weight or change the histology profile of the testicles, which are also rich in androgen receptors. Perhaps cimetidine binds to androgen receptors differently in the prostate and in the testicles because of differences in receptor structure or more probably, cimetidine interacts with zinc metal ion essential to prostate growth and androgen action by lowering zinc prostatic levels and consequently depresses the prostatic weight.     

Hepatoprotective effect of baicalin, a major flavone from Scutellaria radix, on acetaminophen-induced liver injury in mice

The protective effects of baicalin (BA), a major flavone from Scutellaria radix on acetaminophen (AP)-induced hepatotoxicity and the possible mechanism(s) of its protective action were investigated in mice. Treatment with BA (300 mg/kg, p.o.) 0.5 h after AP administration significantly prevented an increase in plasma alanine aminotransferase and aspartate aminotransferase activities and AP-induced hepatic necrosis, and also reduced AP-induced mortality from 43% to 0%. In addition, oral treatment with BA significantly prevented AP-induced depletion of glutathione (GSH) contents. However, BA treatment, by itself, did not affect hepatic GSH contents. The effect of BA on the cytochrome P450 2E1 (CYP2E1), the major isozyme involved in AP bioactivation, was investigated. Oral treatment of mice with BA resulted in a significant decrease in AP-induced CYP2E1 activity together with its inhibition of AP-induced CYP2E1 expression. These results show that the hepatoprotective effects of BA against AP overdose may be due to its ability to block the bioactivation of AP by inhibiting CYP2E1 expression.     

Lobular carcinoma of the male breast associated with the use of cimetidine

A case of carcinoma in the breast of a male patient with a chronic gastric ulcer is described. The patient had received cimetidine for 17 years. Histological examination of an excisional biopsy showed lobular in situ and infiltrating carcinoma. In our review of the English literature, this is the 18th case of lobular carcinoma of the male breast to be reported; it is also the first report of lobular carcinoma associated with the use of cimetidine, and the second in a man with documentation of genotype.     

The inhibition of drug metabolism by cimetidine in patients with liver cirrhosis

Summary The effect of cimetidine treatment, 1 g daily over 6 days, on the disposition of theophylline was studied in nine patients with liver cirrhosis and in nine patients without liver disease. Plasma elimination half-life tended to increase from 14.6±8.2 h to 24.3±14.1 h in the cirrhotic patients (P>0.05) and from 8.3±4.2 h to 10.3±4.1 h in the control patients (P<0.05). Total plasma clearance decreased from 0.50±0.23 ml/kg/min to 0.41±0.21 ml/kg/min (P<0.05) in the cirrhotics and from 0.77±0.34 ml/kg/min to 0.58±0.18 ml/kg/min (P<0.05) in the controls. Pretreatment clearance values were also significantly reduced in the cirrhosis group. No change was observed in the volume of distribution of theophylline. The degree of inhibition of theophylline metabolism did not depend on whether the patients were smokers, or whether they had low pretreatment clearance values. In liver cirrhosis, inhibition of drug metabolism by cimetidine varies widely and is unpredictable in the individual patient.Supported by the Deutsche Forschungsgemeinschaft (Gu 86/8-3)     

Differential effect of NDGA on cisplatin-induced nephrotoxicity in Spargue-Dawley rats

Context: Nephrotoxicity is a highly manifested complication in cancer patients undergoing cisplatin therapy. Oxidative stress, nitrosative stress, and inflammation are the major patho-mechanisms of cisplatin-induced nephrotoxicity.

Objective: The purpose of this study was to determine the protective effect of pretreatment and post-treatment of nordihydroguaiarectic acid (NDGA) on cisplatin-induced nephrotoxicity.

Material and methods: Cisplatin-induced renal damage was accessed by biochemical estimation of nephrotoxicity markers, oxidative and nitrosative stress whereas inflammatory markers were accessed by ELISA technique.

Results and conclusion: Cisplatin administration had resulted in renal injury associated with oxidative stress, nitrosative stress as evident by increased MDA, ROS, and nitrite level with decreased antioxidants such as SOD, catalase and, glutathione. Furthermore, cisplatin treated animals exhibited a noticeable pro-inflammatory response with the substantial increase in renal levels of TNF-α, IL-1β, and IL-6 and decrease in the renal level of IL-10. NDGA pretreatment did not lead to significantly rise in oxidative stress, nitrosative stress, and inflammation along with restored the level of IL-10 in the kidney and preserved renal function. Moreover, NDGA post-treatment also presented nephroprotective effects, but the effects were not as positive as compared to NDGA pretreatment. In conclusion, these results indicate that NDGA pretreatment is renoprotective while on the other hand NDGA post-treatment is not so effective in cisplatin-induced nephrotoxicity.     

