A Phase 2 Open-label Multi-centre Study to Evaluate the Efficacy and Safety of Oxabact® to Reduce Plasma Oxalate in Subjects With Primary Hyperoxaluria Who Are on Dialysis

The purpose of this study is to determine if Oxalobacter formigenes is effective at lowering plasma oxalate levels in patients with primary hyperoxaluria who are on dialysis.

开始日期2014-05-19

申办/合作机构

OxThera AB

NCT01037231

/ Completed临床2/3期

A Phase 2/3, Double-blind, Randomized, Placebo-controlled, Multi-center Study to Evaluate the Efficacy and Safety of OxabactTM to Reduce Urinary Oxalate in Subjects With Primary Hyperoxaluria.

The purpose of this study is to determine if Oxalobacter formigenes is effective at lowering urinary oxalate levels in patients with primary hyperoxaluria.

开始日期2009-12-01

申办/合作机构

OxThera AB

100 项与 Lyophilised Oxalobacter formigenes(OxThera AB) 相关的临床结果

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100 项与 Lyophilised Oxalobacter formigenes(OxThera AB) 相关的转化医学

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100 项与 Lyophilised Oxalobacter formigenes(OxThera AB) 相关的专利（医药）

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项与 Lyophilised Oxalobacter formigenes(OxThera AB) 相关的文献（医药）

2023-02-01·Pediatric nephrology (Berlin, Germany)3区 · 医学

ePHex: a phase 3, double-blind, placebo-controlled, randomized study to evaluate long-term efficacy and safety of Oxalobacter formigenes in patients with primary hyperoxaluria

3区 · 医学

Article

作者: Jarraya, Faical ; Banos, Ana ; Lindner, Elisabeth ; Abroug, Saoussen ; Gould, Edward ; Ben Hmida, Mohamed ; Schalk, Gesa ; Ariceta, Gema ; Fraga, Gloria ; Dehmel, Bastian ; De, Sudarsana ; Moochhala, Shabbir H ; Hunley, Tracy E ; Collard, Laure ; Boussetta, Abir

Abstract:

Background:

Primary hyperoxalurias (PHs) are rare genetic diseases that increase the endogenous level of oxalate, a waste metabolite excreted predominantly by the kidneys and also the gut. Treatments aim to improve oxalate excretion, or reduce oxalate generation, to prevent kidney function deterioration. Oxalobacter formigenes is an oxalate metabolizing bacterium. This Phase III, double-blind, placebo-controlled randomized trial investigated the effectiveness of orally administered Oxabact™, a lyophilized O. formigenes formulation, at reducing plasma oxalate levels in patients suffering from PH.

Methods:

Subjects (≥ 2 years of age) with a diagnosis of PH and maintained but suboptimal kidney function (mean estimated glomerular filtration rate at baseline < 90 mL/min/1.73 m2) were eligible to participate. Subjects were randomized to receive Oxabact or placebo twice daily for 52 weeks. Change from baseline in plasma oxalate concentration at Week 52 was the primary study endpoint.

Results:

Forty-three subjects were screened, 25 were recruited and one was discontinued. At Week 52, O. formigenes was established in the gut of subjects receiving Oxabact. Despite decreasing plasma oxalate level in subjects treated with Oxabact, and stable/increased levels with placebo, there was no significant difference between groups in the primary outcome (Least Squares mean estimate of treatment difference was − 3.80 μmol/L; 95% CI: − 7.83, 0.23; p-value = 0.064). Kidney function remained stable in both treatments.

Conclusions:

Oxabact treatment may have stabilized/reduced plasma oxalate versus a rise with placebo, but the difference over 12 months was not statistically significant (p = 0.06). A subtle effect observed with Oxabact suggests that O. formigenes may aid in preventing kidney stones.

Graphical abstract:

A higher resolution version of the Graphical abstract is available as Supplementary information.

2021-07-23·Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association2区 · 医学

Effects of Oxalobacter formigenes in subjects with primary hyperoxaluria Type 1 and end-stage renal disease: a Phase II study

2区 · 医学

Article

作者: Hoppe, Bernd ; Dehmel, Bastian ; Lindner, Elisabeth ; Herberg, Ulrike ; Pellikka, Patricia A ; Banos, Ana

Abstract:

Background:

In primary hyperoxaluria Type 1 (PH1), endogenous oxalate overproduction significantly elevates urinary oxalate excretion, resulting in recurrent urolithiasis and/or progressive nephrocalcinosis and often early end-stage renal disease (ESRD). In ESRD, dialysis cannot sufficiently remove oxalate; plasma oxalate (Pox) increases markedly, inducing systemic oxalate deposition (oxalosis) and often death. Interventions to reduce Pox in PH1 subjects with ESRD could have significant clinical impact. This ongoing Phase II, open-label trial aimed to evaluate whether long-term Oxabact™ (Oxalobacter formigenes, OC5, OxThera Intellectual Property AB, Sweden) lowers Pox in PH1 ESRD subjects, ameliorating clinical outcome.

Methods:

PH1 ESRD subjects on stable dialysis regimens were examined. Subjects were administered one OC5 capsule twice daily for up to 36 months or until transplantation. Total Pox values, cardiac function and safety were evaluated. Free Pox was evaluated in a comparative non-treated PH1 dialysis group using retrospective chart reviews and analyses.

Results:

Twelve subjects enrolled in an initial 6-week treatment phase. Following a washout of up to 4 weeks, eight subjects entered a continuation study; outcomes after 24 months of treatment are presented. After 24 months, all subjects had reduced or non-elevated Pox compared with baseline. Cardiac function improved, then stabilized. No treatment-related serious adverse events were reported.

Conclusions:

Compared with an untreated natural control cohort, 24 months OC5 administration was beneficial to PH1 ESRD subjects by substantially decreasing Pox concentrations, and improving or stabilizing cardiac function and clinical status, without increasing dialysis frequency. OC5 was safe and well-tolerated.

