利奈唑胺血清药物浓度监测在耐药结核病患者中的应用

利奈唑胺是一种新型的?唑烷酮类抗生素,是治疗耐药结核病的关键药物,该药治疗窗口狭窄,虽然疗效明显,但是临床应用不良反应的发生率高,如何安全有效地应用该药治疗耐药结核病一直困扰临床医生。治疗药物监测（therapeuticdrugmonitoring,TDM）通过监测患者血液中的药物浓度,可为药物剂量调整提供依据,使药物达到有效治疗浓度的同时最大程度地降低不良反应发生。目前国内外均有报道利用TDM研究利奈唑胺在耐药结核病患者中的最佳使用剂量和疗程,探讨利奈唑胺的谷浓度、峰浓度与不良反应发生率之间的关系,特别是对老年人、儿童、肝肾功能不全的患者临床安全使用利奈唑胺个体化治疗进行系列的探索研究。本文对利奈唑胺不良反应的发生机制、利奈唑胺的使用剂量及安全性、利奈唑胺药物浓度的影响因素、TDM的方式和应用等进行综述,为更加安全有效地应用利奈唑胺治疗耐药结核病提供参考。     

利奈唑胺和替考拉宁治疗住院高龄革兰阳性菌感染患者的临床应用分析

目的调查和比较利奈唑胺和替考拉宁治疗住院高龄革兰阳性球菌感染患者的疗效和安全性。方法回顾性分析2008年1月至2011年8月我科住院的高龄革兰阳性球菌感染患者的临床资料,共58例[年龄84-98岁,平均（91．2±4．0）岁],分为利奈唑胺组（30例）和替考拉宁组（28例）,设定临床疗效评价（痊愈、显效、进步、无效）和细菌学疗效评价标准（清除、假设清除、未清除,替换、再感染）,了解利奈唑胺和替考拉宁的疗效和不良反应。结果临床总有效率利奈唑胺组为93．3％,替考拉宁组为78．5％,二者无统计学差异（P=0．103）;细菌清除率利奈唑胺组为86．7％,明显高于替考拉宁组的53．6％（P〈0．05）。治疗过程中利奈唑胺组主要不良反应为血小板减少,替考拉宁组主要不良反应为血肌酐升高。结论利奈唑胺和替考拉宁在临床上治疗高龄革兰阳性球菌感染患者疗效肯定,利奈唑胺在临床疗效和细菌清除率方面优于替考拉宁。在选择用药时,要严格掌握适应证。需注意监测血小板和血肌酐的变化。     

利奈唑胺治疗广泛耐药结核病的临床疗效评价

目的评价利奈唑胺治疗广泛耐药结核病的临床疗效。方法我院收治的24例广泛耐药结核病患者,随机分为两组,对照组12人采用常规化疗,试验组12人加用利奈唑胺,比较不良反应和疗效。结果试验组试验组症状改善、病灶吸收、空洞闭合、抗酸染色涂片阴性、痰结核分枝杆菌阴性、痰定量PCR阴性例数均明显高于对照组,试验组不良反应发生率高于对照组,差异均有统计学意义（P〈0.05）,经对症治疗后均痊愈。结论利奈唑胺治疗广泛耐药结核病疗效显著。     

耐药结核病患者利奈唑胺血药浓度对血液系统毒性发生的影响

目的:分析应用利奈唑胺的耐药结核病患者的血药浓度对发生血液系统毒性的影响，并探索血液系统毒性发生的其他危险因素。方法:采用前瞻性队列研究方法，连续纳入首都医科大学附属北京胸科医院2019年1月至2021年2月应用含利奈唑胺化疗方案治疗的耐药结核病患者作为研究对象，共219例。收集研究对象的临床资料及服药后2 h的血液标本。应用高效相色谱-质谱法测定利奈唑胺的血药浓度。通过绘制受试者工作特征曲线(receiver operating characteristic curve, ROC曲线)确定血药浓度(峰浓度)对血液系统毒性的诊断价值，并确定最佳诊断临界值；采用多因素logistic回归分析研究对象发生血液系统毒性的影响因素。结果:219例研究对象中有92例(42.0%)发生了血液系统毒性反应，包括白细胞计数减少[15.5%(34/219)]、贫血[21.5%(47/219)]、血小板减少症[27.4%(60/219)]等，127例(58.0%)未发生任何相关毒性反应。发生血液系统毒性者利奈唑胺血药峰浓度为17.1(11.8,22.8)μg/ml,明显高于未发生者[14.7(10.4,1...     

