Colchicine

秋水仙碱
  • 文章类型: Journal Article
    急性冠脉综合征(ACS)是全球心血管死亡的重要原因。ACS可能起因于动脉粥样硬化斑块的破坏,最终导致急性缺血和心肌梗死。在动脉粥样硬化的发病机制中,炎症起着关键作用,不仅仅是动脉粥样硬化斑块形成的开始和并发症,而且在心肌对缺血性损伤的反应中。急性炎症过程,再加上再灌注的时间,协调缺血和再灌注损伤,指示梗死程度和急性左心室(LV)重塑。相反,慢性炎症,除了神经体液激活,支配持续性左心室重塑。慢性LV重塑和复发性缺血发作之间的相互作用描绘了疾病向心力衰竭和心血管死亡的进展。秋水仙碱通过调节单核细胞/巨噬细胞的活性发挥影响心肌和动脉粥样硬化斑块的抗炎特性,中性粒细胞,和血小板。这种调节可能会导致更有利的LV重塑并阻止ACS的复发。这篇叙述性综述旨在描述炎症在ACS病理生理学不同阶段的作用,并描述秋水仙碱的机制基础。探索其在调节每个阶段中的所谓作用。
    Acute Coronary Syndrome (ACS) significantly contributes to cardiovascular death worldwide. ACS may arise from the disruption of an atherosclerotic plaque, ultimately leading to acute ischemia and myocardial infarction. In the pathogenesis of atherosclerosis, inflammation assumes a pivotal role, not solely in the initiation and complications of atherosclerotic plaque formation, but also in the myocardial response to ischemic insult. Acute inflammatory processes, coupled with time to reperfusion, orchestrate ischemic and reperfusion injuries, dictating infarct magnitude and acute left ventricular (LV) remodeling. Conversely, chronic inflammation, alongside neurohumoral activation, governs persistent LV remodeling. The interplay between chronic LV remodeling and recurrent ischemic episodes delineates the progression of the disease toward heart failure and cardiovascular death. Colchicine exerts anti-inflammatory properties affecting both the myocardium and atherosclerotic plaque by modulating the activity of monocyte/macrophages, neutrophils, and platelets. This modulation can potentially result in a more favorable LV remodeling and forestalls the recurrence of ACS. This narrative review aims to delineate the role of inflammation across the different phases of ACS pathophysiology and describe the mechanistic underpinnings of colchicine, exploring its purported role in modulating each of these stages.
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  • 文章类型: Journal Article
    水杨酸(SA)是一种重要的植物调节剂,广泛用于促进植物中高价值营养品的合成。然而,它在黄花菜中的应用,一种在中药中很有价值的观赏植物,尚未报告。在这里,我们研究了外源性SA诱导的生理,长黄花菜(LYD)的转录和生化变化。我们发现2mg/L叶面SA处理显着提高了LYD植物的生长和产量。转录组测序和差异表达基因(DEGs)分析显示,苯丙烷生物合成,异喹啉生物碱生物合成,硫代谢,在SA处理的叶片中显着诱导了植物激素信号转导和酪氨酸代谢。在SA处理下诱导了许多转录因子和抗氧化系统相关的DEGs。生化分析表明,叶片中可溶性糖的含量,可溶性蛋白(Cpr),抗坏血酸(AsA)和秋水仙碱显着增加了15.15%(从30.16±1.301到34.73±0.861mg/g),19.54%(从60.3±2.227到72.08±1.617mg/g),30.45%(从190.1±4.56到247.98±11.652μg/g)和73.05%(从3.08±0.157到5.33±0.462μg/g),分别,在SA治疗下。此外,我们确定了15个潜在的候选基因来促进生长,LYD的产量和植物化学含量。我们的结果为秋水仙碱在黄色黄花菜中的生物积累提供了支持,也为在Hemerocallisspp中生物技术辅助生产这种重要的营养食品提供了宝贵的资源。