2019-05-01·Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry3区 · 化学

Endophytic actinomycetes Streptomyces spp mediated biosynthesis of copper oxide nanoparticles as a promising tool for biotechnological applications

3区 · 化学

Article

作者: Awad, Mohamed A ; Salem, Salem S ; Fouda, Amr ; Barghoth, Mohammed G ; Hassan, Saad El-Din ; Abdo, Abdullah M ; Radwan, Ahmed A ; El-Gamal, Mamdouh S

In this study, two endophytic actinomycetes isolates Oc-5 and Acv-11, were isolated from healthy leaves of medicinal plant Oxalis corniculata L. These isolates were identified as Streptomyces zaomyceticus Oc-5 and Streptomyces pseudogriseolus Acv-11 using 16S rRNA gene sequence. Biomass extract of these strains were used as a greener attempt for synthesis of copper oxide nanoparticles (CuO-NPs). The synthesized NPs were characterized by UV-Vis spectroscopy, Fourier transform infra-red (FT-IR) spectroscopy, X-ray diffraction (XRD)' transmission electron microscopy (TEM), energy dispersive X-ray (EDX) and X-ray photoelectron spectroscopy (XPS). Green synthesized NPs showed surface plasmon resonance (SPR) absorption band at 400 nm, crystalline nature, spherical-shaped with an average size of 78 nm and 80.0 nm for CuO-NPs synthesized using strain Oc-5 and Acv-11, respectively. The bioactivities of CuO-NPs were evaluated. Results revealed that CuO-NPs exhibited promising antimicrobial activity against prokaryotic and eukaryotic microbial cells (Gram positive bacteria, Gram negative bacteria, unicellular and multicellular fungi). In addition, it showed antimicrobial potential against phyto-pathogenic fungal strains Fusarium oxysporum, Pythium ultimum, Aspergillus niger and Alternaria alternata. We further explored the in vitro antioxidant activity and cytotoxicity for biosynthesized CuO-NPs. The results revealed that' scavenging and total antioxidant activity for NPs synthesized using Streptomyces pseudogriseolus Acv-11 was better than those synthesized by Streptomyces zaomyceticus Oc-5. Also, the morphological changes and cell viability for Vero and Caco-2 cell line due to NPs treatments were assessed using MTT assay method. Furthermore, Larvicidal efficacy against Musca domestica and Culex pipiens was evaluated. The results obtained in this study clearly showed that biosynthesized CuO-NPs exhibited effective bioactivity and, therefore, provide a base for the development of versatile biotechnological applications soon.

