Radioprotective effects of cimetidine on rats irradiated by long-term, low-dose-rate neutrons and ^(60)Coγ-rays

Background: Cimetidine, an antagonist of histamine type II receptors, has shown protective effects against γ-rays or neutrons. However, there have been no reports on the effects of cimetidine against neutrons combined with γ-rays. This study was carried out to evaluate the protective effects of cimetidine on rats exposed to long-term, low-dose-rate neutron and γ-ray combined irradiation(n-γ LDR).Methods: Fifty male Sprague-Dawley(SD) rats were randomly divided into 5 groups: the normal control group, radiation model group, 20mg/(kg·d) cimetidine group, 80mg/(kg·d) cimetidine group and 160mg/(kg·d) cimetidine group(10 rats per group). Except for the normal control group, 40 rats were simultaneously exposed to fission neutrons(^(252)Cf, 0.085 m Gy/h) for 22 h every day and γ-rays(^(60)Co, 0.097Gy/h) for 1.03 h once every three days, and the cimetidine groups were administered intragastrically with cimetidine at doses of 20, 80 and 160mg/kg each day. Peripheral blood WBC of the rats was counted the day following exposure to γ-rays. The rats were anesthetized and sacrificed on the day following exposure to ^(252)Cf for 28 days. The spleen, thymus, testicle, liver and intestinal tract indexes were evaluated. The DNA content of bone marrow cells and concanavalin A(Con A)-induced lymphocyte proliferation were measured. The frequency of micronuclei in polychromatic erythrocytes(f MNPCEs), superoxide dismutase(SOD), malondialdehyde(MDA), and glutathione peroxidase(GSH-Px) in the serum and liver tissues were detected.Results: The peripheral blood WBC in the cimetidine groups was increased significantly on the 8th day and the 26 th day compared with those in the radiation model group. The spleen, thymus and testicle indexes of the cimetidine groups were higher than those of the radiation model group. The DNA content of bone marrow cells and lymphocyte proliferation in the cimetidine groups were increased significantly, and fMNPCE was reduced 1.41-1.77 fold in cimetidine treated groups. The activities of SOD and GSH-Px in the cimetidine groups were increased significantly, and the content of MDA in the cimetidine groups was decreased significantly.Conclusions: The results suggested that cimetidine alleviated damage induced by long-term, low-dose-rate neutron and γ combined irradiation via antioxidation and immunomodulation. Cimetidine might be useful as a potent radioprotector for radiotherapy patients as well as for occupational exposure workers.

甲氰咪胍(Cimetidine)的试制

抗消化性溃疡新药甲氰咪胍,为组胺 H_2-受体拮抗剂,目前国内外已广泛应用于临床。本文主要叙述了采用还原法制备关键性中间体咪唑醇的新工艺;以乙酰乙酸乙酯为起始原料,经氯化、环合反应而得咪唑酯,再由咪唑酯还原成咪唑醇。由于采用了独创的还原方法,因而为本品的投产,创造了成本低廉、原料易得和操作安全的有利条件。合成总收率中试为19.2～19.9%,小试验可达21.4～22%,高于文献记载的水平。

Effects of temperature and wavelength choice on in-situ dissolution test of Cimetidine tablets

The effects of temperature and wavelength choice on in-situ dissolution test instrument of Cimetidine were studied. Absorbance （A）〈 1.0 is required when using a fiber-optic dissolution test system. The detection wavelength of 2 （218 nm） was replaced by 244 nm to carry out this test. The absorbance of Cimetidine solution at different temperature showed an obvious change. Calibration of Cimetidine solution should be tested at the same temperature （37° C） with the test solution. A suitable wavelength with smaller tangent slope could be chosen for in-situ dissolution test of Cimetidine tablets.

EFFECTS OF PERIOPERATIVE CIMETIDINE ADMINISTRATIONON NATURAL KILLER CELLS IN PATIENTS WITHGASTROINTESTINAL CANCER

Objective: To study the effects of perioperative use of cimetidine on natural killer (NK) cells in gastrointestinal (GI) cancer patients. Methods: 49 GI cancer patients were randomized into treatment group which took cimetidine in the perioperative period, and control group which did not take the drug. NK cells were measured by immunocytochemical method, using mouse-anti-human CD57 monoclonal antibody as the primary antibody. Blood samples from 20 healthy volunteers were treated in the same way as normal control. Comparisons were made within and between groups. Results: The NK cell percentage of normal control was 18.50±2.31. Both groups of patients had significantly lower than normal NK percentages before treatment (P<0.05). NK cell percentages at admission, before operation, on the 2nd and the 10th postoperative days were 14.60±3.91, 15.64±3.61, 17.40±3.28, 20.68±4.13, respectively, for the treatment group, and 14.88±2.76, 13.17±2.93, 14.50±2.77, 15.67±2.55, respectively, for control group. The difference between the two groups was statistically significant. Conclusion: Perioperative cimetidine application can help restore NK cells. The drug may be useful to reverse postoperative immuno-depression in GI cancer patients.

