Subcutaneous Drug Development for Portal Hypertension Ascites

门静脉高压腹水的皮下注射药物开发

基本信息

  • 批准号:
    8930140
  • 负责人:
  • 金额:
    $ 28.03万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2014
  • 资助国家:
    美国
  • 起止时间:
    2014-09-22 至 2017-06-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): The prevalence of all types of ascites, irrespective of the cause, is 41.7 in 100,000 with 80% of these due to cirrhosis. Ascites is treated with a salt restricted diet and pharmacologic therapy using diuretics. However, in 5% to 10% of patients with ascites, the ascites becomes refractory to medical therapy. Half of patients who develop refractory ascites due to advanced liver cirrhosis will die within a year without a liver transplan and therefore expedited referral for liver transplantation is recommended. Temporary treatment while waiting includes large volume paracentesis, transjugular intrahepatic portasystemic shunt (TIPS), and peritoneovenous shunt surgical procedures. Complications from these procedures that can further increase mortality include paracentesis-induced circulatory dysfunction (PICD) and chronic hepatic encephalopathy from TIPS. Pharmacological therapies that can stop the progression or extend survival and act as a therapeutic bridge to liver transplantation are thus desperately needed. Terlipressin, tri-glycyl [8-lys] vasopressin, is a synthetic peptide drug that reduces portal vein pressure, restores hemodynamic balance, and is an effective treatment for portal hypertension ascites. This prodrug is slowly converted to the vasoactive agent [8-lys] vasopressin in the blood; it is well tolerated and has a far better safety profile than human nativ vasopressin ([8-Arg] vasopressin). Intravenous terlipressin has been available in Europe for the past twenty years and it is one of the most cost-effective and economical drugs for treating bleeding varies and hepatorenal syndrome (HRS) with improvement in survival rates that is well documented. Despite its good safety profile, the use of terlipressin is currently limited to the acute care setting because the short half-life (26min) necessitates administration by IV bolus injection every 4-6h. We believe that a formulation of a new terlipressin derivative that can be administered once-daily, ideally subcutaneously, and would have a significant market opportunity in the U.S. in the outpatient setting (which will reduce overall health care cost) for the treatment of refractory ascites from cirrhosis-induced portal hypertension. We developed a new long acting terlipressin (LAT) based on a proprietary drug delivery technology invented by the PI that gives sustained release of modified terlipressin. LAT demonstrated a substantially longer half-life than unmodified terlipressin peptide (3.3 hours vs. 0.8 hours respectively) and was observed to maintain measurable blood concentrations for more than 20 hours, compared to 5 hours for a rapid clearing of terlipressin. This study will optimize the formulation, determin pharmacokinetics of various metabolites to determine the optimum dose needed, and test the efficacy of the formulation for the treatment of cirrhosis-induced ascites in rat.
描述(由申请人提供):无论何种原因,所有类型腹水的患病率为 100,000 人中 41.7 人,其中 80% 是由于肝硬化引起的。腹水可通过限盐饮食和使用利尿剂的药物治疗来治疗。然而,5% 至 10% 的腹水患者的腹水对药物治疗无效。由于晚期肝硬化而出现难治性腹水的患者如果不进行肝移植,将在一年内死亡,因此建议加急转诊进行肝移植。等待期间的临时治疗包括大容量腹腔穿刺术、经颈静脉肝内门体分流术(TIPS)和腹膜静脉分流手术。这些手术的并发症可能进一步增加死亡率,包括腹腔穿刺引起的循环功能障碍 (PICD) 和 TIPS 引起的慢性肝性脑病。因此,迫切需要能够阻止进展或延长生存期并充当肝移植治疗桥梁的药物疗法。特利加压素,即三甘氨酰[8-赖氨酸]加压素,是一种合成肽药物,可降低门静脉压力,恢复血流动力学平衡,是治疗门脉高压性腹水的有效方法。这种前药在血液中缓慢转化为血管活性剂[8-lys]加压素;它具有良好的耐受性,并且比人天然加压素([8-Arg]加压素)具有更好的安全性。过去二十年来,静脉注射特利加压素已在欧洲上市,它是治疗出血性出血和肝肾综合征 (HRS) 最具成本效益和经济的药物之一,其存活率的提高有据可查。尽管其安全性良好,但特利加压素的使用目前仅限于急性护理环境,因为其半衰期短(26 分钟),需要每 4-6 小时静脉推注一次。我们相信,一种新的特利加压素衍生物制剂可以每天一次,最好是皮下注射,并且在美国门诊环境中具有巨大的市场机会(这将降低总体医疗保健成本),用于治疗肝硬化引起的门静脉高压引起的难治性腹水。我们基于 PI 发明的专有给药技术开发了一种新型长效特利加压素 (LAT),该技术可持续释放改良特利加压素。 LAT 的半衰期明显长于未修饰的特利加压素肽(分别为 3.3 小时和 0.8 小时),并且观察到可将可测量的血液浓度维持超过 20 小时,而特利加压素快速清除需要 5 小时。本研究将优化制剂,确定各种代谢物的药代动力学以确定所需的最佳剂量,并测试该制剂治疗大鼠肝硬化腹水的功效。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Gerardo M. Castillo其他文献