项与 Lyophilised Oxalobacter formigenes(OxThera AB) 相关的新闻（医药）

2026-03-04

·奥易精医

细菌与肾结石形成：肠道与泌尿道微生物群的作用机制及最新研究进展

细菌与肾结石形成：肠道与泌尿道微生物群的作用机制及最新研究进展摘要肾结石病是全球范围内一种日益普遍的慢性疾病，其形成与多种遗传和环境因素密切相关。近年来，肠道与泌尿道微生物群在结石发病机制中的作用备受关注，已成为该领域的研究前沿。本报告整合最新文献（截至2026年），系统梳理了细菌参与结石形成的原理与机制。核心发现表明：肠道微生物群通过调节草酸盐代谢、维持肠道屏障功能、产生关键代谢物（如短链脂肪酸和氧化三甲胺）以及影响全身炎症状态，在草酸钙结石形成中扮演核心角色。对于感染性结石（鸟粪石），泌尿道脲酶阳性细菌（如变形杆菌）的直接作用则是关键。最新研究揭示了TMAO通过激活NLRP3炎症小体促进肾损伤的新机制，并探索了粪便微生物移植（FMT）和工程化益生菌等创新干预策略。尽管临床转化仍面临挑战，但靶向微生物群已成为预防和治疗肾结石极具前景的新方向。 1. 引言：肾结石的流行病学与微生物群视角的转变 1.1 肾结石：一种全球性的公共卫生挑战肾结石病是最常见的慢性肾脏疾病之一，其特征是在泌尿系统内形成坚硬的矿物沉积物。流行病学数据显示，该疾病的患病率正呈现持续上升趋势。根据美国国家健康和营养检查调查（NHANES）的评估，美国成人肾结石患病率已从1980年的3.2%显著上升至2014年的10.1% [[1]]。这种增长是全球化趋势，影响着工业化国家2-5%的人口 [[2]]。从人群分布来看，成年男性通常比成年女性更易患此病，但近年来育龄女性和儿童的发病率增长尤为显著 [[3]]。肾结石病阳性家族史会使个体的患病风险增加三倍，凸显了遗传因素的重要性 [[4]]。然而，单纯遗传因素无法解释患病率在几十年内的快速攀升，这强烈指向环境因素、生活方式改变以及微生物群变化的共同作用。肾结石的分类主要基于其化学成分。最常见的类型是含钙结石，其中草酸钙结石约占所有结石的80%，磷酸钙结石约占10% [[5]]。非含钙结石包括鸟粪石（约占10%）、尿酸结石（约占9%）和胱氨酸结石（约占1%） [[6]]。感染性结石（鸟粪石）在女性中的发病率高于男性，这与泌尿道感染的模式相关 [[7]]。不同类型结石的形成机制各异，但有一个共同点逐渐浮出水面：微生物群在其发病机制中扮演着或促进或抑制的关键角色。 1.2 从无菌观念到微生物组中心论传统上，肾结石的形成主要归因于物理化学因素：尿液过饱和、结晶形成、生长和聚集，以及尿液中抑制物（如柠檬酸、镁）的缺乏。然而，这一经典模型难以完全解释结石的形成、复发和个体差异。在过去的十几年中，随着高通量测序技术和宏基因组学的发展，一个更复杂的图景被描绘出来：人体微生物群，特别是肠道和泌尿道微生物群，是影响结石形成的关键环境因素和生理调节者。人体是一个与数以万亿计微生物共生的超级生物体。这些微生物定植于口腔、鼻腔、皮肤、胃肠道和泌尿道等多个部位，主要由细菌、病毒、真菌、古细菌和单细胞真核生物组成 [[8]]。其中，胃肠道拥有最重要、最复杂的微生物群落，主要由拟杆菌门、厚壁菌门和放线菌门等构成 [[9]]。这些微生物群绝非旁观者，它们深度参与宿主的免疫调节、代谢调节、营养吸收和肠道屏障功能维护 [[10]]。微生物群组成和结构的平衡状态被称为“稳态”，而其失衡则被定义为“生态失调”，这与炎症性肠病、肥胖、2型糖尿病、非酒精性脂肪肝、自身免疫性疾病乃至慢性肾脏病（CKD）等多种疾病密切相关 [[11]]。将微生物群与肾脏疾病联系起来的核心概念是“肠-肾轴”。研究表明，肠道生态失调会导致肽聚糖、脂多糖和细菌DNA等产物的分泌增加，这些物质可以破坏肠道屏障的完整性和通透性（即“肠漏”），使细菌产物和毒素进入循环系统 [[12]]。在慢性肾脏病患者中，由于肾功能减退，这些尿毒症毒素蓄积，引发全身性炎症反应，形成恶性循环 [[13]]。肾结石病作为另一种常见的肾脏病理状态，其与微生物群的联系近年来已成为研究热点。本报告旨在深入剖析细菌（及其他微生物）参与肾结石形成的分子与细胞机制，特别关注草酸钙结石和鸟粪石，并整合2022年至2026年的最新研究成果，以期为未来的预防和治疗策略提供科学依据。 2. 肠道微生物群与草酸钙结石：核心机制与最新发现草酸钙结石是最常见的肾结石类型，其形成与尿液中草酸和钙的过饱和密切相关。肠道微生物群通过多种机制直接和间接地影响草酸盐稳态和结石风险。 2.1 肠道草酸盐降解：微生物群的核心功能在人类体内，缺乏能降解草酸的酶。因此，肠道中的草酸盐降解细菌在维持草酸稳态中扮演着至关重要的角色，它们充当了“肠道清道夫”，减少膳食草酸盐的吸收和随后的尿液排泄。 2.1.1 “专家型”草酸盐降解菌：Oxalobacter formigenes Oxalobacter formigenes（产甲酸草酸杆菌）是一种革兰氏阴性专性厌氧菌，是人体大肠中的正常菌群成员，也是已知最有效的草酸盐降解者 [[14]][[15]]。其降解机制已研究得较为清楚： l草酸盐转运蛋白：细菌通过膜转运蛋白OxlT摄取细胞外草酸盐，同时以甲酸盐为交换物。 l关键酶系：细菌内表达两种关键酶：甲酰辅酶A转移酶和草酰辅酶A脱羧酶。Frc激活草酸形成草酰辅酶A，随后Oxc将其脱羧为二氧化碳和甲酸盐。这一过程不仅为细菌提供能量，也清除了肠道内的草酸盐 [[16]][[17]]。大量研究表明，肠道中 O. formigenes 的定植与复发性草酸钙肾结石风险降低存在强烈的负相关关系。Kaufman等人的研究提示，该菌的定植可使结石风险降低约70% [[18]][[19]]。对于囊性纤维化患者，由于其长期使用抗生素导致 O. formigenes 耗竭，常伴有高草酸尿症和肾钙质沉着症 [[20]][[21]]。然而，关于 O. formigenes 补充剂的最新临床试验（2022-2025年）结果却引发了争议。多项系统评价和荟萃分析指出，在原发性高草酸尿症患者中，O. formigenes 补充剂未能显著降低血浆或尿液草酸水平 [[22]][[23]][[24]]。一项II期研究曾显示，治疗可使8名患者的24小时尿液草酸排泄量中位数减少58% [[25]]，但更大规模的后续研究未能一致证实其疗效 [[26]][[27]]。这可能与该菌的脆弱性、定植困难、对多种抗生素敏感以及个体肠道环境差异有关。因此，尽管理论机制明确，但将其转化为有效临床疗法仍面临挑战。 2.1.2 “通才型”草酸盐降解菌：乳酸杆菌与双歧杆菌另一类草酸盐降解菌被称作“通才型草酸营养菌”，它们不完全依赖草酸盐作为碳源，但具备降解草酸盐的能力，主要包括某些乳酸杆菌和双歧杆菌株 [[28]]。 l乳酸杆菌：研究表明，Lactobacillus acidophilus 和 L. gasseri 等菌株中存在 oxc 和 frc 基因，能够表达有功能的草酸盐降解酶 [[29]][[30]][[31]]。在体外研究中，某些嗜酸乳杆菌和加氏乳杆菌分离株能降解超过50%的草酸盐 [[32]][[33]]。 l双歧杆菌：动物研究表明，双歧杆菌可通过降解膳食草酸盐和减少肠道吸收来降低尿液中草酸盐结晶 [[34]][[35]][[36]]。图罗尼等人发现，Bifidobacterium lactis DSM 10140、B. adolescentis MB 238 和 B. longum MB 282 展现出较高的草酸盐降解率（分别为61%、57%和35.2%） [[37]][[38]]。然而，益生菌干预的临床效果同样存在不一致。一些针对特发性高草酸尿症患者的研究显示，使用混合益生菌（包括嗜酸乳杆菌、短乳杆菌、植物乳杆菌、嗜热链球菌和婴儿双歧杆菌）后，尿液和粪便草酸盐水平降低 [[39]][[40]]。但对健康志愿者的类似研究未观察到对尿草酸盐的影响 [[41]][[42]]。2022-2025年的最新荟萃分析进一步指出，当前关于益生菌预防肾结石复发的随机对照试验规模小、周期短、异质性高，且多关注生化指标（如尿草酸排泄）而非临床结局（结石复发率），因此证据尚不足以支持其常规临床应用 [[43]][[44]][[45]]。未来需要更大规模、设计更严谨的试验来验证。 