含贝达喹啉及利奈唑胺方案治疗耐多药结核病视神经病变的发生及危险因素分析

目的 探索耐多药结核病患者接受以贝达喹啉及利奈唑胺为基础的治疗方案期间，视神经病变不良事件的发生情况及影响的危险因素。方法 以2018年3月至2020年3月成都市公共卫生临床医疗中心收治的耐多药结核病(multidrug-resistant tuberculosis, MDR-TB)患者为研究对象，给予贝达喹啉、利奈唑胺联合背景方案抗结核治疗，收集利奈唑胺相关视神经病变不良事件发生情况并探讨其发生的独立危险因素，采用单因素Logistic回归进行自变量的筛选，将P<0.1的变量纳入多因素Logistic回归模型进行分析，P<0.05为差异有统计学意义。结果 完成治疗的68例患者，14例(20.6%,14/68)发生视神经病变，以视物模糊、视力下降、畏光为主要表现，停用或减量利奈唑胺后好转，均考虑与利奈唑胺相关。多因素Logistic回归发现，治疗史为初治(OR=7.686,95%CI=1.152～51.265,P=0.035)、体重<50kg(OR=8.295,95%CI=1.511～45.523,P=0.015)可能是利奈唑胺相关视神经病变发生的独立危险因素。结论 ...     

结核分枝杆菌耐利奈唑胺相关基因研究进展

耐多药结核病(MDR-TB)及耐利福平结核病(RR-TB)均需采用二线抗结核药物治疗。利奈唑胺属恶唑烷酮类抗生素,是治疗MDR-TB及RR-TB的二线核心抗结核药物之一,其抗结核作用较强,但近年来结核分枝杆菌对利奈唑胺耐药现象增多且具体耐药机制尚未完全明确。本文综述了结核分枝杆菌耐利奈唑胺相关基因,旨在为结核分枝杆菌对利奈唑胺的耐药机制研究提供参考。     

口服利奈唑胺在治疗耐药结核中疗效及安全性临床观察

目的对口服利奈唑胺在治疗耐药结核病中疗效及安全性进行系统评估。方法将我院收治的45例耐多药结核病/广泛耐药结核病患者随机分为对照组(共27例)实验组(共18例),对照组给予多药联合化疗,而实验组在对照组多药联合化疗基础上加用利奈唑胺片口服,排除非医疗因素干扰中断治疗及因药物副作用不能耐受的患者,实验组加用利奈唑胺口服至少10个月,如治疗过程因不良反应出现利奈唑胺减量,则治疗时间延长到16个月。对比两组患者临床疗效及不良反应发生率。结果实验组患者临床病症改善情况、空洞闭合率以及痰菌转阴率均较对照组有明显提高,两组比较差异有统计学意义(P0.05),实验组患者药物不良反应发生率高于多药联合对照组,差异有显著性(P0.05)。结论口服利奈唑胺治疗耐药结核病临床疗效显著,配合减量及支持治疗后不良反应可控,值得临床推广。     

利奈唑胺治疗中性粒细胞减少血液病革兰阳性球菌感染76例临床分析

目的分析利奈唑胺治疗中性粒细胞减少血液病患者革兰阳性(G+)球菌感染的疗效和安全性。方法收集2008年8月至2009年5月苏州大学附属第一医院血液科收治的76例中性粒细胞减少疑诊G+球菌感染血液病患者,以利奈唑胺600 mg,每日2次抗感染治疗,从临床表现和病原学方面评价其疗效,同时观察药物不良反应。结果 76例患者总有效率为91.26%。单用利奈唑胺组有效率92.31%;混合感染初始即联合利奈唑胺组有效率92.59%;混合感染初始联合其他抗G+菌药物后换用利奈唑胺组有效率88.89%。3组病例体温控制中位时间分别为3.313、.76及6.58 d。恶性血液病不缓解、长期使用广谱抗生素及合并G-菌感染是影响利奈唑胺疗效的3个重要因素。利奈唑胺不良反应发生率为26.31%,发生肝功能轻度异常患者未予停用利奈唑胺,经保肝治疗后肝功迅速恢复,其余患者均予以停药后3 d至2周后患者。结论利奈唑胺治疗粒细胞减少血液病患者G+菌感染具有明显疗效。轻症感染或病原学检查提示明确G+菌感染病例,针对性单药利奈唑胺即可取得明显疗效。重症混合感染首选联合利奈唑胺者疗效优于利奈唑胺作为二线药物者。恶性血液病完全缓解、避免广谱抗生素长期使用和及时有效病原体检查有助于利奈唑胺发挥抗G+菌感染的疗效。利奈唑胺引发的不良反应较少。     

