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 nephrotoxicity in rats

Acetaminophen as an analgesic and antipyretic drug can induce renal toxicity in high doses. Cimetidine as an H₂-blocker can inhibit the cytochrome P450 enzymes and reduce the toxic effect of acetaminophen on renal tissue. Eighty rats in eight groups comprising normal control group, acetaminophen control group, cimetidine control group, and five different treatment groups (cimetidine was administrated at 0, 1, 2, 4, and 8 h after acetaminophen administration) were used. Acetaminophen was administered at a toxic of dose 3 g/kg orally, and cimetidine (12.5 mg/kg) was administrated by intraperitoneal route at different times after induction of toxicity. Creatinine and urea were measured, and pathologic lesions were determined. In treatment groups 3 and 6, the urea and creatinine concentration showed no significant difference from group 1. In other treatment groups, the urea and creatinine concentrations were increased significantly (p < 0.05). Histopathologic changes in group 6 were mild in comparison to other groups. We concluded that administration of cimetidine at least 2 h after acetaminophen toxicity can reduce renal lesions.     

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.     

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.     

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.     

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)     

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     

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.     

复方雷公藤凝胶剂对大鼠佐剂型关节炎的疗效及肝毒性研究

目的 探讨不同剂量复方雷公藤凝胶剂(TWCG)外用对佐剂型关节炎(AA)大鼠的治疗作用及其对肝功能的影响.方法 以弗氏完全佐剂(FCA)诱导大鼠关节炎模型,用不同剂量TWCG对其外敷治疗,以扶他林乳胶剂为阳性对照,以凝胶基质为空白对照.观察各组大鼠关节肿胀度;ELISA测定大鼠血清中肿瘤坏死因子-α(TNF-α)、白细胞介素-4(IL-4)的含量;免疫组织化学方法检测踝关节软骨中基质金属蛋白酶-3(MMP-3)的含量;以全自动生化分析仪检测大鼠血清中的谷丙转氨酶(ALT)、谷草转氨酶(AST)水平来观察其肝毒性.结果 与空白对照组相比,扶他林乳胶剂组及不同剂量TWCG组均能显著减轻大鼠关节肿胀度(P＜0.05);能明显降低血清中TNF-α的含量并增加血清中IL-4含量(P＜0.05),能显著降低关节组织中MMP-3的含量(P＜0.05),且中、高剂量TWCG组效果明显优于扶他林及小剂量TWCG组(P＜0.05);但各组大鼠之间ALT、AST差异无统计学意义(P＞0.05).结论 TWCG对AA大鼠有明显的抗炎消肿作用,能有效保护关节软骨组织,同时无明显的肝脏毒性.     

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。     

Protective effect of rhIL-11 in a murine model of acetaminophen-induced hepatotoxicity.

Acetaminophen intoxication results in hepatotoxicity associated with increased serum concentrations of hepatocellular leakage enzymes such as aspartate aminotransferase, lactate dehydrogenase, and alanine aminotransferase, centrilobular degeneration and necrosis, and activation of Kupffer cells. Recombinant human Interleukin-11 (rhIL-11) downregulates the production of proinflammatory mediators from activated macrophages and has direct effects on hepatocyte gene expression. Based on these biological activities of rhIL-11, the effect of pretreatment with rhIL-11 in a murine model of acetaminophen-induced hepatotoxicity was examined. Administration of 500 microg/kg acetaminophen to B6C3F1 mice resulted in progressive hepatotoxicity as demonstrated by elevated serum concentrations of hepatocellular leakage enzymes and TNFalpha and histopathology. Pretreatment with 250 or 500 microg/kg of subcutaneously administered rhIL-11 2 hours before acetaminophen administration reduced serum concentrations of hepatocellular leakage enzymes and TNFalpha by 40-50%. This was associated with a statistically significant decrease in mean severity score for centrilobular hemorrhage and necrosis from grade 3 to grade 2 for rhIL-11-treated animals compared to vehicle. These results indicate that treatment with rhIL-11 has a protective effect in a model of acetaminophen-induced liver damage.     

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.     