2.2 肠道屏障功能与系统性炎症：间接促石机制肠道微生物群不仅直接影响草酸盐代谢，还通过维护肠道屏障和调节全身炎症，间接影响结石风险。 2.2.1 肠道屏障完整性受损与“肠漏” 健康的肠道微生物群产生的短链脂肪酸等代谢物，有助于维持肠上皮细胞的紧密连接和屏障功能。生态失调，特别是产生SCFAs的有益菌（如 Faecalibacterium prausnitzii）减少，会导致肠道屏障功能受损，通透性增加，即“肠漏” [[46]][[47]][[48]]。这种屏障破坏有两个重要后果： 1.草酸盐吸收增加：完整的肠道屏障能限制草酸盐的被动扩散。屏障受损后，肠道内草酸盐（无论是膳食来源还是细菌未能降解的）更易进入血液，最终增加尿液排泄。 2.内毒素移位与系统炎症：肠道屏障破坏使得革兰氏阴性菌的细胞壁成分脂多糖更易进入循环。LPS可激活全身性炎症反应，产生促炎细胞因子。研究显示，肾结石患者肠道微生物群中与LPS生物合成相关的代谢途径丰度更高 [[49]][[50]]。过量的LPS可能加剧全身炎症，并对血管内皮细胞和肾小管上皮细胞造成损害 [[51]][[52]]为结晶的形成和滞留创造促炎环境。 2.2.2 短链脂肪酸：抗炎与屏障保护的双刃剑 SCFAs（主要是乙酸盐、丙酸盐和丁酸盐）是肠道微生物群发酵膳食纤维的主要代谢产物，在肠-肾轴中发挥重要作用。 l抗炎作用：SCFAs，特别是丁酸盐，是调节炎症的关键因素。它们可以通过抑制组蛋白去乙酰化酶和激活G蛋白偶联受体，抑制NF-κB等促炎信号通路。Faecalibacterium 是主要的丁酸盐产生菌之一。研究发现，肾结石患者粪便中 Faecalibacterium 耗竭，这可能导致其抗炎能力下降，促进结石形成 [[53]][[54]][[55]]。SCFAs还可以进入循环到达肾脏，改善慢性肾脏病中的炎症反应 [[56]][[57]]。 l肠道屏障维护：SCFAs是结肠上皮细胞的主要能量来源，促进黏液蛋白分泌和紧密连接蛋白表达，从而增强肠道屏障功能。 l潜在的双刃剑：然而，有研究发现，肾结石患者粪便中的乙酸含量反而高于非结石对照组，这可能提示结石患者肠道微生物群对乙酸的利用和吸收能力下降 [[58]][[59]]。SCFAs谱的具体变化及其对结石形成的影响仍需深入研究。 2.3 其他肠道代谢物：TMAO与尿酸等 2.3.1 氧化三甲胺（TMAO）：从心血管风险因子到肾结石促进剂 TMAO是近年来备受关注的肠道微生物群衍生代谢物。膳食中的胆碱、磷脂酰胆碱和左旋肉碱等营养素，被肠道菌群（如 Escherichia coli、Klebsiella spp.）代谢为三甲胺，随后在肝脏黄素单加氧酶的作用下氧化为TMAO [[60]][[61]]。最初，TMAO被认定为心血管疾病的独立风险因子。最新研究（2023-2025年）揭示了其在肾脏疾病，特别是肾结石形成中的潜在作用： l促进肾损伤与纤维化：TMAO是慢性肾脏病进展的独立风险因素，可通过激活NLRP3炎症小体、NF-κB信号通路，诱导肾小管上皮细胞凋亡、铁死亡和氧化应激，促进肾小管间质纤维化 [[62]][[63]][[64]]。 l直接促进草酸钙结石形成：一项关键研究指出，TMAO可通过氧化应激和自噬相关细胞死亡，促进草酸钙结晶在肾脏的沉积，从而加剧肾结石形成 [[65]]。其机制可能涉及： lNLRP3炎症小体激活：TMAO可激活肾小管细胞中的NLRP3炎症小体，导致IL-1β、IL-18等促炎细胞因子释放，引发局部炎症反应，为晶体黏附和生长创造有利环境 [[66]][[67]][[68]]。 l氧化应激与线粒体功能障碍：TMAO诱导活性氧产生和线粒体损伤，破坏细胞稳态。 l内皮功能障碍：TMAO可导致血管内皮功能障碍，影响肾脏微循环。 l临床关联：虽然直接证明TMAO水平与肾结石风险的流行病学数据尚在积累中，但其在CKD患者中升高并与肾功能恶化相关的证据已很充分 [[69]][[70]]。鉴于CKD与肾结石风险增加相关，TMAO可能是一个重要的连接点。 2.3.2 尿酸与嘌呤代谢肠道微生物群也参与嘌呤代谢。某些细菌能产生尿酸酶，将尿酸分解为更易排泄的尿囊素。肠道菌群失调可能影响这一过程，导致血尿酸水平升高，进而促进尿酸结石（约占结石9%）的形成，或作为草酸钙结石的“病灶” [[71]][[72]]。 2.4 抗生素暴露：破坏微生态与增加结石风险大量流行病学研究指出，抗生素暴露是肾结石形成的独立风险因素，特别是在儿童和青少年中。其机制主要在于破坏肠道微生物群的平衡。 l直接抑制草酸盐降解菌：许多抗生素，特别是头孢菌素、磺胺类、氟喹诺酮类、广谱青霉素等，对 O. formigenes 等草酸盐降解菌有强烈抑制作用 [[73]][[74]]。小鼠模型显示，儿科常用的β-内酰胺类和大环内酯类抗生素可导致宿主微生物群改变，粪便中草酸盐水平下降（可能反映了降解菌减少） [[75]][[76]]。 l广义生态失调：抗生素使用导致肠道微生物多样性降低，有益菌（如产SCFAs菌）减少，机会致病菌增多，破坏肠道屏障，增加系统性炎症。一项研究显示，因哮喘接受皮质类固醇治疗的儿童，其肾结石风险是对照组的四倍，这可能与治疗伴随的微生物群改变有关 [[77]][[78]]。 l长期影响：抗生素引起的肠道生态失调可能持续数月甚至更久，其对草酸盐代谢和屏障功能的长期影响可能是结石风险延后出现的原因 [[79]][[80]]。 3. 泌尿道微生物群与感染性结石：鸟粪石的形成机制鸟粪石（磷酸镁铵结石）的形成机制与草酸钙结石截然不同，它是一种典型的感染性结石，与泌尿道细菌感染直接相关。 3.1 脲酶阳性细菌的核心作用鸟粪石的形成必须具备两个条件：尿液中含有尿素和存在产脲酶的细菌。脲酶阳性细菌是鸟粪石形成的始作俑者。 l关键菌种：最典型的细菌是变形杆菌，特别是 Proteus mirabilis（奇异变形杆菌）。其他常见产脲酶细菌包括 Klebsiella pneumoniae（肺炎克雷伯菌）、Pseudomonas aeruginosa（铜绿假单胞菌）、Enterococcus faecalis（粪肠球菌）以及某些葡萄球菌和链球菌 [[81]][[82]]。 l生化机制： 1.尿素水解：细菌分泌的脲酶将尿液中的尿素水解为氨（NH₃）和二氧化碳（CO₂）。 2.尿液碱化：氨迅速水解形成氢氧化铵，使尿液pH值升高至中性或碱性（常>7.2）。 3.晶体沉淀：在碱性环境下，磷酸镁铵（鸟粪石）和碳酸磷灰石溶解度降低，开始沉淀结晶。 4.结石生长：细菌本身可以作为晶核，其产生的生物膜基质为晶体的进一步聚集和生长提供支架，形成特征性的“鹿角形”结石 [[83]][[84]][[85]]。 3.2 细菌毒力因子与结石形成除脲酶外，细菌的其他成分也参与结石形成过程。以大肠杆菌为例，其鞭毛、脂多糖和细菌外膜囊泡可以促进草酸钙晶体的聚集和生长 [[86]][[87]]。对于变形杆菌，研究发现其甲酸氢裂解酶和氢化酶组分不仅参与耐酸性，还促进脲酶活性和结石形成 [[88]][[89]]。氨基酸如天冬酰胺和丝氨酸可充当催化剂，促进结石形成 [[90]][[91]]。 3.3 微生物组视角的扩展：泌尿道微生物群生态传统观念认为健康泌尿道是无菌的，但现代微生物组学研究揭示了其存在低丰度的微生物群落，即“泌尿道微生物群”。泌尿道微生物群的失调可能与下尿路症状、膀胱疼痛综合征和结石风险增加相关。虽然鸟粪石的形成直接与特定病原菌感染相关，但整体泌尿道微生物群平衡可能影响宿主的防御能力和感染易感性。 4. 炎症与免疫反应：连接微生物群与结晶的关键纽带肾结石形成不再被视为单纯的物理化学过程，而是一个炎症驱动的生物过程。微生物群通过调节局部和全身炎症状态，深刻影响结石的起始和发展。 4.1 NLRP3炎症小体的核心作用 NLRP3炎症小体是一种多蛋白复合物，其激活可导致半胱天冬酶-1剪切和释放促炎细胞因子IL-1β和IL-18，引发炎症反应。研究发现，草酸钙晶体和某些细菌产物（如LPS）均可激活肾小管上皮细胞和免疫细胞中的NLRP3炎症小体 [[92]][[93]]。 l晶体诱导的炎症：草酸钙晶体可被肾小管细胞内吞或与细胞膜相互作用，导致溶酶体破裂、线粒体损伤和活性氧爆发，这些危险信号均能激活NLRP3炎症小体 [[94]][[95]]。 