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
- 来源:
- 关键词:AbdomenAcuteAlbuminsAlcoholismAmericanAscitesBloodCalciumCarbonCaringCell Culture TechniquesChronicCirrhosisCleaved cellCreation of peritoneovascular shuntDiureticsDoseDrug Delivery SystemsDrug FormulationsDrug KineticsEnzyme ActivationEquilibriumEuropeFamily suidaeFatty AcidsFluid overloadFunctional disorderFurosemideGlycineGoalsGreater sac of peritoneumHalf-LifeHealthHealth Care CostsHemorrhageHepatic EncephalopathyHepatorenal SyndromeHourHumanInfectionInjection of therapeutic agentIntravenousIntravenous BolusKidneyLeadLiquid substanceLiverLiver CirrhosisLiver diseasesLysineMarketingMeasurableMedicalModelingN-terminalNational Institute of Allergy and Infectious DiseaseNecrosisOperative Surgical ProceduresOutpatientsParacentesisPatientsPeptide HydrolasesPeptidesPeritoneal FluidPharmaceutical PreparationsPhasePolymersPortal HypertensionPortal PressurePortal vein structurePractice GuidelinesPrevalenceProceduresProcessProdrugsQuality of lifeRattusRecommendationRefractoryRiskSafetySerumSideSkinSmall Business Innovation Research GrantSodium ChlorideSodium-Restricted DietSpironolactoneStagingStructureSubcutaneous InjectionsSurvival RateSyndromeTechnologyTestingTherapeuticTimeTransjugular intrahepatic portosystemic shunt procedureVaricosityVasopressinsViral hepatitisWeight Gainbasecost effectivedesigndietary restrictiondrug candidatedrug developmenteffective therapyefficacy testinghemodynamicsliver transplantationmortalitynanocarriernonalcoholic steatohepatitispressurepreventresponsesubcutaneoussuccesssynthetic peptidevasoactive agent
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):所有类型腹水的患病率,无论原因如何,为41.7 / 100000,其中80%由肝硬化引起。腹水的治疗采用限盐饮食和利尿剂的药物治疗。然而,在5%至10%的腹水患者中,腹水对药物治疗变得难治性。由于晚期肝硬化而发生难治性腹水的患者中有一半在不进行肝移植的情况下会在一年内死亡,因此建议尽快转诊进行肝移植。等待期间的临时治疗包括大容量穿刺、经颈静脉肝内门静脉系统分流术(TIPS)和腹膜静脉分流术。这些手术的并发症可进一步增加死亡率,包括穿刺旁诱发的循环功能障碍(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的药物治疗,并作为肝移植的治疗桥梁。Terlipressin (tri-glycyl [8-lys] vas加压素)是一种合成多肽药物,可降低门静脉压力,恢复血流动力学平衡,是治疗门静脉高压腹水的有效药物。这种前药在血液中缓慢转化为血管活性药物[8-lys]血管加压素;它具有良好的耐受性,并且具有比人类天然抗利尿激素([8-Arg]抗利尿激素)更好的安全性。静脉注射特利加压素在欧洲已经有20年的历史了,它是治疗出血和肝肾综合征(HRS)的最具成本效益和经济效益的药物之一,有充分的证据表明它能提高生存率。尽管特利加压素具有良好的安全性,但由于半衰期短(26分钟),需要每4-6小时静脉注射一次,因此目前特利加压素的使用仅限于急性护理环境。我们相信,一种新的特利加压素衍生物的配方可以每天给药一次,理想情况下是皮下给药,并且在美国的门诊环境(这将降低总体医疗成本)中具有重要的市场机会,用于治疗肝硬化引起的门静脉高压症引起的难治性腹水。我们开发了一种新的长效特利加压素(LAT),该技术基于PI发明的专有药物传递技术,可以持续释放改性特利加压素。LAT的半衰期比未修饰的特利加压素肽长得多(分别为3.3小时和0.8小时),并且观察到可测量的血药浓度维持20小时以上,而特利加压素的快速清除需要5小时。本研究将对配方进行优化,测定各种代谢物的药代动力学,确定所需的最佳剂量,并检测该配方治疗肝硬化腹水大鼠的疗效。
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)
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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:
$ 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:
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:
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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$ 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
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8196005 - 财政年份:2011
- 资助金额:
$ 28.03万 - 项目类别:
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