    Salicylic acid (SA) is an essential phytoregulator that is widely used to promote the synthesis of high-value nutraceuticals in plants. However, its application in daylily, an ornamental plant highly valued in traditional Chinese medicine, has not been reported. Herein, we investigated the exogenous SA-induced physiological, transcriptional and biochemical changes in long yellow daylily (LYD). We found that 2 mg/L foliar SA treatment significantly improved LYD plant growth and yield. Transcriptome sequencing and differentially expressed genes (DEGs) analysis revealed that the phenylpropanoid biosynthesis, isoquinoline alkaloid biosynthesis, sulfur metabolism, plant hormone signal transduction and tyrosine metabolism were significantly induced in SA-treated leaves. Many transcription factors and antioxidant system-related DEGs were induced under the SA treatment. Biochemical analyses showed that the leaf contents of soluble sugar, soluble protein (Cpr), ascorbic acid (AsA) and colchicine were significantly increased by 15.15% (from 30.16 ± 1.301 to 34.73 ± 0.861 mg/g), 19.54% (from 60.3 ± 2.227 to 72.08 ± 1.617 mg/g), 30.45% (from 190.1 ± 4.56 to 247.98 ± 11.652 μg/g) and 73.05% (from 3.08 ± 0.157 to 5.33 ± 0.462 μg/g), respectively, under the SA treatment. Furthermore, we identified 15 potential candidate genes for enhancing the growth, production and phytochemical content of LYD. Our results provide support for the bioaccumulation of colchicine in yellow daylily and valuable resources for biotechnological-assisted production of this important nutraceutical in Hemerocallis spp.
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  • 文章类型: Case Reports
    口腔溃疡是全科医生在其办公室看到的最常见的投诉之一。复发性口疮性口炎影响大约20%的普通人群。当溃疡尽管常规治疗仍持续存在时,考虑诸如Behçet病之类的全身性疾病以防止护理延误至关重要。早期识别和适当管理潜在疾病对于改善患者预后和生活质量至关重要。我们介绍了一例41岁的苏格兰男性,他抱怨复发性口腔溃疡和鹅口疮。传染病专家的初步治疗解决了鹅口疮,但没有解决溃疡。尽管有三年的进一步治疗尝试,包括活检和抗病毒治疗,溃疡持续存在。最后,风湿病的转诊导致了全面的自身免疫测试,显示HLAB51阳性和Behçet病的诊断。用局部类固醇和秋水仙碱治疗产生显著改善。
    Oral ulcers are one of the most common complaints seen by general practitioners in their offices. Recurrent aphthous stomatitis affects roughly 20% of the general population. When ulcers persist despite conventional treatment, it is crucial to consider systemic diseases such as Behçet\'s disease to prevent delays in care. Early recognition and appropriate management of underlying conditions are essential for improving patient outcomes and quality of life. We present a case of a 41-year-old Scottish male who came in with complaints of recurrent oral ulcers and oral thrush. Initial treatment by an infectious disease specialist resolved the oral thrush but not the ulcers. Despite further treatment attempts for three years, including biopsy and antiviral therapy, ulcers persisted. Finally, referral to rheumatology led to comprehensive autoimmune testing, revealing positive HLA B51 and a diagnosis of Behçet\'s disease. Treatment with topical steroids and colchicine yielded significant improvement.
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  • 文章类型: Journal Article
    背景:许多研究强调了炎症在动脉粥样硬化所有阶段的重要作用。虽然已经实施了各种抗炎干预措施以减轻炎症引起的损伤,结果是相互矛盾的。鉴于炎症在这些患者中的重要作用以及关于低剂量秋水仙碱作为抗炎药的疗效的数据有限,我们旨在研究低剂量秋水仙碱对伊朗STEMI患者临床结局的疗效.