Compositions de supports a noyau hydrophobe pour l'administration d'agents therapeutiques, et procedes de preparation et d'utilisation
支持治疗剂施用、制备和利用过程的疏水性组合物
  • DOI:
  • 发表时间:
    2006
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Gerardo M. Castillo;Elijah M. Bolotin
  • 通讯作者:
    Elijah M. Bolotin
Erratum to: Protected Graft Copolymer Excipient Leads to a Higher Acute Maximum Tolerated Dose and Extends Residence Time of Vasoactive Intestinal Peptide Significantly Better than Sterically Stabilized Micelles
  • DOI:
    10.1007/s11095-013-1061-0
  • 发表时间:
    2013-05-09
  • 期刊:
  • 影响因子:
    4.300
  • 作者:
    Sandra Reichstetter;Gerardo M. Castillo;Israel Rubinstein;Akiko Nishimoto-Ashfield;ManShun Lai;Cynthia C. Jones;Aryamitra Banerjee;Alex Lyubimov;Duane C. Bloedow;Alexei Bogdanov;Elijah M. Bolotin
  • 通讯作者:
    Elijah M. Bolotin

Gerardo M. Castillo的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Gerardo M. Castillo', 18)}}的其他基金

CMC of Peptide Formulation for the Treatment of ARDS
用于治疗 ARDS 的肽制剂的 CMC
  • 批准号:
    10839580
  • 财政年份:
    2022
  • 资助金额:
    $ 28.03万
  • 项目类别:
CMC of Peptide Formulation for the Treatment of ARDS
用于治疗 ARDS 的肽制剂的 CMC
  • 批准号:
    10379771
  • 财政年份:
    2022
  • 资助金额:
    $ 28.03万
  • 项目类别:
Subcutaneous Drug Development for Portal Hypertension Ascites
门静脉高压腹水的皮下药物开发
  • 批准号:
    10469005
  • 财政年份:
    2014
  • 资助金额:
    $ 28.03万
  • 项目类别:
Medical countermeasure after radiation exposure
放射线照射后的医疗对策
  • 批准号:
    8800541
  • 财政年份:
    2014
  • 资助金额:
    $ 28.03万
  • 项目类别:
Subcutaneous Drug Development for Portal Hypertension Ascites
门静脉高压腹水的皮下药物开发
  • 批准号:
    10320316
  • 财政年份:
    2014
  • 资助金额:
    $ 28.03万
  • 项目类别:
Subcutaneous Drug Development for Portal Hypertension Ascites
门静脉高压腹水的皮下注射药物开发
  • 批准号:
    8776220
  • 财政年份:
    2014
  • 资助金额:
    $ 28.03万
  • 项目类别:
Medical countermeasure after radiation exposure
放射线照射后的医疗对策
  • 批准号:
    8707174
  • 财政年份:
    2014
  • 资助金额:
    $ 28.03万
  • 项目类别:
Nanocarrier-formulated NF-kB inhibitors for Inflammatory diseases
纳米载体配制的用于炎症疾病的 NF-kB 抑制剂
  • 批准号:
    8300786
  • 财政年份:
    2011
  • 资助金额:
    $ 28.03万
  • 项目类别:
Nanocarrier-formulated NF-kB inhibitors for Inflammatory diseases
纳米载体配制的用于炎症疾病的 NF-kB 抑制剂
  • 批准号:
    8196005
  • 财政年份:
    2011
  • 资助金额:
    $ 28.03万
  • 项目类别:
EGF/Gastrin for Islet Regeneration
EGF/胃泌素促进胰岛再生
  • 批准号:
    8455605
  • 财政年份:
    2009
  • 资助金额:
    $ 28.03万
  • 项目类别:

