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.

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.

Gastric mucosal injury due to hemorrhagic reperfusion and efficacy of Salvia miltiorrhizae extract F and cimetidine

AIM: To observe the gastric mucosal injury caused by hemorrhagic shock and reperfusion and to compare the effect between Salvia miltiorrhizae extract F (SEF) and cimetidine (CI) on it. METHODS: A model of hemorrhage/reperfusion injury was produced by Itoh method. Wistar rats were randomly divided into three groups: 0.9% sodium chloride treatment group (NS group), SEF treatment group (SEF group), and CI treatment group (CI group). Saline, SEF and CI were injected respectively. The index of gastric mucosal lesions (IGML) was expressed as the percentage of lesion area in the gastric mucosa. The degree of gastric mucosal lesions was categorized into grades 0, 1, 2, 3. Atom absorption method was used to measure the intracellular calcium content. Radioimmunoassay was used to measure the concentrations of prostaglandins. RESULTS: IGML (%) and grade 3 (%) were 23.18±6.82, 58.44±9.07 in NS group, 4.42±1.39, 20.32±6.95 in SEF group and 3.74±1.56, 23.12±5.09 in CI group, and the above parameters in SEF group and CI group decreased significantly (IGML: SEF vs NS, t=6.712, P=0.000<0.01; CI vs NS, t=6.943, P=0.000<0.01; grade 3: SEF vs HS, t=8.386, P=0.000; CI vs HS, t=8.411, P= 0.000), but the grade 0 and grade 1 damage in SEF group (22.05±5.96, 34.12±8.12) and CI group (18.54±4.82, 30.15±7.12) were markedly higher than those in NS group (3.01±1.01, 8.35±1.95; grade 0: SEF vs HS, t=8.434, P=0.000<0.01; CI vs NS, t=7.950, P=0.000<0.01; grade 1: SEF vs NS, t =8.422, P=0.000<0.01; CI vs NS, t=8.448, P=0.000<0.01). The intracellular calcium content (μg/mg) in SEF group (0.104±0.015) and CI group (0.102±0.010) was markedly lower than that in NS group (0.131±0.019, SEF vs NS, t=2.463, P=0.038<0.05; CI vs HS, t=3.056, P=0.017<0.05). The levels (pg/mg) of PGE_2, 6-keto-PGF_(1α) and 6-keto-PGF_(1α)/TXB_2 were 540±183, 714±124,17.38±5.93 in NS group and 581±168, 737±102, 19.04±8.03 in CI group, 760±192,1 248±158, 33.42±9.24 in SEF group, and the above parameters in SEF group markedly raised (PGE_2: SEF vs NS, t=2.282, P=0.046<0.05; SEF vs CI, t=2.265, P=0.047<0.05; 6-keto-PGF_(1α): SEF vs NS, t=6.583, P=0.000<0.000; SEF vs CI, t=6.708, P=0.000<0.01; 6-keto-PGF_(1α)/TXB_2: SEF vs NS, t=3.963, P=0.003<0.001; SEF vs Cl, t=3.243, P=0.009<0.01), whereas TXB_2 level in SEF group (45.37±7.54) was obviously lower than that in NS group (58.28±6.74, t=3.086, P=0.014<0.05) and CI group (54.32±6.89, t=2.265, P=0.047<0.05). No significant difference was shown between NS group and CI group (PGE_2: t=0.414, P=0.688>0.05; 6-keto-PGF_(1α): t=0.310, P=0.763>0.05; TXB_2: t=1.099, P=0.298>0.05; 6-keto-PGF_(1α)/TXB_2: t=0.372, P=0.718>0.05). CONCLUSION: Both SEF and CI could inhibit reperfusioninduced injury in gastric mucosa, but with different mechanisms. SEF could not only enhance the protective effect of gastric mucosa, but also abate the injury factors, while CI can only abate the injury factors.

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 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 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.

Reduction of Praziquantel Elimination by Cimetidine in Rats

The effect of cimetidine on the elimination of praziquantel(PQT)in rats was studied. The results showed that cimetidine 100 mg/kg,ip 2 reduced the clearances of intravenous and oral PQT by 60 and 69 percent respectively.Cimetidine also markedly reduced liver blood flow of rats(a reduction of 58%)and inhibited PQT metabolism in hepatic microsomes of rats(an inhibition of 55%). The reduction in clearance of intravenous PQT could be attributed to the result of cimetidine lowering liver blood flow,whereas the reduction in clearance of oral PQT might be related mainly to the inhibition of cimetidine on the activity of hepatic drug-metabolizing enzymes.

