Four FDA-approved drugs exhibited inhibition effect on severe fever with thrombocytopenia syndrome virus in vitro

Objective:To screen the anti-SFTSV drugs from 1430 FDA-approved drugs via mini-genome system,and to investigate which stage of the infection process could be suppressed by the identified drugs.Methods:The SFTSV mini-genome system was used to screen drugs with inhibitory effect on SFTSV replication and transcription,and the 50%inhibitory concentration(IC_(50))of each drug was calculated by drug concentration gradient inhibition experiment.Drugs were used to pre-incubate with virus and then incubate with cells,to incubate with virus and cells simultaneously,to incubate with cells after virus invading into cells,or to incubate during the whole infection process,and then qRT-PCR was used to measure the viral RNA copies in the culture supernatant.These experiments were performed to quantitatively determine the inhibition effects of drugs on SFTSV indifferent stages of the whole process including virion stability,entry and post-entry stages,so as to clarify the inhibition mechanism of these drugs.Results:Four drugs including Mycophenolate mofetil,Mycophenolic acid,Nitazoxanide,and Vidofludimus were identified having efficient inhibitory effects on SFTSV RNA replication via minigenome system,with the IC_(50) of 0.014μmol/L,0.627μmol/L,1.283μmol/L,and 0.059μmol/L,respectively.All four drugs showed effective inhibition when adding during the whole SFTSV infection process as well as the post-entry stage.Conclusion:Mycophenolate mofetil,Mycophenolic acid,Nitazoxanide and Vidofludimus show efficient anti-viral effects on SFTSV infection.

Association of KRAS Gene and microRNA-124-3p in Sporadic Colorectal Tumours

Aim: To reveal the exonic and 3’UTR sequences of KRAS, TP53, APC, BRAF, PIK3CA genes in sporadic colorectal tumors and to investigate the clinical relevance of 3’UTR variations in miRNA profiles. Methods: In the study, the exonic and 3’UTR sequences of five genes in 12 sporadic colorectal tumors were extracted by next generation sequencing. In tumors with variation in the 3’UTR region, the changes caused by the variation in the miRNA binding profile were detected. The expression profile of these miRNAs in colorectal and other solid tumors compared to normal tissue was determined. Pathway analysis was performed to determine which signaling pathways miRNAs affect. Results: Case-10 in our study was wild type KRAS and received cetuximab treatment and developed drug resistance. In this case, it was concluded that the expression of KRAS increased and tumorigenesis progressed due to miRNAs that do not bind to this region due to variations in the 3’UTR region. Among these miRNAs, hsa-miR-124-3p was found to have decreased expression in colorectal tumors and to be associated with the ECM-receptor interaction pathway. Conclusion: Variations in the 3’UTR regions of genes critical in the process of carsinogenesis are associated with drug resistance and the process of tumorigenesis.

Azathioprine-induced fever in autoimmune hepatitis

Underdiagnosis of drug-induced fever leads to extensive investigation and prolongation of hospitalization, and may lead to multiple unnecessary invasive procedures and a wrong diagnosis. Azathioprine is a widely used immunosuppressive drug. We report a case of a 53-year-old female patient diagnosed with autoimmune hepatitis treated with azathioprine, who presented to the emergency room with a 6-wk history of fever and chills without other associated symptoms. Since the patient's fever was of unknown origin, she was hospitalized. All treatment was stopped and an extensive workup to explore the source of fever and chills was performed. Results of chest X-ray, viral, urine, and blood cultures, autoimmune serology, transthoracic and transesophageal echocardiography, and abdominal ultrasound revealed no source of infection. A rechallenge test of azathioprine was performed and the fever and chills returned within a few hours. Azathioprine was established as the definite cause following rechallenge. Fever as an adverse drug reaction is often unrecognized. Azathioprine has been reported to cause druginduced fever in patients with inflammatory bowel disease, rheumatoid arthritis, and sarcoidosis. To the bestof our knowledge there have been no previous reports documenting azathioprine-induced fever in patients with autoimmune hepatitis. The occurrence of fever following the readministration of azathioprine suggests the diagnosis of drug-induced fever, particularly after the exclusion of other causes. A careful rechallenge is recommended to confirm the diagnosis.