    结果:2022年和2023年在库姆ShahidBeheshti医院接受STEMI和合格血运重建的参与者被纳入研究。这项研究包括172名STEMI患者(114名男性和58名女性),平均年龄为58.93±7.79。结果表明,秋水仙碱(负荷剂量为2mg,每天0.5mg,持续30天)和安慰剂组在相同的年龄和性别方面没有显着差异。分析显示,在40天的随访期后,临床结果没有显着差异。
    结论:这项研究表明,秋水仙碱的添加在提高STEMI患者的预后方面没有显著的益处。
    背景:这项研究在伊朗临床试验注册登记,与注册号(IRCT20231001059578N1)。
    BACKGROUND: Numerous studies have underscored the essential role of inflammation across all stages of atherosclerosis. While various anti-inflammatory interventions have been implemented to mitigate inflammation-induced injuries, outcomes have been conflicting. Given the essential role of inflammation in these patients and limited data regarding the efficacy of low-dose Colchicine as an anti-inflammatory drug, we aimed to study the efficacy of low-dose Colchicine on clinical outcomes of patients with STEMI in Iran.
    RESULTS: Participants presented with STEMI and qualified revascularization at Shahid Beheshti Hospital in Qom during 2022 and 2023 were included into the study. This study included 172 STEMI patients (114 males and 58 females) within the mean age of 58.93 ± 7.79. Results indicate that colchicine (2 mg for loading dose and 0.5 mg daily for 30 days) and placebo group were not significant differences in identical profiles regarding age and gender. Analyses revealed no significant differences in clinical outcome after the 40-day follow-up period.
    CONCLUSIONS: This study revealed that the addition of colchicine did not yield a significant benefit in enhancing the outcomes of patients with STEMI.
    BACKGROUND: This study was prospectively registered on Iranian registry of clinical trials, with registration number (IRCT20231001059578N1).
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  • 文章类型: Journal Article
    目的:评估秋水仙碱与安慰剂在降低症状发作前3个月内高风险非心源性缺血性卒中或短暂性脑缺血发作后后续卒中风险的有效性和安全性(CHANCE-3)。
    方法:多中心,双盲,随机化,安慰剂对照试验。
    方法:2022年8月11日至2023年4月13日期间,中国有244家医院。
    方法:8343例年龄在40岁或以上的轻度至中度缺血性卒中或短暂性脑缺血发作且高敏C反应蛋白≥2mg/L的患者被纳入研究。
    方法:患者在症状发作24小时内按1:1随机分配接受秋水仙碱(0.5mg,每天两次,第1-3天,然后每天0.5mg)或安慰剂90天。
    方法:主要疗效结果是随机分组后90天内的任何新卒中。主要安全性结果是治疗期间的任何严重不良事件。所有疗效和安全性分析均按治疗意向进行。
    结果:4176例患者被分配到秋水仙碱组,4167例被分配到安慰剂组。秋水仙碱组264例患者(6.3%)和安慰剂组270例患者(6.5%)在90天内发生卒中(风险比0.98(95%置信区间0.83~1.16);P=0.79)。秋水仙碱组91例(2.2%)患者和安慰剂组88例(2.1%)患者出现严重不良事件(P=0.83)。
    结论:该研究没有提供证据表明,与安慰剂相比,低剂量秋水仙碱可以降低急性非心源性轻度至中度缺血性中风或短暂性脑缺血发作且高敏C反应蛋白≥2mg/L的患者在90天内发生卒中的风险。
    背景:ClinicalTrials.gov,NCT05439356.
    To assess the efficacy and safety of colchicine versus placebo on reducing the risk of subsequent stroke after high risk non-cardioembolic ischaemic stroke or transient ischaemic attack within the first three months of symptom onset (CHANCE-3).
    Multicentre, double blind, randomised, placebo controlled trial.
    244 hospitals in China between 11 August 2022 and 13 April 2023.
    8343 patients aged 40 years of age or older with a minor-to-moderate ischaemic stroke or transient ischaemic attack and a high sensitivity C-reactive protein ≥2 mg/L were enrolled.