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.

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。

Liver Damage by the Interaction of Malathion with Cimetidine in Rat

In this study the authors aimed to evaluate the oxidative stress enzymes indicative of liver damage in rats exposed to malathion （M）, subchronic form using cimetidine （C） and cimetidine plus malathion （M ＋ C）. Malathion, widely used organophosphorus insecticide worldwide, induces oxidative liver damage type; cimetidine is an antagonist of histamine H2-receptor, it has been shown to be an inhibitor of various CYP45o isoforms. Male Wistar rats weighing 200-250 g were studied, exposed to malathion orally for 3 weeks （0.15 mg/kg/day, 2 mg/kg/day, 15 mg/kg/day） and cimetidine 10 mg/kg/day. Malathion plus cimetidine affect susceptibility to oxidative stress and possibly modifies the antioxidant defense capacity directly or indirectly.

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.

复方甘草酸苷联合西咪替丁治疗儿童过敏性紫癜的效果

目的探讨过敏性紫癜患儿采用复方甘草酸苷与西咪替丁协同治疗取得的效果。方法选取2021年10月至2023年9月期间本院收治的过敏性紫癜患儿94例,按照随机数字表予以分组。两组患儿均接受常规对症治疗,对照组47例患儿采用西咪替丁治疗,在此基础上观察组47例患儿联用复方甘草酸苷。针对两组患儿的疗效、免疫球蛋白指标、炎症因子指标、不良反应以及治疗后随访6个月的复发情况进行比较。结果总有效率评价显示,观察组结果较对照组更高(P<0.05)。观察组患儿的关节疼痛、腹痛、皮肤紫癜症状消退时间较对照组更短(P<0.05)。治疗后,观察组免疫球蛋白A(IgA)、免疫球蛋白G(IgG)、免疫球蛋白M(IgM)、白细胞介素(IL)-6、C反应蛋白(CRP)指标水平以及随访6个月的复发率均较对照组更低(P<0.05)。不良反应(ADR)评价显示,两组结果差异无统计学意义(P>0.05)。结论复方甘草酸苷联合西咪替丁治疗儿童过敏性紫癜,能够促进患儿的症状消退,改善免疫球蛋白指标,抑制炎症反应,降低病情复发。

西咪替丁片降解试验及降解产物的考察

目的:研究西咪替丁片在光照、高温、酸、碱、氧化等条件下进行强制降解试验及降解产物。方法:采用高效液相色谱法,以十八烷基硅烷键合硅胶为填充剂;以甲醇-水(240∶760)(每1000 mL中含磷酸0.3 mL和己烷磺酸钠0.94 g)为流动相;检测波长为220 nm;流速1.0 mL·min^(-1);进样体积20μL。结果:确定酸破坏降解产物为杂质C,氧化降解产物为杂质E,碱高温破坏降解产物2-氰基-1-(2-巯基乙基)-3-甲基胍未在强制降解产物中检出。结论:成功推测出西咪替丁强制碱、氧化破坏降解产物的结构,并阐明其产生途径,为西咪替丁片的稳定性研究及质量控制提供依据。

HPLC-MS/MS法测定西咪替丁片中11种N-亚硝胺类基因毒性杂质

目的:建立高效液相色谱-串联质谱法(HPLC-MS/MS)同时测定西咪替丁片中11种N-亚硝胺类基因毒性杂质(N-亚硝基二甲胺、N-甲基-N-亚硝苯胺、N-亚硝基二乙醇胺、(2S)-N-亚硝基降烟碱、N-亚硝基二正丙胺、N-亚硝基吗啉、N-亚硝基哌啶、N-亚硝基二正丁胺、N-亚硝基二异丙胺、N-亚硝基-N-乙基异丙胺、N-亚硝基二乙胺)。方法采用ACE EXCEL 3 C18-AR色谱柱(4.6 mm×150 mm,3μm),以0.1%甲酸溶液(A)-甲醇(B)为流动相,梯度洗脱,流速0.8 mL·min^(-1),离子源为APCI离子源,以正离子模式采集。结果:11种N-亚硝胺类基因毒性在1 ng·mL^(-1)~500 ng·mL^(-1)范围内线性关系良好,回收率在80.81%~105.13%,RSD均小于4.0%。结论:该方法操作简单、灵敏度高、重现性好,可用于西咪替丁片中11种N-亚硝胺类基因毒性杂质的质量控制。