相似海外基金

Acute senescence: a novel host defence counteracting typhoidal Salmonella
急性衰老:对抗伤寒沙门氏菌的新型宿主防御
  • 批准号:
    MR/X02329X/1
  • 财政年份:
    2024
  • 资助金额:
    $ 28.03万
  • 项目类别:
    Fellowship
Transcriptional assessment of haematopoietic differentiation to risk-stratify acute lymphoblastic leukaemia
造血分化的转录评估对急性淋巴细胞白血病的风险分层
  • 批准号:
    MR/Y009568/1
  • 财政年份:
    2024
  • 资助金额:
    $ 28.03万
  • 项目类别:
    Fellowship
Combining two unique AI platforms for the discovery of novel genetic therapeutic targets & preclinical validation of synthetic biomolecules to treat Acute myeloid leukaemia (AML).
结合两个独特的人工智能平台来发现新的基因治疗靶点
  • 批准号:
    10090332
  • 财政年份:
    2024
  • 资助金额:
    $ 28.03万
  • 项目类别:
    Collaborative R&D
Cellular Neuroinflammation in Acute Brain Injury
急性脑损伤中的细胞神经炎症
  • 批准号:
    MR/X021882/1
  • 财政年份:
    2024
  • 资助金额:
    $ 28.03万
  • 项目类别:
    Research Grant
KAT2A PROTACs targetting the differentiation of blasts and leukemic stem cells for the treatment of Acute Myeloid Leukaemia
KAT2A PROTAC 靶向原始细胞和白血病干细胞的分化,用于治疗急性髓系白血病
  • 批准号:
    MR/X029557/1
  • 财政年份:
    2024
  • 资助金额:
    $ 28.03万
  • 项目类别:
    Research Grant
Combining Mechanistic Modelling with Machine Learning for Diagnosis of Acute Respiratory Distress Syndrome
机械建模与机器学习相结合诊断急性呼吸窘迫综合征
  • 批准号:
    EP/Y003527/1
  • 财政年份:
    2024
  • 资助金额:
    $ 28.03万
  • 项目类别:
    Research Grant
FITEAML: Functional Interrogation of Transposable Elements in Acute Myeloid Leukaemia
FITEAML:急性髓系白血病转座元件的功能研究
  • 批准号:
    EP/Y030338/1
  • 财政年份:
    2024
  • 资助金额:
    $ 28.03万
  • 项目类别:
    Research Grant
STTR Phase I: Non-invasive focused ultrasound treatment to modulate the immune system for acute and chronic kidney rejection
STTR 第一期:非侵入性聚焦超声治疗调节免疫系统以治疗急性和慢性肾排斥
  • 批准号:
    2312694
  • 财政年份:
    2024
  • 资助金额:
    $ 28.03万
  • 项目类别:
    Standard Grant
ロボット支援肝切除術は真に低侵襲なのか?acute phaseに着目して
机器人辅助肝切除术真的是微创吗?
  • 批准号:
    24K19395
  • 财政年份:
    2024
  • 资助金额:
    $ 28.03万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
Collaborative Research: Changes and Impact of Right Ventricle Viscoelasticity Under Acute Stress and Chronic Pulmonary Hypertension
合作研究:急性应激和慢性肺动脉高压下右心室粘弹性的变化和影响
  • 批准号:
    2244994
  • 财政年份:
    2023
  • 资助金额:
    $ 28.03万
  • 项目类别:
    Standard Grant
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了