Effects of Cimetidine on IL－2 and T Suppressor Cell Function in Rats with Obstructive Jaundice

Susceptibility to infection in patients with obstructive jaundice is much more higher than non-jaundiced patients. The reasons for this are not completely understood. It is postulated that this may have some relation to changes of patients′immune function. This article reported the changes of splenocyte IL-2 production and T Suppressor cell activity in rats with obstructive jaundice. Meanwhile, we also investigated effects of cimetidine on immune function in rats with bile duct ligation. The results show that IL-2 production in obstructive jaundiced rats significantly decreased and T suppressor cell activity markably increased. Cimetidine could remarkably enhance IL-2 production and suppress T Suppressor cell activity. Abmormaility of immune function may be one reason for high susceptibility to infection in patients with obstructive jaundice in perioperative period. Cimetidine, which could clearly improve immune function in rats with obstructive jaundice, might be a valuable agent for strengthening the capacity of fighting infection in patients with obstructive jaundice.

EFFECTS OF PERIOPERATIVE CIMETIDINE ADMINISTRATION ON TUMOR CELL NUCLEAR MORPHOMETRY AND DNA CONTENT IN PATIENTS WITH GASTROINTESTINAL CANCER

Objective: To explore the effects of perioperative cimetidine administration on tumor cell nuclear morphometric parameters and DNA content in patients with gastrointestinal adenocarcinoma. Methods: 49 patients with pathologically confirmed gastrointestinal adenocarcinoma were randomized into test group (n=25) and control group (n=24). The test group started oral cimetidine intake 400 mg, tid, 7–10d before operation, followed by standard curative operation. The control group did not receive cimetidine. Tumor specimens were paraffin embedded for microsection and stained with hematoxylin and eosin (HE) and Feulgen stain. Morphometric studies and DNA content of tumor nuclei were performed on IBAS Image Analyzer. Results: The tumor cell nuclear area (μm2), nuclear perimeter (μm), maximal nuclear diameter (μ) for test group/control group were 23.54 5.08/34.69110.08 (P<0.001), 22.064.43/24.884.05 (P<0.05), 7.8411.64/ 8.6211.24 (P<0.05), 4.4210.61/5.4110.89 (P<0.001), Respectively. The percentages (%) of diploidy, triple-tetraploidy, quintuple ploidy, and >quintuple ploidy tumor cells for test group/control group were 16.6412.58/5.3312.14 (P<0.002), 39.8412.28/35.7013.58 (P>0.50), 12.4215.00/14.4810.74 (P>0.20), 31.1116.86/ 45.9713.82 (P<0.005), respectively. Conclusion: Perioperative administration of cimetidine in gasgtrointestinal cancer patients could decrease the nuclear size and raise the percentage of diploid tumor cells, and convert high aneuploid tumor cells into low-aneuploid tumor cells, which might help reduce the invasiveness of tumor cells.

Perioperative Cimetidine Application Modulates Natural Killer Cells in Patients with Colorectal Cancer: A Randomized Clinical Study

Thirty-eight colorectal cancer patients were randomly assigned to treatment group, which took cimetidine in the perioperative period, and control group to which no drug was given. Twenty healthy volunteers served as normal controls. NK cells were measured by immunocytochemical technique.The results showed that NK percentages before treatment in both groups of patients were sig-nificantly lower than those in normal controls (P<0. 05). NK cell percentages at admission, before operation, on the 2nd and the 10th postoperative days were 14. 84± 4. 41, 15. 74 ± 3. 75, 17. 21 ± 3. 69, 21. 05 ± 4. 54, respectively, for the treatment group, and 15. 00±2. 77, 13.05± 2. 46, 14. 21± 2. 19, 15. 58± 1. 68,respectively, for control group. The difference was statistically significant (P<0. 01 ), suggesting that the perioperative administration of cimetidine could help restore NK cells in colorectal cancer patients.

