Efficacy and safety of Nafamostat mesylate in patients with endstage renal failure

BACKGROUND Recent studies on dialysis anticoagulation therapy in patients with renal failure have shown that Nafamostat mesylate,a broad-spectrum potent serine protease inhibitor,has strong anticoagulation and anti-fiber activity.AIM To evaluate the efficacy and safety of Nafamostat mesylate in patients with end-stage renal failure.METHODS Seventy-five patients with end-stage renal failure who received hemodialysis at our hospital between January 2020 and August 2021 were selected and divided into the observation group(Nafamostat mesylate for injection,n=33)and control group(heparin sodium injection,n=32).General patient data,indicators of clinical efficacy,dialyzer hemocoagulation parameters,coagulation function indices,and hemoglobin concentration and platelet count before and after treatment,and the occurrence of adverse reactions after treatment were compared between the two groups.RESULTS The two groups showed no significant differences in general patient data(P>0.05).The post-treatment effectiveness rate in the control group was lower than that in the observation group(P<0.05).The two groups showed no significant difference in the number of patients in grade I(P>0.05),while the number of patients in grade 0 was lower in the control group,and the number of patients in grades II and III was higher in the control group(P<0.05).The post-treatment prothrombin time,activated partial thromboplastin time,thrombin time,and international normalized ratio values in the control group were higher than those in the observation group,while the fibrinogen level in the control group was lower than that in the observation group(P<0.05).The two groups showed no significant difference in the platelet count and hemoglobin level before and after treatment(P>0.05).The total number of post-treatment adverse reactions in the observation group was lower than that in the control group(P<0.05).CONCLUSION Treatment of patients showing end-stage renal failure with Nafamostat mesylate can significantly improve therapeutic efficacy and has high safety and clinical value.

Antitumor efficacy of multi-target in situ vaccinations with CpG oligodeoxynucleotides,anti-OX40,anti-PD1 antibodies,and aptamers

To overcome immune tolerance to cancer,the immune system needs to be exposed to a multi-target action intervention.Here,we investigated the activating effect of CpG oligodeoxynucleotides(ODNs),mesyl phosphoramidate CpG ODNs,anti-OX40 antibodies,and OX40 RNA aptamers on major populations of immunocompetent cells ex vivo.Comparative analysis of the antitumor effects of in situ vaccination with CpG ODNs and anti-OX40 antibodies,as well as several other combinations,such as mesyl phosphoramidate CpG ODNs and OX40 RNA aptamers,was conducted.Antibodies against programmed death 1(PD1)checkpoint inhibitors or their corresponding PD1 DNA aptamers were also added to vaccination regimens for analytical purposes.Four scenarios were considered:a weakly immunogenic Krebs-2 carcinoma grafted in CBA mice;a moderately immunogenic Lewis carcinoma grafted in C57Black/6 mice;and an immunogenic A20 B cell lymphoma or an Ehrlich carcinoma grafted in BALB/c mice.Adding anti-PD1 antibodies(CpG+αOX40+αPD1)to in situ vaccinations boosts the antitumor effect.When to be used instead of antibodies,aptamers also possess antitumor activity,although this effect was less pronounced.The strongest effect across all the tumors was observed in highly immunogenic A20 B cell lymphoma and Ehrlich carcinoma.

6-Gingerol, asarinin, and deoxyschizandrin improve bronchial epithelium functions in an interleukin-13einduced BEAS-2B cell model

