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:所有类型腹水的患病率(无论病因如何)为41.7/100,000,
其中80%是因为肝硬化。腹水的治疗是限盐饮食和药物治疗,
利尿剂然而,在5%至10%的腹水患者成为难治性药物治疗。半年
由于晚期肝硬化而产生顽固性腹水的患者将在一年内死亡,
肝移植,因此建议加速转诊肝移植。临时救治
等待期间包括大容量穿刺术、经颈静脉肝内门体分流术(TIPS),
腹膜静脉分流外科手术。这些手术的并发症会进一步增加
死亡率包括穿刺引起的循环功能障碍(PICD)和慢性肝性脑病
从TIPS药物治疗可以阻止进展或延长生存期,并作为一种治疗方法。
因此迫切需要肝移植的治疗桥梁。特利加压素,三甘氨酰[8-Lys]
加压素是赖氨酸-加压素(LVP)的无活性前药,其缓慢释放活性LVP,
最小化可导致缺血性副作用的LVP尖峰。LVP降低门静脉压力,恢复
是治疗门脉高压性腹水的有效方法。由于LVP缓慢
释放后,特利加压素耐受性良好,并且具有比人天然加压素好得多的安全性([8- 10])。
精氨酸加压素)。静脉内特利加压素在过去二十年中已在欧洲可用,
是治疗静脉曲张出血和肝肾功能障碍的最经济有效的药物之一。
HRS综合征(HRS)与生存率的改善是有据可查的。尽管安全性很好
由于半衰期短,特利加压素的使用目前仅限于急性护理环境(26
分钟),需要每4- 6小时通过IV推注给药。我们开发了一种新的特利加压素
衍生物(dTer),具有慢得多的LVP释放,并被发现是有效的肝硬化诱导的大鼠模型
每日一次推注皮下给药时,门静脉高压腹水。该产品可以有
在美国,特别是在门诊环境中,这是一个重大的市场机会(这将减少整体
通过消除住院费用的医疗保健费用)用于治疗肝硬化的难治性腹水-
诱发门脉高压性腹水。该产品(dTer)提供活性LVP的持续释放,
证明血液存在时间显著延长,LVP Cmax较低(消除缺血性副作用)
而不是特利加压素本提案旨在收集IND启用数据包,以提交给FDA
开始临床试验。我们已经获得了dTer在肝硬化患者中使用的孤儿药地位
诱导腹水。
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:
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:
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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