Post-Endoscopy Self-Limited Unspecified Fever: Rare or Common Adverse Event after Endoscopy?—An Observational, Cross-Sectional Study

Background: Although post-endoscopy fever (PEF) without colon perforation or haemorrhage is believed to be rare, incidence, risk factors and causes in the adult population have not been fully investigated. The purpose of the present study was to investigate the incidence of PEF and identify the risk factors associated with the development of PEF and its outcomes. Material and Methods: Over a three-month period, 1054 non-hospitalised patients who had an endoscopic procedure at Cleveland Clinic Abu Dhabi received a post-procedure phone call within the first 24 hours. After identifying patients with fever and obtaining verbal consent, patients were enrolled in the study using a standardised telephone interview. Results: Thirty-four patients with PEF were identified. The highest temperature measured was 39.8 degrees Celsius. Oesophagogastroduodenoscopy, as a single procedure, was the most commonly performed (41.2%). Logistic regression revealed that no significant group differences across procedure types existed in terms of adjusted odds of fever. However, results also indicated that age has a significant negative relationship with fever—higher age is associated with lower odds of fever (b = -0.033, p = 0.024). Conclusion: PEF is an unpleasant side effect and it is associated with patient discomfort, dissatisfaction and fear during post-endoscopy recovery. Although our findings do not fully explain the possible mechanisms underlying post-endoscopy fever, this study data should increase awareness about PEF as a common side effect related to endoscopy.

African swine fever virus MGF505-3R inhibits cGAS-STING-mediated IFN-βpathway activation by degrading TBK1

African swine fever virus(ASFV)is an important pathogen causing acute infectious disease in domestic pigs and wild boars that seriously endangers the global swine industry.As ASFV is structurally complex and encodes a large number of functional proteins,no effective vaccine has been developed to date.Thus,dissecting the mechanisms of immune escape induced by ASFV proteins is crucial.A previous study showed that the ASFV-encoded protein is an important factor in host immunity.In this study,we identified a negative regulator,MGF505-3R,that significantly downregulated cGAS/STING-and poly(dG:dC)-mediated IFN-βand interferon stimulation response element(ISRE)reporter activity and suppressed IFNB1 and IFIT2 mRNA levels.In addition,TBK1,IRF3 and IκBαphosphorylation levels were also inhibited.Mechanistically,MGF505-3R interacted with cGAS/TBK1/IRF3 and targeted TBK1 for degradation,thereby disrupting the cGAS-STING-mediated IFN-βsignaling pathway,which appears to be highly correlated with autophagy.Knockdown MGF505-3R expression enhanced IFN-βand IL-1βproduction.Taken together,our study revealed a negative regulatory mechanism involving the MGF505-3R-cGAS-STING axis and provided insights into an evasion strategy employed by ASFV that involves autophagy and innate signaling pathways.

Significance of IL-1Ra and IL-6 gene variants in Turkish patients with Crimean-Congo hemorrhagic fever

Objective: To investigate the association between IL-1 Ra variable number of tandem repeat(rs2234663), IL-6-597 GA(rs1800797), IL-6-572 GC(rs1800796) and the risk of CrimeanCongo hemorrhagic fever(CCHF) in the Turkish patients. Methods: This study included 50 patients infected with CCHF and 50 healthy controls. These variants were genotyped using polymerase chain reaction and/or restriction fragment length polymorphism method. Results: The distribution of the IL-6-572 GC genotypes and alleles varied significantly between the patients and the controls. The subjects carrying IL-6-572 GC GG genotype and G allele had increased risk of developing CCHF compared to the control group(P=0.006, P=0.014, respectively). IL-6-572 GC GC genotype was higher in the controls than the patients(P=0.006). For the triple genotype combinations, the 1/2-GC-GG genotype combination was detected more frequently in the control group than CCHF patients(P=0.016). IL-6(-572/-597) GG-GG genotype was significantly higher in the patient group(P=0.015), while the GC-GG genotype was significantly lower in the patient group(P=0.005). Additionally, the G-G haplotype was significantly higher in the patient group(P=0.042), whereas C-G was found to be significantly lower in the patients than the control group(P=0.037). Conclusions: The results of this study suggest the IL-6-572 GC variant might be genetic markers of sensitivity to CCHF in the Turkish population and may facilitate greater protection against the disease.