Objective:To explore the effects of 6-gingerol,asarinin,and deoxyschizandrindthe main components of Zingiber officinale(Willd.)Rosc.(Gan Jiang),Asarum heterotropoides f.var.mandshuricum(Maxim.)(Xi Xin),and Schisandra chinensis(Turcz.)Baill.(Wu Wei Zi),respectivelydon an interleukin(IL)-13einduced BEAS-2B cell model in vitro.Methods:The BEAS-2B cell model was established using 25 ng/mL IL-13 combined with 1%fetal bovine serum(FBS)in vitro.Mitoquinone mesylate(Mito-Q)treatment was used as a positive control group,and different concentrations of 6-gingerol,asarinin,and deoxyschizandrin were used to treat the models.The level of reactive oxygen species(ROS)production was detected by flow cytometry.The expression levels of LC3B,Beclin1,adenosine 50-monophosphate(AMP)eactivated protein kinase(AMPK),phosphory-lated-AMPeactivated protein kinase(P-AMPK),dynamin-related protein 1(DRP1),and mitochondrial fusion protein 2(MFN2)were detected by Western blot.Mitochondrial membrane potential(MMP)assay kit with JC-1 was utilized to detect the level of MMP.Results:The BEAS-2B cells exposed to 25 ng/mL IL-13 with 1%FBS showed an increased ROS level and a decreased MMP.6-Gingerol,asarinin,and deoxyschizandrin were able to downregulate ROS level and upregulate the MMP in the BEAS-2B model.Asarinin and deoxyschizandrin reduced the expression of autophagy protein LC3B,while deoxyschizandrin significantly increased the expression of DRP1 in the BEAS-2B model.Conclusion:6-Gingerol,asarinin,and deoxyschizandrin can reduce ROS generation and increase MMP,but have different regulatory effects on the expression of autophagy protein and mitochondrial mitotic protein.The three components have both synergistic and complementary effects in classic medicine compatibility.This study may provide an innovative strategy to reduce the lung inflammation related to IL-13.

Yizhi Xingnao prescription improves the cognitive function of patients after a transient ischemic attack

Patients with mild cognitive impairment after a transient ischemic attack were included in this study. They were treated with Yizhi Xingnao prescription, ergoloid mesylates or aspirin for 60 days. Evaluation using the Montreal Cognitive Assessment Scale showed that cognitive function was significantly improved in all patients, especially after the combined treatment of Yizhi Xingnao and aspirin. The scores from the Montreal Cognitive Assessment Scale were improved overall and the effective treatment rate was as high as 79%, which was higher than patients treated with a combination of ergoloid mesylates and aspirin, or aspirin alone. Our experimental findings indicate that YizhiXingnao prescription can improve mild cognitive impairment after a transient ischemic attack, and that it is more effective than ergoloid mesylates.

硫丙麦角林对帕金森病的疗效观察

目的:观察硫丙麦角林并用复方左旋多巴治疗帕金森病(PD)的疗效与副作用.方法:回顾性分析我院PD专病门诊中应用本药长期治疗观察的31例(2例单用硫丙麦角林).结果:26/31例(83.4%)用该药有效,维持剂量150μg～500μg/d.34%有轻微不良反应,便秘常见.结论:用硫丙麦角林有效率83%,耐受性较好.与安坦、金刚烷胺、左旋多巴合用能增加疗效.本荆为临床可选用的DA受体激动剂之一.

胃肠道间质瘤的治疗进展

胃肠道间质瘤是消化道最常见的间叶细胞肿瘤。近年来,随着抗肿瘤药物Gleevec的临床应用,胃肠道间质瘤的治疗方法起了重大的变化,由原先单一的手术治疗转为手术、药物的联合治疗。此文回顾近几年来国内外学者的研究及经验,对胃肠道间质瘤的治疗作一综述。

A gist of gastrointestinal stromal tumors: A review

Gastrointestinal stromal tumors (GISTs) have been recognized as a biologically distinctive tumor type, different from smooth muscle and neural tumors of the gastrointestinal tract (GIT). They constitute the majority of gastrointestinal mesenchymal tumors of the GIT and are known to be refractory to conventional chemotherapy or radiation. They are defined and diagnosed by the expression of a proto-oncogene protein detected by immunohistochemistry which serves as a crucial diagnostic and therapeutic target. The identification of these mutations has resulted in a better understanding of their oncogenic mechanisms. The remarkable antitumor effects of the molecular inhibitor imatinib have necessitated accurate diagnosis of GIST and their distinction from other gastrointestinal mes-enchymal tumors. Both traditional and minimally invasive surgery are used to remove these tumors with minimal morbidity and excellent perioperative outcomes. The revolutionary use of specific, molecularlytargeted therapies, such as imatinib mesylate, reduces the frequency of disease recurrence when used as an adjuvant following complete resection. Neoadjuvant treatment with these agents appears to stabilize disease in the majority of patients and may reduce the extent of surgical resection required for subsequent complete tumor removal. The important interplay between the molecular genetics of GIST and responses to targeted therapeutics serves as a model for the study of targeted therapies in other solid tumors. This review summarizes our current knowledge and recent advances regarding the histogenesis, pathology, molecular biology, the basis for the novel targeted cancer therapy and current evidence based management of these unique tumors.