5－Fu、Cimetidine对急性胰腺炎患者的免疫调节作用

应用单克隆抗体技术测定４５例急性胰腺炎外周血Ｔ淋巴细胞亚群，通过对５－Ｆｕ、Ｃｉｍｅｔｉｄｉｎｅ治疗组和抑肽酶治疗组的对照分析以及治疗后的动态观察发现：急性胰腺炎患者存在细胞免疫平衡紊乱，表现为１４↓、Ｔ８↑、Ｔ４／Ｔ８↓，治疗组于治疗后７～９天起Ｔ细胞亚群恢复，而对照组仅Ｔ４恢复，认为急性胰腺炎免疫平衡紊乱可能是感染性易感性增高的原因之一。５－Ｆｕ、Ｃｉｍｅｔｉｄｉｎｅ不仅能有效地抑制胰腺外分泌功能，还可改善患者免疫状况，提高抗感染能力。

Meta-Analysis of the Efficacy of Cimetidine in the Treatment of Mumps

Objective:To compare the efficacy of cimetidine and ribavirin in the treatment of mumps by meta-analysis.Methods:Controlled trials of cimetidine and ribavirin in the treatment of mumps were searched through China National Knowledge Infrastructure(CNKI),Wanfang data,Cqvip,Pubmed,The Cochrane Library and EMBase databases up to September 2022.The effective rate,the time of swelling regression in parotid gland area and the rate of adverse reactions were analyzed by Review Manager 5.3 software.Results:The final 10 articles included 920 children,including 427 in the trial group and 447 in the control group.Meta analysis showed that the effective rate of cimetidine in the treatment of mumps was higher than that of ribavirin in routine treatment,with a statistically significant difference(odds ratio[OR]=5.2,P<0.00001);The time of swelling regression was statistically significant(OR=-1.28,P<0.00001);The difference of adverse reaction rate was not statistically significant(OR=0.73,P=0.62).Conclusions:Compared with ribavirin,cimetidine is more effective in the treatment of mumps,with shorter swelling regression time without increases of adverse reactions.

Vitamin B12-induced spermatogenesis recovery in cimetidine-treated rats： effect on the spermatogonia number and sperm concentration

The H2-receptor antagonist cimetidine is an antiulcer drug also used for the treatment of cancer due to its antiangiogenic effect. However, this drug has caused structural changes in the seminiferous tubules. Vitamin B12 has been used as a therapeutic agent for the treatment of male infertility. The supplementation of rats with vitamin B12 during cimetidine treatment has recovered the damaged seminiferous tubules, but how this vitamin restores the seminiferous epithelium has not been clarified. In this study, we evaluated whether vitamin B12 improves the number of spermatogonia, spermatocytes, and sperm concentration in cimetidine-treated rats. Adult male rats were treated for 50 days as follows： cimetidine group received 100 mg kg^-1 b.w. of cimetidine, cimetidine-B12 group received cimetidine and 3 μg of vitamin B12-hydroxocobalamin, B12 group received only 3 μg of vitamin, and control group received saline. Sperm concentration was calculated and historesin-embedded testes sections were used for the quantitative analyses of spermatogonia （A; In/B） and spermatocytes. TUNEL method and PCNA immunofluorescence were performed. Cimetidine caused a significant reduction in sperm concentration. TUNEL-positive spermatogonia and spermatocytes were correlated to a significant reduction in the number of these cells. In cimetidine-B12 group, sperm concentration was higher than cimetidine group and a significant increase in the number of spermatogonia （stages Ⅱ-Ⅵ） was correlated to a high incidence of PCNA-immunolabeled spermatogonia and spermatocytes. The results show that the supplementation of rats with vitamin B12 during cimetidine treatment increases sperm concentration and exerts a potential effect in the recovery of spermatogonia and spermatocytes.

Effects ofm perioperative cimetidine administration on tumor cell nuclear morphology and DNA content in patients with gastric and colorectal cancer