l微生物群代谢物的调节： lLPS：来自肠道屏障漏出的LPS可作为“信号2”，与晶体提供的“信号1”协同，强烈激活NLRP3炎症小体 [[96]][[97]]。 lTMAO：如前所述，最新研究表明TMAO可通过氧化应激和线粒体功能障碍等途径激活NLRP3炎症小体，加剧肾损伤和晶体沉积 [[98]][[99]]。 lSCFAs：相反，SCFAs（特别是丁酸盐）可抑制NLRP3炎症小体激活，发挥抗炎作用，这可能是益生菌保护作用的机制之一 [[100]][[101]]。 4.2 免疫细胞的招募与结晶滞留炎症反应导致中性粒细胞、巨噬细胞等免疫细胞浸润肾脏。这些细胞释放的细胞因子、趋化因子和活性氧可进一步损伤肾小管上皮，暴露基底膜和细胞外基质蛋白（如透明质酸、骨桥蛋白），为晶体黏附提供锚点。此外，中性粒细胞胞外诱捕网的形成也与结石形成相关。 5. 新兴干预策略：靶向微生物群防治肾结石基于对微生物群在结石形成中作用的深入理解，一系列靶向微生物群的创新干预策略正在被探索。 5.1 粪便微生物移植 FMT通过将健康供体的粪便微生物群移植到患者肠道，旨在重建健康、平衡的肠道微生态。 l理论基础：FMT可能通过：1）引入或富集草酸盐降解菌；2）恢复产生SCFAs的有益菌群；3）修复肠道屏障功能；4）降低系统性炎症，从而影响结石风险。 l临床前证据：动物模型（大鼠）研究显示，FMT可减轻高草酸饮食诱导的高草酸尿症和肾脏草酸钙结晶沉积 [[102]][[103]]。这些研究为FMT在肾结石中的应用提供了原理验证。 l临床转化挑战：截至2026年，尚无公开发表的、专门针对预防肾结石复发的FMT临床试验结果。FMT目前主要用于治疗艰难梭菌感染，其在肾结石中的应用仍处于早期探索阶段 [[104]][[105]]。关键挑战包括：供体筛选标准化（需筛查传染病、代谢性疾病等）、移植途径（结肠镜、灌肠、胶囊）、剂量和频次的确定，以及长期安全性和疗效的评估 [[106]][[107]]。对于肾结石患者，可能需要选择本身无结石病史、肠道菌群特征健康的供体。 5.2 工程化益生菌与合成生物学鉴于天然益生菌疗效不稳定和 O. formigenes 定植困难，利用合成生物学方法改造益生菌以高效降解草酸盐，已成为前沿研究方向。 l策略：将编码高效草酸盐降解酶（如来自 O. formigenes 或 Bacillus subtilis 的草酰辅酶A脱羧酶、草酸脱羧酶）的基因，转入易于培养、定植且安全性高的益生菌（如 Escherichia coli Nissle 1917、乳酸杆菌）中。 l代表成果：SYNB8802 是一款工程化的大肠杆菌Nissle菌株，旨在消耗肠道草酸盐。临床前研究和早期临床试验显示，其在健康志愿者和胃旁路术后患者中能降低尿液草酸盐水平 [[108]][[109]][[110]]。2021年的Ib期研究证明了其“机制验证”和“概念验证”，计划启动III期试验 [[111]][[112]]。 l优势：工程化细菌可能具有更高的草酸盐降解效率、更好的肠道存活能力和可调控性。 l挑战：基因工程细菌的环境释放监管、在复杂肠道环境中的长期稳定性以及潜在副作用需要严格评估。 5.3 益生元与合生元益生元（如低聚糖）可选择性促进肠道中有益菌（特别是草酸盐降解菌和产SCFAs菌）的生长。合生元是益生菌与益生元的组合，理论上能产生协同效应。虽然临床证据尚不充分，但这是一个有潜力的研究方向。 5.4 靶向代谢物的干预针对特定微生物代谢物进行干预也是一种可能策略： l降低TMAO：通过饮食调整（减少红肉、加工肉类摄入）、使用胆碱氧化酶抑制剂或靶向抑制TMAO生成的肠道菌群酶，可能降低TMAO水平及其相关风险。 l补充SCFAs或促进其产生：直接补充丁酸盐或食用富含膳食纤维的饮食以刺激内源性SCFAs产生，可能具有抗炎和屏障保护作用。 5.5 抗生素使用的审慎评估鉴于抗生素与结石风险的关联，临床医生在处方抗生素时（尤其对儿童）应考虑其对肠道微生物群的长期影响，避免不必要的使用，并在必要时考虑同时或之后补充益生菌以减轻生态失调。 6. 挑战、争议与未来研究方向尽管该领域进展迅速，但将微生物群研究成果转化为临床实践仍面临诸多挑战。 6.1 疗效证据的异质性与不确定性如前所述，O. formigenes 补充剂和多种益生菌干预的临床试验结果不一致。这可能归因于： l菌株特异性：不同菌株的草酸盐降解能力差异巨大。 l个体差异：宿主肠道环境、饮食、遗传背景影响细菌的定植和功能。 l研究设计：现有研究样本量小、周期短、缺乏硬终点（如结石复发率）。 l给药方式：口服益生菌可能无法在通过胃酸和胆汁后保持足够活性到达结肠。 6.2 微生物群分析的标准化与生物标志物发现用于分析微生物群的方法（16S rRNA测序、宏基因组测序、代谢组学）缺乏标准化，导致不同研究间可比性差。亟需发现可靠的微生物组生物标志物用于预测结石风险或复发。例如，有研究指出，肠道中 Escherichia coli 的丰度可能是复发性草酸钙结石的独立风险因素 [[113]][[114]]。未来需要整合多组学数据构建更精准的预测模型。 6.3 机制研究的深化许多机制尚未完全阐明。例如： l肠道微生物群如何具体调节肾小管上皮细胞对草酸盐、柠檬酸盐等溶质的转运？ lTMAO激活NLRP3炎症小体促进晶体沉积的精确分子信号通路是什么？ l泌尿道微生物群在健康和结石状态下的具体构成和功能如何？ 6.4 未来研究方向 1.大规模、长期、设计严谨的临床试验：评估益生菌、合生元、FMT和工程化益生菌对结石复发率等临床终点的疗效。 2.个性化微生物群干预：根据个体的微生物群特征定制干预方案，可能包括特定的菌株组合、益生元或饮食建议。 3.深入研究关键代谢物的作用：如TMAO、SCFAs、次级胆汁酸等在结石形成中的具体作用机制。 4.开发新型工程化微生物疗法：利用合成生物学构建更安全、高效、可控的“活体生物药”。 5.探索泌尿道微生物群的作用：阐明其构成、功能及其与结石形成的关系，可能开辟局部治疗新途径。 7. 结论肾结石的形成是一个多因素参与的复杂过程，肠道和泌尿道微生物群在其中扮演着不可忽视的角色。本报告系统梳理了细菌参与结石形成的多层次机制： 1.直接代谢机制：肠道草酸盐降解菌通过降解膳食草酸盐，降低尿草酸排泄，是预防草酸钙结石的第一道防线。泌尿道脲酶阳性细菌通过碱化尿液，直接驱动鸟粪石形成。 2.间接屏障与炎症机制：肠道微生物群通过维护肠道屏障完整性，防止草酸盐过量吸收和内毒素移位。生态失调导致的“肠漏”和系统性炎症，为肾小管晶体黏附和生长创造了促炎环境。 3.代谢物介导的机制：微生物代谢物如TMAO和SCFAs，分别作为促炎和抗炎因子，通过NLRP3炎症小体等信号通路，深刻影响肾脏局部免疫微环境和结石形成倾向。最新研究（2022-2026年）进一步揭示了TMAO通过激活NLRP3炎症小体促进肾损伤的新机制，并推动了工程化益生菌（如SYNB8802）和FMT等创新疗法向临床转化的步伐。然而，现有临床证据仍存在异质性和不确定性，尤其是在益生菌疗效和FMT标准化方面。展望未来，靶向微生物群及其代谢通路已成为肾结石防治策略中一个极具前景的新兴领域。成功的关键在于深化机制研究、优化干预策略、开展大规模临床验证，并最终实现个性化微生物组医学，为肾结石患者提供更有效的预防和治疗手段。微生物群研究不仅深化了我们对肾结石病因学的理解，也打开了从“杀灭病原菌”到“调理共生生态”的疾病治疗新范式的大门。文献来源 [56,57,65,546]. 