Effect of PDGF-Rb antagonist imatinib on endometrial injury repairing in mouse model

Objective: To study the effects of PDGF-Rb antagonists imatinib on endometrial injury repairing in the mouse model. Methods: The cultured MSCs cells from male mice were marked with Brd U in vitro, and then transplanted to the female mice which suffered from radiation injury through tail vein, PDGF-Rb antagonists imatinib was injected through abdominal cavity. Four groups were arranged, which were radiation transplantation group, normal control group, imatinib intervention group and radiation control group. Brd U incorporation, SRY expression and MVD status were detected in uterus of mice. Results: SRY gene was negative expressed in normal control group and radiation control group. SRY gene presented positive in radiation transplantation group and imatinib intervention group; Brd U incorporation showed negative in radiation control group and normal control group which died in the early stage in mice; the incorporation of Brd U was higher in radiation transplantation group compared with imatinib intervention group; CD34 was positive on the uterus of all the four groups,which showed highest in radiation control group and lowest in radiation control group; The MVD in imatinib intervention group was lower than radiation control group; the difference of MVD was significantly compared with normal control group(P<0.05). Conclusions: PDGF-Rb antagonists imatinib could inhibit the repairing function of MSCs in the endometrial lesions in mice.

Hepatitis B reactivation in chronic myeloid leukemia patients receiving tyrosine kinase inhibitor

Hepatitis B virus(HBV) reactivation is a well-recognized complication in patients with chronic HBV infection receiving cytotoxic or immunosuppressive chemotherapy.Imatinib mesylate and nilotinib are selective Bcr/Abl tyrosine kinase inhibitors,which are now widely used in the treatment of patients with chronic myeloid leukemia.Although HBV reactivation induced by imatinib mesylate has been reported,nilotinib-related HBV reactivation has not been reported in the English literature.We report here 2 cases of HBV reactivation in chronic myeloid leukemia patients receiving imatinib mesylate and a novel case of nilotinib related HBV reactivation.

Current update on molecular cytogenetics, diagnosis and management of gastrointestinal stromal tumors

Gastrointestinal stromal tumors(GISTs)are the most common mesenchymal tumors of the gastrointestinal(GI)tract and are thought to arise from precursors of the interstitial cells of Cajal.GISTs can arise anywhere in the GI tract,but most commonly originate from the stomach and small intestine.The majority of GISTs occur as a result of activating mutations in two receptor protein tyrosine kinases:KIT and/or platelet-derived growth factor receptor-α.Mutational analyses allow for predicting patient prognosis and treatment response.Clinical presentations can vary from no symptoms,typical in the case of small incidentally found tumors,to GI bleeding,abdominal discomfort,and ulcer-related symptoms when the tumor is enlarged.Imaging plays a critical role in the diagnosis and management of these tumors with multiphasic computed tomography serving as the imaging modality of choice.Magnetic resonance imaging and positron emission tomography-computed tomography can serve as imaging adjuncts in lesion characterization,especially with liver metastases,and subsequent staging and assessment for treatment response or recurrence.Surgical resection is the preferred management for small GISTs,while tyrosine kinase inhibitors−imatinib mesylate and sunitinib malate−serve as crucial molecular-targeted therapies for locally advanced and metastatic GISTs.This review article highlights the clinical presentation,pathology and molecular cytogenetics,imaging features,and current management of GISTs.