西咪替丁在皮肤科门诊的使用情况分析

目的探究南通瑞慈医院西咪替丁在皮肤科门诊中的使用情况,从而提高西咪替丁合理用药水平。方法选择南通瑞慈医院2021年7月~2022年6月西咪替丁的使用数据,并对其进行处方分析。结果该院近1年西咪替丁使用量为18400片,用药频度DDDs为383.33。结论临床开具西咪替丁要注意合理用药,减少不良反应的发生,使用药更加安全。

痰热清注射液治疗慢性阻塞性肺病急性加重期作用机制探讨

目的:研究痰热清注射液治疗慢性阻塞性肺病急性加重期作用机制。方法:在线查询TCMSP数据库、既往文献获取黄芩、熊胆粉、山羊角、金银花、连翘等中药的主要活性成分,利用swisstargetprediction数据库获取其活性成分对应靶点;利用GeneCards、OMMI、Drug Bank等数据库获取慢性阻塞性肺病急性加重期靶点。利用Venny平台在线获取药物与疾病靶点交集,通过DAVID数据库对相交靶点进行基因本体分析和通路富集分析,使用STRING数据库构建蛋白相互作用网络,借助Cytoscapr软件行可视化处理并筛选主要活性成分、关键靶点。最后通过AutoDock vina软件将核心靶点与核心成分进行分子对接验证,并利用pymol可视化处理。结果:痰热清注射液中含主要活性成分90个,对应靶点557个;连翘、黄芩、金银花为痰热清注射液的关键作用药物;baicalein、Norwogonin、5,7,4’-Trihydroxy-8-methoxyflavone、5,2’,6’-Trihydroxy-7,8-dimethoxyflavone、(2R)-7-hydroxy-5-methoxy-2-phenylchroman-4-one、Panicolin、Skullcapflavone II、Moslosooflavone、5,7,2,5-tetrahydroxy-8,6-dimethoxyflavone、quercetin等为核心活性成分;STAT3、HSP90AA1、ESR1、SRC、EP300、AKT1、JUN、PIK3R1、RELA等靶点为蛋白互作网络中的核心靶点。结论:痰热清注射液治疗主要通过黄酮类物质调节细胞炎症反应、细胞增殖、凋亡等对慢性阻塞性肺病急性加重期发挥潜在作用。

西咪替丁结合双嘧达莫片治疗过敏性紫癜的效果及安全性

目的分析西咪替丁联合双嘧达莫片治疗过敏性紫癜患儿的效果及安全性。方法选取2019年2月至2022年4月武夷山市立医院收治的64例过敏性紫癜患儿作为研究对象,按照用药方案不同分为参照组与研究组,每组32例。参照组给予西咪替丁药物治疗,研究组给予西咪替丁联合双嘧达莫片治疗,比较两组临床疗效、不良反应法发生率、症状消失时间、免疫功能及血清炎症因子水平。结果研究组治疗总有效率为96.88%,高于参照组的75.00%,差异有统计学意义(P<0.05)。两组不良反应发生率比较差异无统计学意义。研究组紫癜、皮疹、腹痛、关节肿痛、消化道症状消失时间均短于参照组,差异有统计学意义(P<0.05)。治疗后,研究组IgM、IgA、IgG、CD3^(+)水平及CD4^(+)/CD8^(+)均高于参照组,差异有统计学意义(P<0.05)。治疗后,研究组肿瘤坏死因子-α(TNF-α)、超敏C反应蛋白(hs-CRP)、白细胞介素(IL)-4、IL-6水平均低于参照组,差异有统计学意义(P<0.05)。结论西咪替丁联合双嘧达莫片治疗过敏性紫癜患儿可增强治疗效果,促进疾病症状消失,并改善患儿免疫功能和血清炎症因子水平。