    Patients were randomly assigned 1:1 within 24 h of symptom onset to receive colchicine (0.5 mg twice daily on days 1-3, followed by 0.5 mg daily thereafter) or placebo for 90 days.
    The primary efficacy outcome was any new stroke within 90 days after randomisation. The primary safety outcome was any serious adverse event during the treatment period. All efficacy and safety analyses were by intention to treat.
    4176 patients were assigned to the colchicine group and 4167 were assigned to the placebo group. Stroke occurred within 90 days in 264 patients (6.3%) in the colchicine group and 270 patients (6.5%) in the placebo group (hazard ratio 0.98 (95% confidence interval 0.83 to 1.16); P=0.79). Any serious adverse event was observed in 91 (2.2%) patients in the colchicine group and 88 (2.1%) in the placebo group (P=0.83).
    The study did not provide evidence that low-dose colchicine could reduce the risk of subsequent stroke within 90 days as compared with placebo among patients with acute non-cardioembolic minor-to-moderate ischaemic stroke or transient ischaemic attack and a high sensitivity C-reactive protein ≥2 mg/L.
    ClinicalTrials.gov, NCT05439356.
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  • 文章类型: Journal Article
    2型糖尿病(T2DM),一种普遍的慢性代谢紊乱,与持续的低度炎症密切相关,为其发展和进步做出了重要贡献。本文综述了T2DM的炎症机制。重点关注NLRP3炎性体和白细胞介素-1β(IL-1β)在介导炎症反应中的作用。我们讨论了IL-1抑制剂和秋水仙碱的治疗潜力,强调了它们抑制NLRP3炎性体和减少IL-1β产生的机制。最近的研究表明,这些药物可以有效缓解炎症,为T2DM的预防和管理提供了有希望的途径。通过探索代谢紊乱和慢性炎症之间的复杂联系,这篇综述强调需要新的抗炎策略来解决T2DM及其并发症.
    Type 2 diabetes mellitus (T2DM), a prevalent chronic metabolic disorder, is closely linked to persistent low-grade inflammation, significantly contributing to its development and progression. This review provides a comprehensive examination of the inflammatory mechanisms underlying T2DM, focusing on the role of the NLRP3 inflammasome and interleukin-1β (IL-1β) in mediating inflammatory responses. We discuss the therapeutic potential of IL-1 inhibitors and colchicine, highlighting their mechanisms in inhibiting the NLRP3 inflammasome and reducing IL-1β production. Recent studies indicate that these agents could effectively mitigate inflammation, offering promising avenues for the prevention and management of T2DM. By exploring the intricate connections between metabolic disturbances and chronic inflammation, this review underscores the need for novel anti-inflammatory strategies to address T2DM and its complications.