Nafamostat mesylate attenuates the pathophysiologic sequelae of neurovascular ischemia

Nafamostat mesylate,an apparent soi-disant panacea of sorts,is widely used to anticoagulate patients undergoing hemodialysis or cardiopulmonary bypass,mitigate the inflammatory response in patients diagnosed with acute pancreatitis,and reverse the coagulopathy of patients experiencing the commonly preterminal disseminated intravascular coagulation in the Far East.The serine protease inhibitor nafamostat mesylate exhibits significant neuroprotective effects in the setting of neurovascular ischemia.Nafamostat mesylate generates neuroprotective effects by attenuating the enzymatic activity of serine proteases,neuroinflammatory signaling cascades,and the endoplasmic reticulum stress responses,downregulating excitotoxic transient receptor membrane channel subfamily 7 cationic currents,modulating the activity of intracellular signal transduction pathways,and supporting neuronal survival brain-derived neurotrophic factor/TrkB/ERK1/2/CREB,nuclear factor kappa B.The effects collectively reduce neuronal necrosis and apoptosis and prevent ischemia mediated disruption of blood-brain barrier microarchitecture.Investigational clinical applications of these compounds may mitigate ischemic reperfusion injury in patients undergoing cardiac,hepatic,renal,or intestinal transplant,preventing allograft rejection,and treating solid organ malignancies.Neuroprotective effects mediated by nafamostat mesylate support the wise conduct of randomized prospective controlled trials in Western countries to evaluate the clinical utility of this compound.

Imatinib mesylate in clinically suspected gastric stromal tumors

Gastrointestinal stromal tumors （GISTs） occur most frequently in the stomach.Diagnosis of gastric GIST is not always clear before surgery.Flexible endoscopy may suggest the nature of the lesion （a bulky tumor with preserved mucosa）; however,biopsy is rarely diagnostic.Therefore,diagnostic medication with safe drugs may provide a feasible way under such conditions after an informed consent is obtained.Based on the excellent efficacy of imatinib mesylate （IM） in the treatment of GIST,we successfully applied it in the diagnostic medication of two patients with clinically suspected gastric stromal tumors.In conclusion,the diagnostic medication with IM can be an alternative option for patients with suspected GIST that can not be confirmed pathologically.

Intra-abdominal desmoid tumors mimicking gastrointestinal stromal tumors——8 cases: A case report

BACKGROUND Intra-abdominal desmoid tumors(DTs) can mimic recurrence or progression of gastrointestinal stromal tumors(GISTs). Differential diagnosis is important to avoid unnecessary or inappropriate treatment.CASE SUMMARY All 8 patients experienced surgical resection of GIST, and median time to diagnosis of DT was 1.8 years after surgical resection. All sites of DT were in the peritoneum around the surgical sites of GIST. The following clinical suspicion coupled with radiological findings contributed to the suspicion of intraabdominal DTs:(1) Occurrence of a new single lesion in the peritoneum around the surgical sites of GIST;(2) uncontrolled lesion with imatinib while other lesions being controlled with imatinib;(3) well-defined ovoid shaped lesion with delayed or mild enhancement and absence of necrosis, hemorrhage, and cystic change on computed tomography; and(4) a lesion showing mild or no hypermetabolic activity on 18 fluorodeoxyglucose-positron emission tomography,contrary to initially hyperactive lesion of GIST. All DTs were surgically removed except for one unresectable DT and only one DT recurred at another site of peritoneum, which was also surgically removed.CONCLUSION Intra-abdominal DT should be a differential diagnosis for a new single lesion in patients with GIST.

Evaluation of imatinib mesylate(Gleevec) on KAI1/CD82 gene expression in breast cancer MCF-7 cells using quantitative real-time PCR

Objective: To evaluate the effect of imatinib mesylate on cell viability, anti cancer effect through modulation of KAI1/CD82 gene expression in breast cancer MCF-7 cell line.Methods: The effects of imatinib mesylate on cell viability in MCF-7 cell line were assessed using MTT assay and IC_(50) value was determined. GAPDH and KAI1/CD82 were selected as reference and target genes, respectively. Quantitative real time PCR technique was applied for investigation of KAI1/CD82 gene expression in human breast cancer MCF-7 cells. Subsequently, the quantity of KAI1 compared to GAPDH gene expressions were analyzed using the formula; 2^(-DDCt).Results: Imatinib was showed to have a dose-dependent inhibitory effect on the viability of MCF-7 cells. CD82/GAPDH gene expression ratios were 1.322 ± 0.030(P > 0.05),2.052 ± 0.200(P < 0.05), 2.151 ± 0.270(P < 0.05) for 10, 20 and 40 mmol/L of imatinib concentrations.Conclusions: Based on the present data, imatinib mesylate might modulate metastasis by up-regulating KAI1/CD82 gene expression in human breast MCF-7 cancer cell line.