Synthesis of (2S,4S)-2-Substituted-3- (3-Sulfanylpropanoyl)-6- Oxohexahydropyrimidine-4-Carboxylic Acids as Potential Antihypertensive Drugs

Proceeding from natural amino acid L-asparagine and commercially available aldehydes a stereoselective synthesis was developed of (2S,4S)-2-alkyl(aryl)-3-(3-sulfanylpropanoyl)-6-oxohexahy- dropyrimidine-4-carboxylic acids, potential antihypertensive drugs, inhibitors of the angiotensin converting enzyme.

TCM TREATMENT OF CHEMOTHERAPY-INDUCED FEVER IN LEUKEMIA PATIENTS

Chemotherapy is a major means in the treatment of leukemia, yet it often induces high fever which makes a successful treatment impossible. From January 1992 to February 1996, we adopted

从补中益气汤管窥李东垣脾胃观之阴火论

“阴火”即内伤之火,其实质为脾胃亏虚,元气虚损所生之内热。“阴火”理论是李东垣提出并应用于临床阐明病机、诊治疾病、遣方用药的重要学说。其产生机制复杂,涵盖内容广泛,自古存在诸多争议,至今未有定论,临床价值尚未完全体现。补中益气汤既是东垣脾胃内伤学说的核心方,也是理解其内伤发热之“阴火”理论的关键。文章将通过探讨李东垣脾胃内伤理论体系中最重要的方剂“补中益气汤”的药物配伍特点及其理论基础,阐述李东垣脾胃观之“阴火”论的学术思想,以及“益气升阳”“甘温除热”的制方思想,浅析“阴火”理论的学术渊源,总结后世医家基于“阴火”理论的临床诊疗应用思路,以期为日后临床工作者应用“阴火”理论临床辨证论治、组方加减提供理论依据。

临床药师参与1例万古霉素致药物性肝损伤及药物热临床实践

目的促进临床合理使用万古霉素。方法临床药师参与1例万古霉素致药物性肝损伤(DILI)及药物热的救治过程,为患者提供药学服务,结合文献及患者每日检查指标的变化,及时发现导致DILI及药物热的线索,及时停药并对症处理。结果通过DILI因果关系评估量表(RUCAM)评分发现导致DILI的药物,通过排除性诊断发现导致药物热的药物,查阅文献并结合患者的检查指标,推断万古霉素致DILI和药物热同时发生,与体液免疫的超敏反应有关。结论临床使用万古霉素时除要关注患者的肾功能不良反应外,还需关注患者的肝功能、体温变化,若出现肝功能损伤、体温升高等,则需警惕万古霉素诱发的药品不良反应。

β-内酰胺类抗生素致药物热的临床特征

目的探讨β-内酰胺类抗生素所致药物热(drug-fever)的临床特征,为药物热的临床诊断提供依据。方法回顾性分析本院2000年～2006年期间明确诊断为β-内酰胺类抗生素致药物热的病例,对临床特点进行总结分析。结果β-内酰胺类抗生素致药物热常见,临床表现多种多样,可有多种伴随症状,也可以单纯以发热为表现,所有病例体温均在停药后48h内下降,无任何后遗症。结论β-内酰胺类抗生素所致药物热临床常见,尤其常见于氧哌嗪青霉素,临床有一定难度,容易漏诊、误诊,应引起重视。

