华法林个体化用药影响因素的研究进展

华法林等维生素K拮抗剂是目前临床上应用最广泛的抗凝药物,主要用于预防心脏瓣膜置换、心房颤动等疾病血栓事件的发生.但影响其临床疗效的因素较多,不同个体的华法林有效剂量差异较大.随着对华法林的药物基因组学的深入研究,华法林个体化用药逐渐成为可能,但目前基因指导华法林用药的有效性仍存在争议.本文拟对影响华法林剂量的非遗传因素...     

载脂蛋白E基因多态性对华法林抗凝疗效的影响

遗传因素是华法林存在个体差异的最重要因素,与药代动力学、药效学及药物转运相关的基因都能够影响华法林的抗凝治疗.近年研究发现,载脂蛋白E(ApoE)基因多态性与华法林个体剂量差异相关.本文就ApoE基因多态性对华法林稳定剂量的影响以及华法林个体化给药方案的研究进展作一综述.     

氟伐他汀对华法林使用剂量的影响

目的 探讨氟伐他汀对使用华法林患者的影响.方法 通过临床使用华法林抗凝合用氟伐他汀与使用华法林抗凝合用阿托伐他汀两例患者国际标准化比值(INR)的比较,分析氟伐他汀对华法林的影响.结果 使用华法林抗凝的患者合用氟伐他汀后的患者INR值比合用阿托伐他汀的患者INR值高.结论氟伐他汀增加了华法林的抗凝效果.     

基因多态性对华法林低强度抗凝治疗稳定剂量影响的前瞻陛研究

目的 对影响华法林代谢及作用的多个相关基因进行测定,探讨其对中国人群低强度华法林抗凝稳定剂量的影响程度.方法 共纳入170名拟采取低强度华法林抗凝治疗患者,对其与华法林代谢及作用相关的3个基因CYP2C9（rs1057910）、VKORC1（rs9923231）、CYP4F2 （rs2108622）位点的基因多态性（SNP）进行检测,随后给予华法林治疗,目标国际标准化比值（INR）1.8-2.5,观察90天,同时记录患者的临床因素、INR值及华法林稳定剂量,分别判断临床及基因因素对华法林稳定剂量水平的影响作用.结果 CYP2C9、VKORC1、CYP4F2的5个SNP位点的SNP对华法林稳定剂量存在显著影响（P＜0.05）.经多元回归分析,年龄、体表面积、抗凝第4天INR值以及CYP2C9、VKORC1、CYP4F2 的SNP是华法林抗凝稳定剂量的独立影响因素;其中SNP可以独立解释18.6%的华法林稳定剂量的差异.结论 在目标强度为INR1.8-2.5的低强度华法林抗凝治疗中,CYP2C9（rs1057910）、VKORC1（rs9923231）、CYP4F2 （rs2108622）多态性对稳定剂量存在显著影响,可在临床工作中对上述3个SNP位点进行检测,对抗凝初期华法林的剂量进行预先调整.     

2010年第5期中文目录

华法林作为最常用的口服抗凝药物,广泛应用于慢性心房颤动、静脉血栓、肺栓塞,及心脏瓣膜置换术后等的抗凝治疗中。然而,由于华法林有效治疗剂量的范围狭窄和在个体间差异显著,加之剂量过高会导致严重出血的危险,华法林在临床上的应用受到了极大地限制。如何安全有效地应用华法林,使之达到最佳治疗效果,一直是心血管领域研究的热点和亟待解决的难题。近年来,对华法林的药物基因组学研究发现,决定华法林代谢和作用的两个主要候选基因CYP2C9和VKORC1的遗传变异型,很大程度上决定了华法林有效抗凝治疗剂量的个体间差异。本文总结了CYP2C9和VKORC1的基因变异型对华法林剂量的影响,还对近年来通过结合基因和临床因素建立的华法林剂量计算模型对预测有效华法林剂量和副作用的意义进行了综述。     

华法林抗凝治疗剂量的药物基因组学研究——理论和应用前景

华法林作为最常用的口服抗凝药物,广泛应用于慢性心房颤动、静脉血栓、肺栓塞,及心脏瓣膜置换术后等的抗凝治疗中。然而,由于华法林有效治疗剂量的范围狭窄和在个体间差异显著,加之剂量过高会导致严重出血的危险,华法林在临床上的应用受到了极大地限制。如何安全有效地应用华法林,使之达到最佳治疗效果,一直是心血管领域研究的热点和亟待解决的难题。近年来,对华法林的药物基因组学研究发现,决定华法林代谢和作用的两个主要候选基因CYP2C9和VKORC1的遗传变异型,很大程度上决定了华法林有效抗凝治疗剂量的个体间差异。本文总结了CYP2C9和VKORC1的基因变异型对华法林剂量的影响,还对近年来通过结合基因和临床因素建立的华法林剂量计算模型对预测有效华法林剂量和副作用的意义进行了综述。     

华法林出血并发症相关药物基因组学研究进展

华法林作为一线口服抗凝药广泛应用于血栓栓塞性疾病的预防与治疗中,但如何安全有效地应用华法林并达到最佳抗凝效果,一直是临床上亟待解决的难题。近年对华法林药物基因组学的研究表明,华法林代谢和作用相关基因(CYP2C9、VKORC1、CYP4F2)的变异很大程度上影响华法林的治疗剂量,还可能与华法林的出血并发症密切相关。本文对上述基因变异与华法林的过度抗凝及出血的相关研究作一综述,以期为临床华法林的个体化抗凝治疗提供参考依据。     

华法林必须用、必须会用（三）

在应用华法林进行抗凝治疗时，还要注意到有很多因素会影响华法林的抗凝强度。这种影响包括两方面，或者增强华法林的抗凝作用，或者抑制华法林的抗凝作用，前者使得出血风险增加，后者使得血栓不能避免。本文讲讲具体有哪些影响因素。     

142例心房颤动住院患者华法林使用情况的回顾性分析

目的回顾分析心房颤动住院患者华法林抗凝情况,初步探讨基层医院心房颤动患者的华法林治疗现状。方法选择2006年—2007年住院的心房颤动患者142例,全面收集患者血栓栓塞的高危因素、抗凝禁忌症,华法林的用法、用量,以及未用华法林的原因等。结果房颤患者总体接受抗栓治疗（华法林或阿司匹林）者85.28%,其中华法林治疗61.97%,〈65岁组华法林治疗66.19%,65岁～75岁组华法林治疗71.69%,〈75岁组华法林治疗仅16.67%;高危组华法林治疗71.3%,中危组华法林治疗46.7%,低危组华法林治疗为零。结论住院以房颤动患者总体接受华法林抗凝治疗的情况较好,但〉75岁高、中危的老年房颤患者抗凝治疗不足,加强医生对华法林抗凝的认识以及采用更方便安全有效的抗凝新药可能会进一步提高老年患者的抗凝治疗。     

影响华法林抗凝作用(INR值)的影响因素?

<正>答:华法林是双香豆素衍生物,通过干扰维生素K的环化与2,3环氧化物生成,进而抑制维生素K依赖的凝血因子Ⅱ、Ⅶ、Ⅸ、Ⅹ因子的产生而发挥抗凝作用。华法林的抗凝效应受细胞色素P450基因位点突变和肝酶对华法林代谢的活性在内的遗传因素和环境因素的影响,以及各种药物相互作     

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.     

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.     

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.     

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.