Influence of Timing of Administration of Liposome-encapsulated Superoxide Dismutase on Its Prevention of Acetaminophen-induced Liver Cell Necrosis in Rats

The possible participation of acute oxidative stress in the in vlvo mechanism by which acetaminophen (APAP) induces hepatocellular injury was examined. Male Sprague-Daw-ley rats were administered 3-methylcholanthrene, fasted for 18 h, then given APAP and sacrificed after a further 6 h of fasting. Extensive centrilobular liver cell necrosis along with markedly elevated serum activity of aminotrans-ferases was observed. Liposome-encapsulated human recombinant Cu-Zn superoxide dismutase (LSOD) administered 1 or 0.5 h prior to APAP or simultaneously with the toxin completely prevented APAP-induced hepatocellular injury. In contrast, LSOD administered 5 or 2.5 h before or 1, 2.5 or 5 h after the toxin treatment did not prevent APAP toxicity. Incomplete protection against APAP-induced injury was obtained when LSOD was administered 0.5 h after the toxin. These results support the proposal of an oxidative mechanism for APAP hepatotoxicity.     

Studies on preventive effects of diphenyl diselenide on acetaminophen-induced hepatotoxicity in rats

Organoselenium are compounds with important antioxidant activity and with many biological activities interesting from pharmacological point of view. The aim of this study was to evaluate the protective effect of diphenyl diselenide (PhSe)₂ on hepatotoxicity caused by administration of acetaminophen (AA) in rats. Rats received (PhSe)₂ orally (31 mg/kg, dissolved in canola oil) for 2 days. After the second day of treatment, rats received AA orally (2 g/kg) in unique dose. Twenty-four hours after the last administration of AA, plasma was used for biochemical assays aspartate (AST) and alanine aminotransferases (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), γ-glutamyl transferase (γ-GT) activities. Glutathione-S-transferase (GST), δ-aminolevulinic dehydratase (δ-ALA-D) and catalase activities as well as ascorbic acid and TBARS levels were determined in the liver of rats. (PhSe)₂ protected against the increase in AST, ALT, ALP, LDH and γ-GT activities induced by AA exposure to rats. The histological data showed that sections of liver from AA-exposed rats presented intense cellular necrosis, characterized by the presence of Kupffer cells and other infiltrating cells, mainly around of the centrilobular vein. (PhSe)₂ significantly attenuated AA-induced hepatic histopathological alterations. Administration of (PhSe)₂ protected against the increase in TBARS levels and the decrease in δ-ALA-D and GST activities as well as ascorbic acid content induced by AA exposure in rats. Catalase activity remained unaltered in all treated groups. The protective effect of (PhSe)₂ against hepatotoxicity caused by AA exposure in rats was demonstrated.     

谷氨酸钠反复注射对家兔体温的影响

本研究用14只新西兰兔进行实验,观察了反复多次使用谷氨酸钠(MSG)对其降温效应的影响。动物分两组,实验组家兔静脉注射中等剂量MSG(0.5g/kg)连续三天,每天一次,体温均明显下降。(与对照组相比,P<0.05)。第四次(时间间隔1周,以同样的剂量和方式注射MSG,则几乎不出现降温作用(与对照组比,P>0.05)。第五次(时间间隔2周)注射MSG的效应与第四次相似。实验结果提示:MSG反复多次使用后,其降温效应逐渐减弱。作者暂称之为“降温耐受”现象,并对降温效应减弱的机制进行初步讨论。     

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.     

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.     

Effect of cimetidine on experimental atherogenesis in rabbits

Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 115, N ^o 4, pp. 380–383, April, 1993     

Protective effect of kombucha tea against acetaminophen-induced hepatotoxicity in mice: a biochemical and histopathological study

Acetaminophen overdose causes severe hepatotoxicity leading to liver failure in experimental animals and humans. This study was undertaken to evaluate the protective effect of kombucha tea (KT) against acetaminophen-induced hepatotoxicity. Forty male Balb/c mice were divided into four equal groups: (1) the control group, (2) KT-treated group, (3) acetaminophen-treated group, and (4) KT/acetaminophen-treated group. All mice in group 4 were given KT orally for 7?days before a single hepatotoxic dose of acetaminophen (1,000?mg/kg orally). Activities of liver marker enzymes in serum; aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), and alkaline phosphatase (ALP); and total protein (TP), albumin (ALB), and direct and total bilirubin levels were determined. Acetaminophen challenge caused significant increases in the levels of bilirubin and liver enzymes (AST, ALT, ALP, and LDH), while TP and ALB levels were reduced significantly. Histopathologic assessments showed that severe glycogen storage in hepatocytes, hepatocellular degeneration and necrosis, mononuclear cell infiltration in portal area, dilation of central veins, and capillarization also reduced in KT/acetaminophen group compared to acetaminophen-treated mice. In conclusion, these findings suggest that KT has protective effect on acetaminophen-induced hepatotoxicity.