Effect of combination therapy with cimetidine and pirenzepine on plasma parathyroid hormone and calcitonin levels in hemodialyzed patients

Summary In this study we evaluated the effects of an oral combination therapy with cimetidine and pirenzepine on plasma parathyroidhormone (PTH) and calcitonin (CT) levels in 24 patients on maintenance hemodialysis (mean age: 50 years; mean duration of dialysis treatment: 23 months). As compared to the pre-treatment plasma levels of PTH and CT, there were no significant changes of their plasma concentrations during a 4-week administration of 800 mg cimetidine or 100 mg pirenzepine daily, and the concentrations also did not change significantly during the following 4 weeks of combination therapy with cimetidine and pirenzepine in the above mentioned dosage. Serum concentrations of calcium and phosphate and the activity of the alkaline phosphatase showed no significant changes either. Therefore, we suggest that this therapeutic approach cannot be considered for the treatment of uremic hyperparathyroidism.     

Dose-dependent hepatoprotective effect of emodin against acetaminophen-induced acute damage in rats

Protective effect of emodin (1,3,8-trihydroxy-6-methyl anthraquinone), an active compound of Ventilago madraspatana Gaertn., was evaluated against acetaminophen-induced biochemical and histological alterations in rats. Acetaminophen (2 g/kg, po) administration caused significant elevation in the release of serum transaminases, alkaline phosphatase, lactate dehydrogenase, serum bilirubin and serum protein with concomitant decrease in hemoglobin and blood sugar after 24 h of its administration. Toxicant exposure intensified the lipid peroxidation and altered glutathione status, activities of adenosine triphosphatase, acid phosphatase, alkaline phosphatase as well as major cellular constituents i.e., protein, glycogen and total cholesterol in liver and kidney. Treatment of emodin (20, 30 and 40 mg/kg, po) significantly lessened the toxicity by protecting acetaminophen-induced alterations in various blood and tissue biochemical variables after 24 h of its administration. Acetaminophen administration initiated histological damage in liver. Some degree of protection was seen after emodin therapy in a dose-dependent manner. Emodin at doses of 30 and 40 mg/kg effectively reversed toxic events induced by acetaminophen as same as silymarin (50 mg/kg, po). Thus, the study concluded that emodin at a dose of 30 mg/kg (po) possesses optimum hepatoprotective ability against acetaminophen-induced toxicity.     

Effects of erdosteine on acetaminophen-induced hepatotoxicity in rats

We investigated the effects of erdosteine on acetaminophen (APAP)-induced hepatotoxicity in rats. Superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), AST (aspartate aminotransferase), and ALT (alanine transaminase) activities, and malonyldialdehyde (MDA) and nitric oxide levels as oxidant/antioxidant biochemical parameters were investigated with light microscopic evaluation in adult female Wistar Albino rats. APAP administration produced a decrease in hepatic SOD, CAT, and GSH-Px activities, and coadministration of erdosteine (150 and 300 mg/kg) resulted in increases in the activities. MDA and NO levels increased in the APAP group, and erdosteine treatments prevented these increases. Significant elevations in serum AST and ALT levels were observed in the APAP group, and when erdosteine and APAP were coadministered, their serum levels were close to those in the control group. Light microscopic evaluation of livers showed that there were remarkable centrilobular (zone III) hepatic necrosis and mild to moderate sinusoidal congestion in the APAP group, whereas in the erdosteine group, cellular necrosis was minimal and the hepatocytes maintained a better morphology when compared to the APAP group. Erdosteine prevented APAP-induced liver injury and toxic side effects probably through the antioxidant and radical scavenging effects of erdosteine.     

Inhibitory effect of DS-4574, a peptidoleukotriene antagonist with mast cell stabilizing action,on compound 48/80-induced gastric mucosal lesions in rats

We evaluated the inhibitory effect of DS-4574, a peptidoleukotriene antagonist with mast cell stabilizing action, on rat gastric mucosal lesions induced by compound 48/80 (C48/80: a mast cell degranulator), in comparison with those of disodium cromoglycate (DSCG: a mast cell stabilizer), LY171883 (a peptidoleukotriene antagonist) and cimetidine (a histamine H₂ receptor antagonist). Subcutaneous administration of C48/80 (1 mg/kg) once daily for four consecutive days produced extensive gastric lesions in the fundic mucosa. DS-4574 (20, 50 and 100 mg/kg/day, oral) and DSCG (200 mg/kg/day, intraperitoneal) treatment markedly inhibited formation of these mucosal lesions, but LY171883 (100 and 200 mg/kg/day, oral) and cimetidine (400 mg/kg/day, oral) treatment did not. Moreover, DS-4574 and DSCG significantly suppressed both hyperhistaminemia and histamine release from rat peritoneal mast cells induced by C48/80. These results indicate that the inhibitory effect of DS-4574 on gastric lesions induced by C48/80 may be related to its mast cell stabilizing action, but to neither its antisecretory nor its peptidoleukotriene antagonistic activity.