A novel fixed-combination timolol-netarsudillatanoprost ophthalmic solution for the treatment of glaucoma and ocular hypertension

Currently commercial fixed-concomitant three agents have multiple problems such as multiple dosing administration,poor efficacy and side effects.Once-daily fixed-combination timolol-netarsudil-latanoprost ophthalmic solution(FC-TNL)has the ability to treat glaucoma by lowering the intraocular pressure(IOP)with great efficacy and improving patient compliance.However,the commercialized netarsudil dimesylate precipitated when the p H of the solution was above 5.4,or when maleic acid,the salt of commercial timolol maleate,was mixed with netarsudil dimesylate.Consequently,the homologous salt engineering strategy was used to make netarsudil dimesylate soluble in p H 4.8–5.2 solution by synthesizing timolol mesylate.Next,the morphology of timolol mesylate was observed by scanning electron microscopy,differential scanning calorimetry,thermogravimetric analysis,and powder X-ray diffraction.The prepared FC-TNL showed good stability during refrigeration storage.Additionally,FC-TNL exerted no influence on the intraocular penetration of each active compounds in the pharmacokinetic study.Importantly,oncedaily FC-TNL exerted potent IOP-lowering effect and protective effect on retinal ganglion cells.The FC-TNL was stable,safe and effective,being a promising glaucoma therapeutic.

Pancreatic extragastrointestinal stromal tumor:A case report and comprehensive literature review

AIM: To provide an overview of the literature on pan-creatic extragastrointestinal stromal tumors(EGISTs).METHODS: We report a case of pancreatic EGIST and review published studies on pancreatic EGIST ac-cessed via the PubMed, MEDlInE, Google Scholar, and Google databases. The keywords used were "pancreas and GIST", "pancreas and extra GIST", "pancreas and gastrointestinal stromal tumor", and "pancreas and ex-tragastrointestinal stromal tumor". literature reviews and/or duplicate studies were excluded. The search included articles published in the English language be-tween January 1, 2000 and May 15, 2014.RESULTS: From our literature survey, 30 manuscripts on pancreatic EGISTs were considered, of which 27met the search criteria and three were excluded. The studies involved 30 patients(15 men, 15 women) with a mean age of 55.3 ± 14.3 years(range 30-84 years). The mean age of the male patients was 50.8 ± 13.7 years(range 30-84 years); that of the female patients was 59.9 ± 13.3 years(range 38-81 years). Tumor dimensions were obtained for 28 cases(mean 114.4 ± 78.6 mm; range 20-350 mm). Tumors were diagnosed incidentally in 23.3% of patients; abdominal discomfort and weight loss were the major complaints in symp-tomatic patients. Risk of aggressive behavior according to Fletcher criteria was determined in 25 of 30 patients(68%: high risk, 28%: intermediate risk, 4%: low risk). Histopathological examination revealed the presence of spindle cells in 96.1% of cases; CD117 and CD34 were present immunohistochemically in 96.6% and 84% of patients, respectively. The most common surgical pro-cedures were distal pancreatectomy with splenectomy(n = 9) and pancreaticoduodenectomy(n = 7). The to-tal follow-up period for the 28 patients ranged from 3-66 mo, during which locoregional or distant metastases were diagnosed in six patients and two patients died.CONCLUSION: Studies on EGISTs have only been published in the last decade. The lack of studies with large patient cohorts and long-term follow-up limits evidence-based commentary. In theory, each case should be assessed individually and further genetic and immunohistochemical studies are needed.

治疗转移性乳腺癌新药——甲磺酸阿贝西尼(abemaciclib mesylate)

治疗转移性乳腺癌新药甲磺酸阿贝西尼(abemaciclib mesylate)是周期蛋白依赖激酶(CDK)4/6抑制药,由美国礼来公司(Eli Lilly and company)研发,曾用名为Bemaciclib,用于治疗激素受体(HR)阳性(HR+)及人表皮生长因子受体2(HER2)阴性(HER2-),经内分泌治疗后乳腺癌已进展或转移的成人晚期患者。阿贝西尼于2015年10月9日获得美国食品药品管理局(FDA)突破性疗法的认定,给予在HR+/HER2-乳腺癌患者中优先评审资格,2017年9月28日批准上市,商品名为Verzenio。该文对甲磺酸阿贝西尼的非临床和临床药理毒理学、临床研究、不良反应、适应证、剂量与用法、用药注意事项及知识产权状态和国内外研究进展等进行介绍。