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Recent advances in fecal microbiota transplantation for Clostridium difficile infection-associated diarrhea after kidney transplantation [270,271,272,273,275,276,277,278,279,283,284,285,286,287,288,290,291,364,367,368,370,372,378,381,382,383,543]. The gut-kidney axis in urolithiasis: roles of gut microbiota, metabolites, and therapeutic implications [274,317,318,320,321,322,323,324,327,328,329,330,337,338,340,341,556,557]. Dysbiotic Gut Microbiota Correlates with Altered Serum and Urinary Biomarkers in Recurrent Calcium Oxalate Stone Patients [280,282]. Gut microbiota-derived indole-3-acetic acid ameliorates calcium oxalate renal stone formation via AHR/NF-κB axis [281]. Analysis of risk factors for kidney stones in patients with hyperuricemia: a cross-sectional study based on NHANES [289]. The Role of the Probiotics in Urolithiasis [292,296,302]. 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Thiazides for kidney stone recurrence prevention [358,359,363]. Management of recurrent urolithiasis: advances in prevention strategies [360]. UROLOGIC NURSE FORUM [361]. Revista Brasileira de Análises Clínicas Brazilian Journal of Clinical Analyses [379,387]. What Causes Calcium Oxalate Kidney Stones to Form? An Update on Recent Advances [380,386]. Research progress on the mechanisms of interleukin and chemokine families in driving calcium oxalate nephrolithiasis formation [391,400,404,405,406,415,417]. An engineered bacterial therapeutic lowers urinary oxalate in preclinical models and in silico simulations of enteric hyperoxaluria [393,399,552]. Nephrolithiasis and Microbiota: Urinary Microbiota, Gut Microbiota, Sample Collection, 16S rRNA Gene Sequencing; Advances and prospective. [401,407,418,553]. Synlogic Announces Progress Toward 2022 Clinical Milestones and Participation at Upcoming Investor Conferences [402,410,413,416,419,554]. Synlogic Announces Achievement of Proof of Concept for SYNBB802 in Enteric Hyperoxaluria Based on Urinary Oxalate Lowering in Phase 1b Study [403]. Development of a Synthetic Biotic, SYNB8802, for the Treatment of Enteric Hyperoxaluria. [408,414]. Synlogic Annual Report 2025 Form 10-K (NASDAQ:SYBX) [409,411,555]. Synlogic Announces SYNB8802 Will Advance to Phase 1B Proof of Concept Study After Proof of Mechanism Demonstrated in Dietary Hyperoxaluria [412]. SYNB8802v1 Lowers Urinary Oxalate Using a Controlled Dietary Model of Hyperoxaluria in Patients with Roux-en-Y Gastric Bypass [421,423,426,427]. 高盐饮食相关肠道菌群及炎症变化与肾草酸钙结石发生的关联性分析 [422]. Trimethylamine-N-Oxide Promotes Osteoclast Differentiation and Bone Loss via Activating ROS-Dependent NF-κB Signaling Pathway [424]. Nephrolithiasis: A Red Flag for Cardiovascular Risk [428]. Differences in macrophage pyroptosis and polarization induced by nano-/micro-calcium oxalate crystals [430]. Decoding TMAO in the Gut-Organ Axis: From Biomarkers and Cell Death Mechanisms to Therapeutic Horizons [431]. 肠道菌群代谢物 TMAO 上调 NLRP3 炎性小体：海马相关认知障碍致病机制的研究 [436,442,550]. Fecal Microbiome Transplantation for Recurrent CDI: Treatment Efficacy and Safety with Oral Capsules [437]. Safety and feasibility of faecal microbiota transplantation for patients with Parkinson's disease: a protocol for a self-controlled interventional donor-FMT pilot study [439]. Safety and feasibility of fecal microbiota transplantation for Parkinson’s disease patients: a protocol for a self-controlled interventional donor-FMT pilot study [440]. Donor screening for fecal microbiota transplantation with a direct stool testing-based strategy: a prospective cohort study [464]. Trimethylamine N-oxide [495]. February 2022 References [515]. N-óxido de trimetilamina e doenças renais: o que sabemos? Trimethylamine N-oxide and kidney diseases: what do we know? https://www.cn-healthcare.com/articlewm/20221118/content-1468724.html