利奈唑胺不良反应文献分析

目的探讨利奈唑胺不良反应发生的一般规律及特点,为临床医师、临床药师合理用药提供科学依据。方法检索2000～2012年中国知网《CHKD期刊全文数据库》和《万方数据知识服务平台》内收录的50例利奈唑胺不良反应患者的文献资料并进行统计分析。结果利奈唑胺所致不良反应常在用药第1周（46.43%）、第2周（30.36%）发生;50例患者中70岁以上高龄患者占66%;不良反应多为对血液系统的影响（86%）,主要表现为血小板减少（76%）,64.10%血小板减少患者血小板低至50×109/L以下,最低值4×109/L,其他表现为全血细胞减少、贫血、粒细胞减少、白细胞减少,再次为血乳酸水平升高、血压升高等。结论临床医师、药师应重视利奈唑胺所致的严重不良反应,注意加强用药监护,确保用药安全、有效。     

利奈唑胺治疗儿童白血病化疗后重症感染12例效果观察

目的观察利奈唑胺治疗儿童白血病化疗后重症感染的临床疗效及安全性。方法对12例儿童白血病化疗后重症感染者予利奈唑胺静注,10 mg/kg,每8 h1次,疗程8～18 d。观察致病菌清除率,临床疗效及不良反应。结果致病菌清除率为100%;痊愈8例、显效3例、进步0例、无效1例,总有效率为92%;不良反应均较轻微,停药后自行恢复。结论利奈唑胺治疗儿童白血病化疗后重症感染疗效较好,且较为安全。     

The immunoneuroendocrine role of melatonin

Abstract: A tight, physiological link between the pineal gland and the immune system is emerging from a series of experimental studies. This link might reflect the evolutionary connection between self-recognition and reproduction. Pinealectomy or other experimental methods which inhibit melatonin synthesis and secretion induce a state of immunodepression which is counteracted by melatonin. In general, melatonin seems to have an immunoenhancing effect that is particularly apparent in immunodepressive states. The negative effect of acute stress or immunosuppressive pharmacological treatments on various immune parameters are counteracted by melatonin. It seems important to note that one of the main targets of melatonin is the thymus, i.e., the central organ of the immune system. The clinical use of melatonin as an immunotherapeutic agent seems promising in primary and secondary immunodeficiencies as well as in cancer immunotherapy. The immunoenhancing action of melatonin seems to be mediated by T-helper cell-derived opioid peptides as well as by lymphokines and, perhaps, by pituitary hormones. Melatonin-induced-immuno-opioids (MHO) and lymphokines imply the presence of specific binding sites or melatonin receptors on cells of the immune system. On the other hand, lymphokines such as -γ-interferon and interleukin-2 as well as thymic hormones can modulate the synthesis of melatonin in the pineal gland. The pineal gland might thus be viewed as the crux of a sophisticated immunoneuroendocrine network which functions as an unconscious, diffuse sensory organ.     

Changes in connexin43, the gap junction protein of astrocytes, during development of the rat pineal gland

Abstract: The abundance of gap junctions between rat pineal astrocytes formed by connexin43 (Cx43) was studied during development. Levels and distribution of Cx43 were measured by immunoblotting and indirect immunofluorescence, respectively. The amount of Cx43 in cells located within the gland was low until about the 7th postnatal day and increased to adult values between the 14th and 21st days postpartum. Although astrocytes, recognized by their vimentin immunoreactivity, were scarce before birth, they were abundant by the 7th postnatal day suggesting that the low levels of Cx43 found at this age corresponded to a low expression of this protein. Localization of the immunoreactivity to Cx43 and vimentin showed a close correlation, indicating that mature or immature pineal astrocytes form gap junctions made of Cx43. Since Cx43 levels attained their adult values at about the time the innervation and the functional state of the gland reached maturity (2–3 weeks after birth), it is proposed that astrocyte gap junctions are involved in the function of the adult rat pineal gland.     

Conservative management of perforated duodenal diverticulum： A case report and review of the literature

Duodenal diverticula are a relatively common condition. They are asymptomatic, unless they become complicated, with perforation being the rarest but most severe complication. Surgical treatment is the most frequently performed approach. We report the case of a patient with a perforated duodenal diverticulum, which was diagnosed early and treated conservatively with antibiotics and percutaneous drainage of secondary retroperitoneal abscesses. We suggest this method could be an acceptable option for the management of similar cases, provided that the patient is in good general condition and without septic signs.     

Response of rat pineal melatonin to calcium, magnesium, and lithium is circadian stage dependent

Abstract: Herein we documented the response of pineal melatonin production to electrolytes known to be effective on pineal function in view of a possible circadian stage dependence. We studied the release of melatonin by perifused rat pineal glands at 2 different circadian stages corresponding to the middle of the light and dark periods, i.e., respectively, 7 and 19 HALO (Hours After Light Onset, L:D = 12:12). The initial efflux rates were, as expected, much higher in the perifusates of glands removed from rats sacrificed during the dark phase than of those removed during the light phase. After 3 hr of perifusion, melatonin release reached similar levels which were found constant up to the 8th hr of perifusion, whatever the circadian stage. Perifusion of the glands with physiological concentrations for the rat of calcium (5.2 mmol/1) and magnesium (1.34 mmol/1) resulted in a stimulatory effect on the pineal glands removed from rats sacrificed in the middle of the dark period (19 HALO), whereas no effects were observed on the pineal glands removed from rats sacrificed during the light (7 HALO). Lithium (0.28 and 0.55 mmol/1) was ineffective on melatonin release in pineal glands removed 7 and 19 HALO. Our results show differences in the initial efflux rates of melatonin and in the response of perifused pineal glands to calcium and magnesium according to the circadian stage.     

