Subcutaneous Drug Development for Portal Hypertension Ascites
门静脉高压腹水的皮下药物开发
基本信息
- 批准号:10469005
- 负责人:
- 金额:$ 98.23万
- 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 2023-07-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAlcoholismAmericanAnimalsAscitesBindingBloodBolus InfusionCessation of lifeChronicCirrhosisClinical TrialsConfidential InformationCreation of peritoneovascular shuntDataDiureticsDoseEquilibriumEuropeExcipientsFluid overloadFormulationFunctional disorderFundingFurosemideGreater sac of peritoneumHalf-LifeHealth Care CostsHemorrhageHepatic EncephalopathyHepatorenal SyndromeHospital CostsHumanInfusion proceduresInjectionsIntravenousIntravenous BolusLeadLiquid substanceLiver CirrhosisLiver diseasesLysineMedicalModelingModificationNecrosisNo-Observed-Adverse-Effect LevelOperative Surgical ProceduresOrphan DrugsOutpatientsParacentesisPatientsPeritoneal FluidPharmaceutical PreparationsPharmacologyPhasePortal HypertensionPortal vein structurePractice GuidelinesPrevalenceProceduresProdrugsQuality of lifeRattusRecommendationRefractorySafetySecureSmall Business Innovation Research GrantSodium ChlorideSodium-Restricted DietSpironolactoneSurvival RateTestingTherapeuticTherapeutic IndexTimeTissuesToxic effectTransjugular intrahepatic portosystemic shunt procedureTransplant RecipientsUrineVaricosityVasopressinsViral hepatitisacute careanalytical methodbasecost effectivedietary restrictiondrug developmenteffective therapyefficacy testinghemodynamicsinfection risklead candidateliquid formulationliver transplantationmeetingsmethod developmentmortalitynonalcoholic steatohepatitispharmacokinetics and pharmacodynamicsphase 1 studypreferencepressurereceptorside effectsubcutaneoussuccess
项目摘要
ABSTRACT: 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 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
transplant 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 an inactive pro-drug of Lysine-vasopressin (LVP) that releases active LVP slowly to
minimize LVP spike that can cause ischemic side effect. LVP reduces portal vein pressure, restores
hemodynamic balance, and is an effective treatment for portal hypertension ascites. Because of slow LVP
release, terlipressin is well tolerated and has a far better safety profile than human native 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 varices 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 (26
min) that necessitates administration by IV bolus injection every 4-6h. We developed a new terlipressin
derivative (dTer) that has much slower LVP release and found to be effective rat model of cirrhosis induced
portal hypertension ascites when administered subcutaneously as once-daily bolus. This product can have
a significant market opportunity in the U.S. especially in an outpatient setting (which will reduce overall
health care cost by eliminating cost of hospitalization) for the treatment of refractory ascites from cirrhosis-
induced portal hypertension ascites. This product (dTer) provides sustained release of active LVP and
demonstrated a substantially longer blood presence with lower LVP Cmax (eliminating ischemic side effect)
than terlipressin. This proposal is intended to collect IND enabling data package for submission to the FDA
to begin clinical trial. We already secured an orphan drug status for the use of dTer in patient with cirrhosis
induced ascites.
PharmaIN Corp. Confidential Information
摘要:无论原因如何,所有类型腹水的患病率为每10万人中有41.7人患有腹水
其中80%是由于肝硬变。腹水的治疗是用盐限制的饮食和药物治疗
利尿剂。然而,在5%到10%的腹水患者中,药物治疗变得难治。一半的人
晚期肝硬变导致顽固性腹水的患者将在没有肝脏的情况下在一年内死亡
建议进行肝移植,因此建议加快肝移植的转诊。临时治疗
等待期间包括大容量穿刺术、经颈静脉肝内门体分流术(TIPS)和
腹膜静脉分流术的外科手术。这些手术的并发症可能会进一步增加
死亡率包括穿刺性循环功能障碍(PICD)和慢性肝性脑病
来自小费。可以阻止病情发展或延长生存时间的药物疗法
因此,迫切需要通往肝移植的治疗桥梁。特利加压素,三甘氨基[8-赖氨酸]
加压素是赖氨酸加压素(LVP)的一种非活性前体药物,它能缓慢释放活性LVP
尽量减少可能导致缺血副作用的LVP峰值。LVP降低门静脉压力,恢复
血液动力学平衡,是治疗门脉高压性腹水的有效方法。因为LVP速度慢
释放,特利加压素耐受性良好,安全性远远好于人的天然加压素([8-
Arg]加压素)。静脉注射特利加压素在欧洲已经有20年的历史了,它是
治疗静脉曲张和肝肾出血的最具成本效益和最经济的药物之一
综合征(HRS)与存活率的改善,这是很好的记录。尽管它的安全性很好
特利加压素的使用目前仅限于急性护理环境,因为较短的半衰期(26
分钟),需要每4-6小时静脉推注一次。我们开发了一种新的特利加压素
具有慢得多的LVP释放的衍生物(Dter),被发现是有效的肝硬变大鼠模型
门脉高压症每天一次皮下注射时会出现腹水。此产品可以拥有
在美国有巨大的市场机会,特别是在门诊方面(这将减少总体
消除住院费用的医疗保健费用)治疗肝硬变顽固性腹水-
诱发性门脉高压腹水。本产品(Dter)提供活性LVP的持续释放和
表现出更长的血液存在时间和更低的LVP Cmax(消除缺血副作用)
而不是特利加压素。该提案旨在收集IND支持数据包以提交给FDA
开始临床试验。我们已经获得了在肝硬变患者中使用dter的孤儿药物地位。
诱发腹水。
Pharmain Corp.机密信息
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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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
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{{ 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:
$ 98.23万 - 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:
$ 98.23万 - 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:
$ 98.23万 - 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:
8930140 - 财政年份:2014
- 资助金额:
$ 98.23万 - 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:
$ 98.23万 - 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
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8300786 - 财政年份:2011
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$ 98.23万 - 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:
$ 98.23万 - 项目类别:
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