Objective To explore the effects of perioperative cimetidine administration on tumor cell nuclear morphometric parameters and DNA content in patients with gastric and colorectal adenocarcinoma (GCRA) Past studies have attributed the antitumor effect of cimetidine to its immunomodulatory property, which led to an increase of cellular immunity Whether there are other possible mechanisms by which cimetidine exerts its antitumor function is unknown 49 patients with GCRA were randomized into treatment group (n=25) and control group (n=24) based on whether cimetidine was applied to them during the perioperative periold The treatment group started oral cimetidine intake 400mg, tid, 7-10d before oiperation, followed by curative surgery 'The control group did not receive cimetidine Tumor specimens were paraffin embedded for 4μm thick microsection and stained with (1) hematoxylin and eosin (HE) for the morphometric measurements of tumor cell nuclear area (NA), nuclear perimeter (NP), maximal nuclear diameter (MMND) and minimal nuclea4r diameter (MNND); (2) feulgen stain for tumor nuclear DNA content analysis by IBAS Image Analyzer The percentages (%) of diploidy (2C), tripletetraploidy (3C 4C), quintuple ploidy (5C) and >quintuple ploidy (>5C) tumor cells were calculated, using the mean value of DNA content of 50 lymphocytes as normal 2C control 3C 5C cells were designated as law aneuploid cells and >5C cells as high aneupoid cells Results The clinicopathological variables between the two groups were balanced and comparable There were no statistically significant differences between bthe treatment and control groups in regard of the following parameters: age, gender, tumor location, pathological type, TNM stage, and degree of differentiation The NA (μm 2), NP (μm), MMND (μm) and MNND (μm) for treatm ent group/control group were 23 54±5 08/34 698±10 18 ( P <0 001), 22 06±4 43/24 88±4 05 ( P <0 05),7 84±1 64/8 62±1 24 ( P >0 05), and 4 42±0 61/5 41±0 89 ( P <0 001), respectively The percentages (%) of 2C, 3C 4C, 5C and >5C tumor cells for treatment group/control group were 16 64±2 58/5 35±2 14 ( P <0 002), 39 84±2 28/35 70±3 58 ( P >0 50), 12 42±5 00/14 48±0 74 ( P >0 20), 31 11±6 86/45 97±3 82 ( P <0 005), respectively In the treatment group, there was a tendency tiowards low aneuploid tumor cells from high an euploid tumor cells However, high aneuploid tumor cells predominated in the control group Conclusion Perioperative administration of cimetidine to GCRA patients could decrease the size of tumor cell nuclei, raise the percentage of diploid tumor cells, and partially convery high aneuploid tumor cells into low aneuploid tumor cells All of these effects may in turn help reduce the proliferative potential and invasiveness of tumor cells The direct inhibitory functions on tumor cell nuclei may be a new antitumor mechanism of cimetidine, in addition to its immunomodulatory action

《国际药学文摘》在药学情报源中的地位

《国际药学文摘》(InternationalPharmaceutical Abstract简称IPA),自1964年创刊,到现在已有30年的历史,作为一种新的药学专业检索刊,IPA与EM、IM等医学情报源相比,究竟有什么特色呢?本文拟就IPA的收录期刊、文献量进行分析,并用药学主题词进行文献检索,与EM、IM、《医学中央杂志》、《中国药学文摘》进行比较,从而分析IPA的文献主题侧重。

Thioperamide treats neonatal hypoxic-ischemic encephalopathy by postsynaptic H1 receptors

Thioperamide, a selective histamine H3 receptor antagonist, can increase histamine content in the brain, improve brain edema, and exert a neuroprotective effect. This study aimed to examine the mechanism of action of thioperamide during brain edema in a rat model of neonatal hypoxic ischemic encephalopathy. Our results showed that thioperamide significantly decreased brain water content and malondialdehyde levels, while significantly increased histamine levels and superoxide dismutase activity in the hippocampus. This evidence demonstrates that thioperamide could pre vent oxidative damage and attenuate brain edema following neonatal hypoxicischemic encepha Iopathy. We further observed that changes in the above indexes occurred after combined treatment of thioperamide with the H1 receptor antagonist, pyrilamine, and the H2 receptor antagonist, ci metidine. Experimental findings indicated that pyrilamine reversed the effects of thioperamide; however, cimetidine had no significant influence on the effects of thioperamide. Our present findings suggest that thioperamide can increase brain histamine content and attenuate brain edema and oxidative damage by acting in combination with postsynaptic H1 receptors in a rat model of neo natal hypoxicischemic encephalopathy.