2025-01-08

·PRNewswire

1cBio and Alesta Therapeutics Announce Exclusive Global Licensing Agreement for a Novel Potentially First-in-Class Small Molecule for Hypophosphatasia

SAN FRANCISCO and LEIDEN, Netherlands, Jan. 8, 2025 /PRNewswire/ -- 1cBio, Inc. ("1cBio") an emerging biotech company developing precision medicines for significant unmet needs, and Alesta Pharmaceuticals ("Alesta") a leader in developing first-in-class small molecules for rare diseases, announced an exclusive worldwide licensing agreement. Under this agreement, Alesta will develop, commercialize, and manufacture OC-1(also known as ALE1), an orally active therapeutic candidate for hypophosphatasia (HPP). HPP is a rare genetic disorder caused by mutations in the ALPL gene, leading to defective bone and tooth mineralization. This results in skeletal abnormalities, fragile bones, early tooth loss, and, in older patients, significant muscle weakness, fatigue, and pain. Affecting tens of thousands of patients worldwide, HPP is believed to be underdiagnosed, particularly in older populations. OC-1 is a novel oral therapeutic that inhibits a novel target to reduce levels of inorganic pyrophosphate (PPi), a key metabolite driving disease pathology. Currently progressing through GLP toxicology studies, OC-1 is expected to enter clinical trials in the second half of 2025. OC-1 was developed by combining 1cBio's expertise in medicinal chemistry and translational sciences with thought partners in clinical and basic sciences to guide its innovation. "We are excited to partner with Alesta Therapeutics, who is pioneering the development of transformative medicines for rare disease and can help us to reach HPP patients more rapidly," said Andrew Wong, Chief Executive Officer at 1cBio. "OC-1 is another example of the 1cBio team's capabilities to identify white spaces in disease treatments and develop highly differentiated molecules for precision medicine. We look forward to collaborating with Alesta's innovative development team to efficiently progress a potentially first-in-class, oral therapy for HPP patients." "With the support of 1cBio, the expertise and commitment of our team, and collaborations with leading academics and disease advocacy groups, we are poised to make significant strides in addressing the unmet needs of HPP patients," said Ilan Ganot, Chief Executive Officer of Alesta Therapeutics. "We look forward to advancing OC-1 toward clinical proof of concept and bringing us closer to delivering this transformative therapy to address the entire spectrum of HPP in this underserved disease." Under the terms of the agreement, Alesta will assume responsibility for Phase I preparation activities, including submission of the Clinical Trial Application (CTA) and Investigational New Drug (IND) application, and all subsequent clinical-development activities and global commercialization activities. 1cBio is eligible to receive potential development, regulatory and commercial milestone payments, including an equity investment, and tiered royalties on global sales, contingent upon successful development and commercialization. About 1cBio 1cBio is an emerging biotechnology company which strives to identify white spaces in cancer therapies and develop molecules that can serve as precision medicines. The company's programs are geared to treat the disease and preemptively counter mechanisms for acquired or intrinsic resistance. Core expertise in medicinal chemistry and translational sciences along with thought partners in clinical and basic sciences guides 1cBio's innovation. 1cBio's second lead program is OC-3, a selective-PARP1 inhibitor with the potential to be best-in-class for HR-deficient and HR-proficient tumors when combined with approved targeted therapies. For more information, visit . About Alesta Therapeutics Alesta Therapeutics is a Netherlands-based biotechnology company committed to developing novel oral small molecule therapies for underserved rare diseases. The company's lead asset, ALE1, is being developed for hypophosphatasia (HPP), a rare genetic disorder with significant unmet needs. Alesta is also advancing ALE2, a promising candidate to treat Charcot-Marie-Tooth (CMT) disease. In January 2025 Alesta announced a €65 million Series A financing supported by leading biotech and life science investors. For more information, visit . SOURCE 1cBio WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

