Stroke Treatment by Chemically-induced Hypothermia

ABSTRACTWhile acute stroke is a leading cause of human death and disability in the United Statesunfortunatelyclinical therapies for stroke are limited and unsatisfactoryThe overwhelming failures of stroke treatments in clinical trials strongly indicate thatto battle this multifaceted brain disordernovel strategies that target multiple cell types and afford different mechanisms of protection are needed to achieve positive therapeutic effectsOne strategymechanical induction of mild hypothermiadefined as aoC decrease in body temperaturehas shown remarkable neuroprotective effects against brain ischemia in both animal and human studiesAt this timehoweveravailable physical cooling techniques are ineffectual and usually impracticalA more recent focus has been to identify pharmacological compounds that can be used to induce hypothermiaIn theorypharmacologically induced hypothermiaPIHcan be initiated much earlier after the stroke event and in the absence of mechanical coolingEven a smalloCdecrease in body temperature during early hours after stroke prevents detrimental post stroke hyperthermiawhile mild hypothermiaoC reductiondecreases the extent of ischemic injuryIn our Phase I and Phase II investigationswe demonstrated that rapid and reproducible hypothermia is induced by several novel neurotensin receptorNTRagonistsresulting in significant neuroprotection against brain damage induced by ischemic strokehemorrhage strokeor traumatic brain injuryTBIin rodent modelsThe key breakthrough is that the NTRagonists do not induce shivering in the subject animalsthe major problem associated with other agents that mechanically or pharmacologically induce hypothermiaThe NTRcompounds also act synergistically with tissue plasminogen activatortPAthe only FDA approved thrombolytic treatment at this timeDuring Phases I and IIwe also demonstrated hypothermia induction by our leads in non human primatesand completed a number of IND enabling tasks with satisfactory outcomesFor this Phase IIb studyin Specific Aimwe will continue to study the hypothermic effect of our compounds in monkeyswith the overall opportunity of providing a clear bridge between rodentnon human primatesand human clinical studiesIn particularwe will demonstrate the stroke protection synergism between tPA and our NTRagonistsas was previously demonstrated in rodentsIn Specific Aimrequired IND enabling preclinical evaluations will be completedwhile in Specific Aimwe will commissionday toxicity studies in two speciesrat and dogwhich also are necessary for IND preparationFinallyin Specific Aimwe will prepare and submit the INDWhen these four Specific Aims are completed satisfactorilyour lead will be ready to enter human clinical trialswhich will serve as a major value influx point for seeking further funding to support the program NARRATIVEIschemic stroke is the third leading cause of human death and disability in the USOur goal is to develop a clinically effective and feasible hypothermia therapy that could serve as an adjunct toor replacethe only FDA approved therapytissue plasminogen activatortPAWe have completed Phase I and II of this projectIn Phase Iwe synthesized and identified neurotensin receptor I derivatives for induction of hypothermia that served to dramatically decrease the size of an induced infarctIn Phase IIwe demonstrated improvement of the therapeutic window of tPA with our leaddemonstrated the lack of negative behavioral and toxicity effectsand demonstrated that the hypothermic effect can be induced in non human primatesIn Phase IIbother necessary preclinical studies will be completed and an IND will be written and submitted