Presence of immunoreactive growth hormone and prolactin in the ovine pineal gland

Abstract: The use of antisera raised against bovine growth hormone (GH) and ovine prolactin (PRL) enabled the detection of related immunoreactive (ir) sequences of proteins in ovine pineal tissue. The isolation of PRL-like ir-material was accomplished using a 0.25 M ammonium sulphate (pH 5.5) extraction followed by ethanol precipitation, whereas the resulting 2.0 M ammonium sulphate (pH 7.0) precipitate contained a GH-like immunoreactivity. Gel chromatography of the GH-like immunoreactivity (Sephadex G-100) indicated the presence of several GH-like fragments ranging in the M_r range of 7,000 to 55,000. Analyses of the PRL-like ir-material found in pineal tissue on HPLC using a TSK 545-DEAE column led to the resolution into a single peak of immunoreactivity. A single peak of activity was also observed following chromatofocusing and hydrophobic interaction chromatography of the ir-peak from the TSK 545-DEAE column. The PRL-like ir-material inhibited the binding of [¹²⁵I]ovine PRL-S14 to anti-ovine PRL antibodies without showing an affinity for binding to anti-rat PRL or anti-bovine GH antibodies. Scatchard analysis of the binding of pineal PRL-like ir-material and pituitary ovine PRL-S14 to liver membranes from day-20 pregnant rats revealed similar affinity constants (K_a of 4.7 ± 0.2 × 10⁹ M^-1). In addition, the replication of Nb 2 Node rat lymphoma cells was stimulated by pineal PRL-like ir-material, an effect known to be specific for lactogenic hormones. The pineal PRL-like immunoreactivity appeared on sodium dodecyl sulfate polyacrylamide gels as a single major band of M_r 24,000. The functional status of PRL-and GH-like ir-material in the ovine pineal remains to be determined, but evidence is presented that the overall protein synthesis rate of the rat pineal responded to circulating concentrations of PRL.     

Microbiology of human immunodeficiency virus anorectal disease

PURPOSE: Individuals who are seropositive for the human immunodeficiency virus are at high risk for opportunistic infection and anorectal disorders. Little prospective information is available regarding anorectal pathogens in these patients. METHODS: One hundred sixty-three HIV-seropositive patients presented to the colorectal clinic between 1989 and 1992. Forty-seven (29 percent) patients were thought to have an infectious process and were prospectively studied using a standardized multiculture protocol. RESULTS: Mean age was 33 (range, 19–59) years. All were male; high-risk behavior accounted for 87 percent of HIV transmissions. Presenting complaints included anorectal pain (79 percent), pus per anum (28 percent), and blood per anum (26 percent). Examination revealed perianal tenderness (60 percent), condyloma (38 percent), perianal ulcers (38 percent), and anal fissures (34 percent). Sixty-six sets of cultures were performed; 28 patients had one set, 15 had two sets, and 4 had three sets. Thirty-two of these 47 patients (68 percent) had positive cultures including herpes (50 percent), cytomegalovirus (25 percent),Neisseria gonorrhoeae (16 percent), chlamydia (16 percent), acidfast bacilli (2 percent), and others (9 percent). Six of 32 patients with positive cultures had more than one organism cultured. Sixteen (50 percent) patients with positive cultures were treated medically, 8 (25 percent) were treated surgically and 8 (25 percent) were treated with both modalities. Sixty-one procedures were performed on 17 patients for condylomata. Eighteen patients had 20 procedures for abscesses, 50 percent of whom had positive cultures for other than common bowel flora; all improved. Fourteen patients underwent 33 procedures for perianal fistulas.Mycobacterium fortuitum was cultured from one patient who required 13 procedures for abscesses and fistulas. Forty-five (96 percent) patients were followed for an average of 12.5 months ±2.9 SEM (range, 1–94 months). Symptoms were improved or resolved in 22 of 32 (69 percent) patients with positive cultures and in 11 of 13 (84 percent) with negative cultures. CONCLUSIONS: Specific pathogens may often be identified in human immunodeficiency virus-seropositive patients with anorectal disorders if aggressively sought. Although patients without specific pathogens identified may be expected to improve with planned empiric treatment, positive identification allows more directed therapy.