甲型和乙型副伤寒同时暴发流行事件中菌株分子分型、毒力及耐药特征分析

目的对一起甲型和乙型副伤寒同时暴发流行事件中菌株的分子分型、毒力及耐药特征进行分析,为不同型别副伤寒同时传播的防治提供参考依据。方法回顾分析2018年9月至11月新疆生产建设兵团医院就诊的副伤寒确诊病例31例。对分离菌株进行血清学分型及药物敏感试验,采用多重PCR、脉冲场凝胶电泳、多位点序列分析进行分子分型,并检测毒力基因及耐药基因。结果31例确诊病例共分离出32株副伤寒沙门菌,血清学分型分为甲型19株、乙型13株,所有菌株对环丙沙星中介率为100%。11株代表菌株的M-PCR分子分型与血清学分型结果一致;甲型与乙型副伤寒沙门菌的PFGE指纹图谱均一致;甲型副伤寒沙门菌MLST为ST85型,乙型副伤寒沙门菌MLST为ST86型;所有菌株均携带毒力岛SPI1~SPI5代表基因invA、sitC、sseL、sifA、mgtC、siiE、sopB和调节基因phoP,甲型副伤寒沙门菌还携带三聚体结构的伤寒毒素(cytolethal distending toxin,CDT)基因cdtB、pltA、pltB,毒力质粒基因pefA、prot6E、spvB检测均为阴性。结论甲型和乙型副伤寒沙门菌同时传播具有致病性强及环丙沙星药物敏感性差的特点,应引起临床及实验室的高度关注。

高效液相色谱-离子阱质谱法测定人血浆中的头孢拉定和青霉素G

目前,β-内酰胺类抗生素在临床抗感染药物中占有十分突出的地位[1],但在近年来的药品不良反应报告中,抗生素类药物引起的不良反应也占据了很高的比例,其中有我国生活环境影响、感染性疾病多的客观因素,但病人用药盲目性大、医生用药随意性多的问题也普遍存在.……

小儿退热解毒颗粒对发热大鼠下丘脑中β-内啡肽和神经降压素含量的影响

目的观察小儿退热解毒颗粒对发热大鼠下丘脑中β-内啡肽(β-EP)和神经降压素(NT)含量的影响。方法将36只大鼠随机分为3组,即正常对照组10只和模型对照组、小儿退热解毒颗粒组各13只。模型对照组、小儿退热解毒颗粒组用酵母混悬液造模。造模结束后,小儿退热解毒颗粒组给予小儿退热解毒颗粒42g/kg,灌胃容量10mL/kg;模型对照组给予等容量蒸馏水,正常对照组不予处理。观察给药后2 h体温变化值(△T),测定β-EP和NT含量,并将△T分别与下丘脑中β-EP和NT的含量变化进行相关分析,观察是否存在相关性。结果小儿退热解毒颗粒组给药2h后体温明显下降,与模型对照组比较差异有统计学意义(P<0.01);小儿退热解毒颗粒组给药2 h时△T与模型对照组比较差异有统计学意义(P<0.01);小儿退热解毒颗粒组β-EP、NT与模型对照组比较差异均有统计学意义(P<0.01);正常对照组、模型对照组、小儿退热解毒颗粒组的△T与β-EP、NT含量均呈正的直线关系。结论小儿退热解毒颗粒可通过影响下丘脑中β-EP和NT的含量而发挥其解热作用。

强α_(1)受体拮抗的非典型抗精神病药物导致精神分裂症患者自感发热不适1例

本文报道了1例精神分裂症患者服用强α_(1)受体拮抗的非典型抗精神病药物奥氮平、利培酮、帕利哌酮和氯氮平后出现自感身体发热不适,考虑系药物副反应,换用阿立哌唑后,患者自感发热不适消失。该病例报道旨在提示精神科医生关注强α_(1)受体拮抗的非典型抗精神病药物导致的副反应,并需结合药物作用机制、患者的病理生理、个体差异等综合考虑,提高患者的治疗依从性,改善预后。