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  • 文章类型: Journal Article
    我们评估了秋水仙碱和低剂量纳曲酮(LDN)的疗效和安全性,单独和组合,在预防发展为严重急性呼吸道综合征冠状病毒2(SARS-CoV-2)感染。在这个前景中,随机化,开放标签试用,在不需要高水平通气支持的SARS-CoV-2住院患者中,将秋水仙碱和LDN与标准治疗(SOC)进行了比较。患者被随机分配到单独的秋水仙碱,仅LDN,秋水仙碱/LDN组合,或SOC。主要结果是疾病恢复时间。次要结果包括住院总时间,研究招生,护理水平,氧气支持,和不良事件。137名患者被随机分组(Nc=34,Nc+ldn=33,Nldn=35,Nsoc=35)。84名患者(61%)在第5天实现疾病恢复。在接受秋水仙碱治疗的患者中,经历主要疗效结局的患者比例没有显着差异,LDN,或者在四个学习臂之间。接受秋水仙碱的患者的入组时间较短,但住院时间没有显着减少。腹泻是最常见的不良反应。在SARS-CoV-2住院的成年人中,不需要高水平的通气支持,秋水仙碱和LDN,单独和组合,与严重疾病进展的显著减少无关。
    We assessed the efficacy and safety of colchicine and low-dose naltrexone (LDN), alone and in combination, in preventing progression to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In this prospective, randomized, open-label trial, colchicine and LDN were compared to standard of care (SOC) in patients hospitalized with SARS-CoV-2 not requiring high levels of ventilatory support. Patients were randomly assigned to colchicine alone, LDN alone, colchicine/LDN in combination, or SOC. The primary outcome was time to disease recovery. Secondary outcomes included total time hospitalized, study enrollment, level of care, oxygen support, and adverse events.  One-hundred and thirty-seven patients were randomized (Nc = 34, Nc+ldn = 33, Nldn = 35, Nsoc = 35). Eighty-four patients (61%) achieved disease recovery by day 5. There was no significant difference in the proportion of patients who experienced the primary efficacy outcome among those who received colchicine, LDN, or between the four study arms.Patients receiving colchicine had a shorter length of enrollment but not a significant reduction in the length of stay. Diarrhea was the most common adverse reaction. In adults hospitalized with SARS-CoV-2 not requiring high-level ventilatory support, colchicine and LDN, alone and in combination, were not associated with significant reductions in progression to severe disease.
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  • 文章类型: Clinical Trial Protocol
    背景:对于长期COVID,目前尚无有效的药物治疗,其特点是范围广,多系统,波动,或在大部分急性COVID幸存者中出现复发症状。这项随机对照试验旨在评估抗炎药秋水仙碱的安全性和有效性。以减轻那些有长期COVID风险的人的症状。
    方法:这种多中心,平行臂,1:1个随机个体,安慰剂对照,双盲优势试验将招募350名患有持续性COVID后症状的个体。参与者将被随机分配给秋水仙碱0.5mg,每天一次(<70kg)或每天两次(≥70kg)或匹配的安慰剂,持续26周,并将在随机分组后随访至52周。主要试验目标是证明秋水仙碱优于安慰剂在从基线开始52周时6分钟内改善步行距离。次要目标是评估秋水仙碱与安慰剂相比在肺功能方面的疗效。炎症标志物,宪法症状,和心理健康状况。在100名参与者的子样本中,将使用MRI比较心肌损伤和心肌水肿的心脏生物标志物。
    结论:SARS-CoV-19后持续的炎症反应是长期COVID的假定病理生理机制之一。秋水仙碱,一种低成本的抗炎药,通过多种炎症途径起作用,并具有既定的安全性。该试验将为重要的健康优先事项提供证据,可以迅速转化为实践。
    背景:该临床试验已在www上进行了前瞻性注册。
    结果:gov,注册CTRI/2021/11/038234,日期为2021年11月24日。
    BACKGROUND: There is no known effective pharmacological therapy for long COVID, which is characterized by wide-ranging, multisystemic, fluctuating, or relapsing symptoms in a large proportion of survivors of acute COVID. This randomized controlled trial aims to assess the safety and efficacy of an anti-inflammatory agent colchicine, to reduce symptoms among those at high risk of developing long COVID.
    METHODS: This multi-centre, parallel arm, 1:1 individual randomized, placebo-controlled, double-blind superiority trial will enrol 350 individuals with persistent post-COVID symptoms. Participants will be randomized to either colchicine 0.5 mg once daily (< 70 kg) or twice daily (≥ 70 kg) or matched placebo for 26 weeks and will be followed up until 52 weeks after randomization. The primary trial objective is to demonstrate the superiority of colchicine over a placebo in improving distance walked in 6 min at 52 weeks from baseline. The secondary objectives are to assess the efficacy of colchicine compared to placebo with respect to lung function, inflammatory markers, constitutional symptoms, and mental health state. In a sub-sample of 100 participants, cardiac biomarkers of myocardial injury and myocardial oedema using MRI will be compared.