Effect of Lanthanum on Acid Secretion from Isolated Mouse Stomach in Vitro

To explore the effect and the mechanism of La^(3+) on gastric acid secretion (GAS) of isolated mouse stomach with perfused lumen, 12 cm H_2O column intragastric pressure-provided, whole stomach preparations from mice were incubated in buffer at 37 ℃ in vitro, and perfusate was measured for pH with a pHS-3 type pH meter. The results show that La^(3+) (0.41～820×10^(-6) mol·L^(-1)) significantly promotes GAS in a concentration-dependant manner. Proglutamine, a blocker of gastrin receptor, potently inhibits GAS, and it may block the promotive effect of La^(3+) on GAS, and this effect increases with the increase of proglutamin concentration. Cimetidine, a blocker of histamine H_2 receptor, also potently inhibits GAS, and blocks the promotive effect of La^(3+) on GAS in the same manner with proglutamine. These results suggest that La^(3+) promotes GAS in isolated stomach possibly by stimulating the releases of gastrin from G cell and Histamine from ECL cell or by activating the gastrin receptors and Histamine H_2 receptors on the parietal cell, thereby accelerating the acid secretion of parietal cells in stomach.

Pharmacological effects of aqueous-ethanolic extract of Hibiscus rosasinensis on volume and acidity of stimulated gastric secretion

Objective:To explore the effects of extract of Hibiscus rosasinensis(H.rosasinensis) on the volume,free and total acidity of gastric secretion induced by carbachol.Methods:Animals were kept on fasting for 48 h.then the pylorus of each animal was ligated.They were randomly divided into 5 groups and treated by carbachol at 600μg/kg.Then animals in groupⅡ-Ⅴwere treated by H.rosasinensis extract at 250 and 500 mg/kg body weight,cimetidine at 2.5 mg/ kg and verapamil at 10 mg/kg body weight intraperitoneally,respectively.The volume,free and total acidity of gastric secretion were observed and compared.Results:It was found that the extract significantly reduced the volume,free and total acidity of gastric secretion(P【0.01). These reductions were comparable to cimetidine and verapamil.And the reduction in the volume and free acidity were more significant in cimetidine and verapamil treated group indicating that cimetidine and verapamil were more effective.Conclusions:The extract of H.rosasinensis can reduced the volume,free and total acidity of gastric secretion,and can be used effectively in the treatment of peptic ulcer.

Effects of ranitidine on contraction and action potentials in normal and potassium depolarized isolated papillary muscles of the guinea pig

The purpose of these experiments was to investigate the possible ionicbases for ranitidine （Ran） in isolated papillary muscles of the guinea pig.Ran,when the concentration was below 300μmol/L,had no influence on contraction ofnormal muscles and only above 0.3 mmol/L,it showed weak negative inotropic ef-fect.The contractile activity elicited by histamine in potassium depolarized mus-cles was depressed by Ran markedly and dose-dependently.The IC50 of Ran was0.273μmol/L.This depressant effect was reversed by an elevation of externalCa2+concentration to 7.7mmol/L.The contraction induced by isoproterenol inpotassium depolarized preparations was not altered by Ran.Ran at theconcentrations of 1,10 and 100μmol/L failed to show influences on fast actionpotentials.However,Ran at 0.5μmol/L time-dependently inhibited slow action po-tentials.It is concluded that the ionic mechanism of Ran might be attributed toantagonized H2 receptor of myocardium which in turn decreases Ca2+ inward cur-rent.

甲氰咪胍的新用途

甲氰咪胍又称西米替丁,是一种H2-受体阻断剂,能显著地减少胃液分泌,降低胃酸与氢离子浓度,抑制胃蛋白酶分泌,因此有促进溃疡愈合的作用。此药一般应用于治疗胃、十二指肠溃疡及上消化道出血等症,疗效良好。随着本药的普遍使用,以及对本药药理研究的不断深入,近年来开始应用于一些其他疾病的治疗,亦取得显著疗效。现介绍如下:

抗酸剂对法莫替丁生物利用度的影响

法莫替丁（甲磺噻咪,Famotidine）是继西米替丁（Cimetidine）、雷尼替丁（Ranitidine）之后,含有噻唑环及丙脒基的一种新的长效、强效第三代组胺H2受体拮抗剂。主要用于治疗消化性溃疡,也可用于治疗Zollinger-Ellisin综合征,以控制胃酸的大量分泌。临床为减轻病人的症状,特别在治疗的早期,常与一些抗酸剂同服。许多研究结果表明,抗酸剂（主要含氢氧化铝。

甲氰咪胍与一些药物的相互作用

甲氰咪胍（西咪替丁,Cimetidine CMD）为H2受体阻滞剂,具有明显的促进十二指肠溃疡愈合作用,不良反应较少,临床应用广泛。它与某些药物配伍联用,曾有人报道。本文对近几年来国内外有关CMD与一些药物相互作用文献,作一简要概述。1.异搏定 两药并用后,廓清率从29.6±2.1～23.4±9.1ml/kg·min减少21％,t1/2延长50％。