环氧酶-2选择性抑制剂的再认识

非甾体抗炎药（nonsteroidal anti-inflammatory drugs，NSAIDs）是一类具有抗炎与镇痛作用的药物，可以改善风湿性疾病的炎性症状并可缓解疼痛，是世界范围内使用最广泛的一类处方药。NSAIDs的作用机制是通过抑制环氧酶（cyclooxygenanse，COX）的活性进而阻断花生四烯酸转化为前列腺素、前列环素和血栓素A，（TXA，）而发挥其药理作用。但使用NSAIDs的过程中，尤其是长期、大量服用时可出现副作用，其中最常见的副作用是对胃肠道的损害。

1例万古霉素治疗菌血症持续低谷浓度伴出现可逆性耳聋和药物热的药学监护

目的探讨万古霉素持续低谷浓度的原因,出现可逆性耳聋和药物热的判断和处置。方法MRSA菌血症先心患者使用万古霉素治疗过程中,临床药师参与万古霉素谷浓度剂量方案调整、对不良反应ADR分析,做出判断和处置。结果在临床药师的多环节的干预,及时调整治疗方案,患者恢复。结论临床使用万古霉素在行TDM基础上,还需密切监测患者,在评价药物疗效时同时关注药物使用中的用药安全。

甘温除热法治疗乳腺癌化疗后并发症

乳腺癌的发病以气郁、痰凝、血瘀为因,患之日久,积聚为核,囿于乳络,终耗气伤血,应用化疗药物后,毒邪进入体内最先伤及脾胃,脾胃受损则气血生化无本,输布无源,进而影响其他脏腑生理功能,致正气虚损、气血耗伤。甘温除热法可扶正祛邪、调畅气机、补益气血、安和诸脏,病及于心可用泻火升阳汤,病及于肝可用补中益气汤,病及于肺可用升阳益胃汤,病及于肾可用神圣复气汤。临证时需把握甘温除热法对应证的病机变化,选用方除李东垣著作中所载方外,亦可选黄芪建中汤、人参养荣汤、十全大补汤、七味白术散等符合甘温除热思想之方。

1例利奈唑胺替换万古霉素致中性粒细胞缺乏发热病例的诊疗分析

目的:分析1例利奈唑胺替换万古霉素致中性粒细胞缺乏伴发热病例的诊疗过程,为临床利奈唑胺和万古霉素的用药安全提供参考。方法与结果:患者因“外伤致右膝关节疼痛伴活动受限9 d”而入院治疗,膝关节镜检查显示存在化脓性关节炎,随即经验性予以万古霉素治疗,后续关节引流液果然培养出耐甲氧西林金黄色葡萄球菌;万古霉素治疗10 d后,血液和关节引流液培养均呈阴性,但患者仍时有发热,且中性粒细胞计数呈进行性下降,低至1.29×10^(9)/L;感染科专家会诊认为,此中性粒细胞缺乏伴发热可能是由万古霉素所致,并建议可改用利奈唑胺;改用利奈唑胺的1周内,中性粒细胞计数仍持续下降,甚至已低于0.1×10^(9)/L,遂立即停用利奈唑胺,并予以重组人粒细胞集落刺激因子;3 d后中性粒细胞计数明显回升,13 d后中性粒细胞计数恢复正常且未再下降。结论:非化疗药物引起的中性粒细胞减少是一种严重的药物不良反应,而万古霉素和利奈唑胺均可以引发粒细胞缺乏,临床应做好药物不良反应监测,警惕无其他明显诱因的中性粒细胞减少,为患者安全用药保驾护航。

重组人白介素-2致间歇性药物热1例

1例61岁男性患者,因结肠息肉入院行腹腔镜下结肠部分切除术,术后给予重组人白介素-2,200万IU静脉滴注,每日一次。用药7d后出现间歇性发热,每于午后及傍晚出现,体温最高达38℃,次日清晨降至正常。综合患者临床表现,考虑与重组人白介素-2有关,建议医师停药。停药后患者体温降至正常后未再出现间歇性发热。此病例提醒广大临床医生对重组人白介素-2引起的药物热应给予足够认识。