    CONCLUSIONS: Persistent inflammatory response following SARS-CoV-19 is one of the postulated pathophysiological mechanisms of long COVID. Colchicine, a low-cost anti-inflammatory agent, acts via multiple inflammatory pathways and has an established safety profile. This trial will generate evidence for an important health priority that can rapidly translate into practice.
    BACKGROUND: This clinical trial has been registered prospectively on www.
    RESULTS: gov with registration CTRI/2021/11/038234 dated November 24, 2021.
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  • 文章类型: Journal Article
    在接受经皮冠状动脉介入治疗(PCI)的患者中,使用秋水仙碱抗炎治疗可减少复发性缺血事件.这些发现的机制尚未完全阐明。
    探讨秋水仙碱与阿司匹林对急性冠脉综合征(ACS)患者PCI术后炎症和血小板反应性的影响。
    这项观察性研究比较了接受替格瑞洛或普拉格雷加秋水仙碱(MACT)单一抗血小板治疗(n=185)与阿司匹林加替格瑞洛或普拉格雷(n=497)的常规双联抗血小板治疗(DAPT)的ACS患者的实验室测量结果。主要结果是高残留炎症的频率,定义为PCI术后1个月高敏C反应蛋白(hs-CRP)≥2mg/L。对主要结局进行了多重敏感性分析,包括多变量调整,倾向得分匹配,和逆概率加权方法。
    PCI后一个月,与接受DAPT治疗的患者相比,接受MACT治疗的患者的hs-CRP水平显着降低(0.6[0.4-1.2]vs.0.9[0.6-2.3]mg/L,p<0.001)。在MACT组中,高残留炎症的频率也较低(10.8%vs.27.2%,p<0.001)(比值比[95%置信区间]=0.33[0.20-0.54],p<0.001)。这种影响在敏感性分析中是一致的。MACT和DAPT之间的血小板反应性没有差异(49.6±49.0vs.通过VerifyNow测量51.5±66.4P2Y12反应单元[PRU],p=0.776)。
    在接受PCI的ACS患者中,与常规DAPT相比,MACT与较低的高残留炎症发生率相关,而不会增加血小板反应性。
    用于MACT试点试验的NCT049516和用于庆尚国立大学医院注册的NCT04650529。
    UNASSIGNED: In patients undergoing percutaneous coronary intervention (PCI), the use of anti-inflammatory therapy with colchicine is associated with a reduction of recurrent ischemic events. The mechanisms of such findings are not fully elucidated.
    UNASSIGNED: To investigate the effects of colchicine versus aspirin on inflammation and platelet reactivity in patients with acute coronary syndrome (ACS) undergoing PCI.
    UNASSIGNED: This observational study compared laboratory measurements in ACS patients receiving single antiplatelet therapy with ticagrelor or prasugrel plus colchicine (MACT) (n = 185) versus conventional dual-antiplatelet therapy (DAPT) with aspirin plus ticagrelor or prasugrel (n = 497). The primary outcome was the frequency of high residual inflammation, defined as high-sensitivity C-reactive protein (hs-CRP) ≥2 mg/L at 1 month post-PCI. Multiple sensitivity analyses were performed for the primary outcome, including multivariable adjustment, propensity-score matching, and inverse-probability weighted methods.
    UNASSIGNED: One month after PCI, patients treated with MACT had significantly lower levels of hs-CRP compared to those treated with DAPT (0.6 [0.4-1.2] vs. 0.9 [0.6-2.3] mg/L, p < 0.001). The frequency of high residual inflammation was also lower in the MACT group (10.8% vs. 27.2%, p < 0.001) (odds ratio [95% confidence interval] = 0.33 [0.20-0.54], p < 0.001). This effect was consistent across sensitivity analyses. There was no difference in platelet reactivity between MACT and DAPT (49.6 ± 49.0 vs. 51.5 ± 66.4 P2Y12 reaction unit [PRU] measured by VerifyNow, p = 0.776).