引进/卖出临床1期

2023-10-13

·CPHI制药在线

研发 | 浅谈原发性高草酸尿症治疗进展

关注并星标CPHI制药在线原发性高草酸尿症（PH）是一种常染色体隐性遗传病，临床上以尿草酸排泄增加、反复草酸钙尿石形成、肾钙质沉着和全身不溶性草酸盐沉积为特征。PH发病是因基因突变导致肝脏产生过量草酸引起，根据基因突变类型的不同，PH可分为3型。其中Ⅰ型PH（PH1）与2号染色体上AGXT 基因突变有关。AGXT基因编码丙氨酸乙醛酸转氨酶(AGT)，该酶可将乙醛酸转化为甘氨酸，其缺乏可使乙醛酸在细胞质中积聚，从而导致乙醇酸和草酸增多。 Ⅱ型PH（PH2）与10号染色体上GRHPR基因突变有关。GRHPR基因编码乙醛酸羟基丙酮酸还原酶 (GRHPR)，该酶可将乙醛酸转化为乙醇酸，其缺乏会导致乙醛酸积聚，最终被乳酸脱氢酶 (LDH) 转化为草酸。 Ⅲ型PH（PH3）与9号染色体上HOGA1基因突变有关。HOGA1基因编码4-羟基2-酮戊二酸醛缩酶，其缺乏会限制4-羟基2-酮戊二酸转化为乙醛酸，这将使更多的酮戊二酸转向草酸途径。这三种类型中，PH1最常见且最严重，约占80%，据统计全球约有5.8万例PH1患者。而PH2和PH3分别占10%。目前，PH治疗手段有限，包括药物/保守治疗、透析治疗、肝肾联合移植等。其中肝肾联合移植治疗效果有限，且复发率高，患者需要终身免疫抑制以防止器官排斥。治疗药物方面，PH患者直到2020年才迎来首款药物，即Alnylam制药公司的Oxlumo(Lumasiran)。该药是一种皮下给药的RNA干扰(RNAi)疗法，其靶向编码乙醇酸氧化酶的HAO1基因，通过沉默HAO1，从而耗尽乙醇酸氧化酶，抑制草酸的生成。2020年11月，该药被FDA批准用于治疗PH1，以降低儿科和成人患者的尿草酸盐水平。2022年11月，该药又被FDA批准用于治疗PH1，以降低儿童和成人患者的尿草酸盐和血浆草酸盐水平。今年9月，FDA又批准一款PH新疗法，即诺和诺德的Rivfloza（Nedosiran）。该药是Dicerna利用专有GalXC™RNAi技术平台开发的RNAi疗法，通过与表达肝乳酸脱氢酶（LDH）的mRNA结合发挥作用。2021年11月，诺和诺德通过收购Dicerna，将nedosira纳入囊中。已公布的2期临床试验PHYOX™结果显示：接受Nedosiran治疗的PH患者（包括PH1和PH2）的尿草酸盐排泄量与基线差值相较于安慰剂组具有统计学意义(p＜0.0001)差异。而且，与安慰剂相比，接受Nedosiran治疗的患者在第90天后两次或更多次连续随访时达到并维持正常或接近正常Uox水平的比例显著更高（p=0.0025）。 Lumasiran和Nedosiran均属于RNAi疗法，但适应症稍有差异，Nedosiran适应症人群更加广泛，不局限于PH1患者。此外，目前全球还有几款在研PH新疗法，如Chinook Therapeutics的CHK-336、OxThera的Oxabact、BridgeBio的BBP-711。其中CHK-336是一款肝脏靶向的口服LDHA抑制剂，在PH1小鼠模型实验中能有效地将尿液中草酸含量降至正常水平，且展现出良好的安全性。已公布的CHK-336治疗PH和其他肾结石疾病的1期临床试验结果显示：CHK-336通常耐受性良好，具有良好的药代动力学特征，其半衰期支持每日一次的给药频率。而且，研究人员利用新型示踪剂证明了CHK-336能够阻断健康受试者肝脏草酸盐的生成。值得一提的是，今年6月，诺华斥资35亿美元收购Chinook Therapeutics，将包括CHK-336在内的多款药物纳入囊肿。 Oxabact是一种双模式肠道生物疗法，是含有产甲草酸杆菌的冻干制剂，以包衣胶囊形式口服给药。通过促进草酸盐从血浆主动和被动分泌到肠道，Oxabact能够增加草酸盐的排泄。遗憾的是，2021年6月，OxThera宣布Oxabact治疗PH的关键3期临床试验OC5-DB-02错失主要终点。 BBP-711是一种口服给药的乙醇酸氧化酶 (GO) 小分子抑制剂。靶向GO是一种经过临床验证的方法，可通过降低乙醛酸的浓度来减少尿中的草酸。BBP-711治疗高草酸尿症的首次人体1期试验已于2021年5月启动。整体来看，PH领域还存在很大未满足的市场需求，虽然诺和诺德Rivfloza已于近日获批。期待随着企业的不懈努力，PH领域可以早期迎来更多新疗法。扫码参与制药在线周年庆游园会来源：CPHI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com▼更多制药资讯，请关注CPHI制药在线▼点击阅读原文，进入智药研习社~

临床2期临床结果并购信使RNA临床3期

100 项与 Lyophilised Oxalobacter formigenes(OxThera AB) 相关的药物交易

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适应症	最高研发状态	国家/地区	公司	日期
原发性高草酸尿症	临床3期	美国	OxThera AB	2007-10-01

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT02000219 (CTgov)	临床2期	原发性高草酸尿症	12	Oxalobacter formigenes	鑰鹹憲鏇鹹糧廠鏇築觸(觸繭鹽鹹齋糧選鬱網築) = 獵鑰網簾醖廠製醖鏇獵鹹製艱襯鑰鬱鹹艱壓選 (鹹醖範簾壓壓範蓋顧齋, 39.63) 更多	-	2021-12-09
NCT03116685 (CTgov)	临床3期	原发性高草酸尿症	25	Oxabact OC5 - Oxalobacter formigenes HC-1 (Oxabact OC5 Capsules)	艱積網襯齋簾廠顧選糧(襯糧憲糧鬱齋繭蓋鹽製) = 糧膚鏇鹹願鑰艱齋襯窪願觸衊網網簾繭襯鹹蓋 (遞觸夢鹽觸範襯積窪餘, 5.7) 更多	-	2021-12-09
NCT03116685 (CTgov)	临床3期	原发性高草酸尿症	25	Placebo (Placebo Capsules)	艱積網襯齋簾廠顧選糧(襯糧憲糧鬱齋繭蓋鹽製) = 蓋蓋餘蓋膚鬱鹹鏇醖壓願觸衊網網簾繭襯鹹蓋 (遞觸夢鹽觸範襯積窪餘, 5.4) 更多	-	2021-12-09