Primary Extra-Gastrointestinal Stromal Tumor (GIST) arising from mesentery of small bowel and presenting as abdominal mass: A rare entity

Introduction: Majority of mesenchymal tumors of gastrointestinal tract are Gastrointestinal Stromal Tumor (GIST). It is, however, a rare tumor, accounting for less than 1% of primary gastrointestinal (GI) neoplasms. Though, these tumors are refractory to conventional chemotherapy or radiotherapy but show a good response to targeted adjuvant chemotherapy with tyrosine kinase inhibitors following surgical resection. Case Report: we report here a case of primary Extra-GIST tumor arising from mesentry of small bowel near duodeno-jejunal junction in a 69 years old male patient. The patient presented with a palpable mass in upper abdomen for past 15 days. On examination, a non-tender mobile lump of size around 17 × 10 cm, with bosselated surface and firm in consistency was palpable involving epigastric, left hypochondrium and umbilical region. Contrast enhanced computed tomography of abdomen revealed a heterogenous mesentric mass. On surgical intervention a mass was found involving mesentery near dudenojejunal junction without involvement of gastrointestinal tract. Complete surgical resection of the tumor was done and adjuvant chemotherapy with Imatinib mesylate was started as HPE revealing GIST with mitotic index of >10/50 HPF and 17 × 10 cm size placed the patient in high risk category. Patient was discharged on 12th of post-operative day with advice of regular follow-up. Conclusion: GIST occurrence is not restricted to bowel but can involve unusual sites also. The mainstay of treatment remains surgical resection with adequate margin. In cases where tumour has malignant potential (high mitotic figures on histopathology) adjuvent treatment with tyrosine kinase may prevent or delay relapse.

Cannabinoids Increase Mechanosensitivity of Trigeminal Ganglion Neurons Innervating the Inner Walls of Rat Anterior Chambers via Activation of TRPA1

Our previous study found that some trigeminal ganglion（TG） nerve endings in the inner walls of rat anterior chambers were mechanosensitive, and transient receptor potential ankyrin 1（TRPA1） was an essential mechanosensitive channel in the membrane. To address the effect of cannabinoids on the mechanosensitive TG nerve endings in the inner walls of anterior chambers of rat eye, we investigated the effect of the（R）-（＋）-WIN55, 212-2 mesylate salt（WIN）, a synthetic cannabinoid on their cell bodies in vitro. Rat TG neurons innervating the inner walls of the anterior chambers were labeled by 1,1＇-dilinoleyl-3,3,3＇,3＇-tetramethylindocarbocyanine, 4-chlorobenzenesulfona（FAST Di I）. Whole cell patch clamp was performed to record the currents induced by drugs and mechanical stimulation. Mechanical stimulation was applied to the neurons by buffer ejection. WIN evoked inward currents via TRPA1 activation in FAST Di I-labeled TG neurons. WIN enhanced mechanosensitive currents via TRPA1 activation in FAST Di I-labeled TG neurons. Our results indicate that cannabinoids can enhance the mechanosensitivity of TG endings in the inner walls of anterior chambers of rat eye via TRPA1 activation.

Gastrointestinal stromal tumors and second primary malignancies before and after the introduction of imatinib mesylate

Gastrointestinal stromal tumor （GIST） is the most common mesenchymal malignancy of the gastrointestinal tract.GISTs may coexist with different types of cancer,either synchronous or metachronous （1）.Most GISTs develop in a sporadic fashion,but familial occurrence,such as neurofibromatosis and Carney-triad,has also been reported （2）.The overall frequency of second tumors in different series varied from 4.5% to 33%.The most frequent types of GIST-associated cancers were gastrointestinal carcinomas （47%）,lymphoma/leukemia （7%）,carcinomas of prostate （9%）,breast （7%）,kidney （6%）,lung （5%）,female genital tract （5%）,carcinoid tumors （3%）,soft tissue and bone sarcomas （3%）,malignant melanoma （2%） and seminoma （1%） （1,3-5）.