    UNASSIGNED: In ACS patients undergoing PCI, MACT was associated with a lower rate of high residual inflammation without increasing platelet reactivity compared to conventional DAPT.
    UNASSIGNED: NCT04949516 for MACT pilot trial and NCT04650529 for Gyeongsang National University Hospital registry.
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  • 文章类型: Journal Article
    背景:先前在保加利亚进行的研究表明,随着来自该国两家医院的秋水仙碱剂量的增加,COVID-19的死亡率降低了五倍。我们在这里报告了另外333例COVID-19住院患者,用不同剂量的秋水仙碱治疗及其对死亡率的影响。
    方法:在增加剂量的秋水仙碱和添加溴己新治疗标准(SOC)与当前SOC之间进行了另外两家医院的病例对照比较。风险和赔率比,以及亚组分析,是用新报告的数据进行的,以及所有医院中心的汇总数据,以确定COVID-19住院患者死亡率降低的程度。
    结果:秋水仙碱剂量增加后,住院患者的死亡率明显下降-在2倍至7倍之间。4mg的秋水仙碱负荷剂量比2mg的秋水仙碱负荷剂量更有效。尽管这些剂量高于所谓的“标准剂量”,“秋水仙碱住院患者的死亡率低于SOC患者(5.7%vs.19.53%)。这种死亡率益处在不同年龄的亚组中很明显,4-mg负荷剂量的秋水仙碱被证明略优于2-mg负荷剂量。秋水仙碱导致总体相对风险降低70.7%,SOC患者的死亡几率更高3.91。剂量的安全性与产品特性摘要中报告的没有差异。
    结论:在SOC中添加秋水仙碱和溴己新的保加利亚住院患者比单独使用SOC的患者获得了更好的临床和死亡率结果。这些结果质疑世界卫生组织推荐的抑制病毒复制的策略。我们认为,我们的治疗策略是通过吸入溴己新和高剂量秋水仙碱的超活化NLRP3炎性体来抑制严重急性呼吸综合征冠状病毒2进入细胞,防止细胞因子风暴的发展。开始治疗的时机似乎很关键。
    BACKGROUND: Previous research done in Bulgaria demonstrated a fivefold reduction in mortality from COVID-19 with increased doses of colchicine from two hospitals in the country. We report here a further 333 cases of COVID-19 inpatients, treated with different doses of colchicine and its effect on mortality.
    METHODS: A case-control comparison from two additional hospitals was conducted between increased doses of colchicine and added bromhexine to standard of care (SOC) versus current SOC. Risk and odds ratio, as well as subgroup analysis, was conducted with newly reported data, alongside aggregate data from all hospital centers to determine the extent of mortality reduction in COVID-19 inpatients.
    RESULTS: There was a clear reduction in the mortality of inpatients with increasing doses of colchicine-between twofold and sevenfold. Colchicine loading doses of 4 mg are more effective than those with 2 mg. Despite these doses being higher than the so-called \"standard doses,\" colchicine inpatients experienced lower mortality than SOC patients (5.7% vs. 19.53%). This mortality benefit was evident in different age subgroups, with a 4-mg loading dose of colchicine proving slightly superior to a 2-mg loading dose. Colchicine led to an overall relative risk reduction of 70.7%, with SOC patients having 3.91 higher odds of death. The safety of the doses was not different than the reported in the summary of product characteristics.
    CONCLUSIONS: Inpatients in Bulgaria with added colchicine and bromhexine to SOC achieved better clinical and mortality outcomes than those on SOC alone. These results question the World Health Organization-recommended strategy to inhibit viral replication. We posit that our treatment strategy to inhibit the Severe acute respiratory syndrome coronavirus 2 entry into the cell with inhaled bromhexine and the hyperactivated NLRP3 inflammasome with higher doses of colchicine, prevents the development of cytokine storm. The timing of the initiation of treatment seems critical.
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