SBIR-STTR Award

Arterial thrombotic diseases such as myocardial infarction and stroke are the leading cause of death in the U.S. Their socioeconomic and psychological impacts are immense. Drugs that can efficaciously reduce or eliminate these diseases are of great clinical importance and should have major commercial applications. Unfortunately efficacious drugs are limited. We consider it important to develop new anti-thrombotic drugs. In our pilot work we have identified anti-platelet properties in the ethanol-soluble fraction of a Chinese fungus, Cordyceps sinensis. The fraction exhibited inhibitory activity against platelet aggregation and secretion. Its inhibitory effect appears to be independent of thromboxane A2 and may be related to cAMP elevation. We propose in this SBIR application to purify the active component, evaluate its biological activity, elucidate its mechanism of action and assess its anti- thrombotic efficacy. The Phase I study will determine the feasibility of the purifying procedures and testing anti-platelet properties. We plan to carry out a sequence of solvent-solvent extractions which have been developed in our laboratory and is effective in segregating active compounds on the basis of their polarity into one or two highly enriched fractions. The inhibitory effect of the concentrated fractions on platelet aggregation and secretion will be evaluated in a lumiaggregometer. The fractions will be then processed by step-by-step procedures to isolate the active component. The Phase I study will lay the foundation essential for the full development of the active component into anti-thrombotic drugs in Phase II and subsequent clinical studies.

Thesaurus Terms:
Blood coagulation, anticoagulants, platelet aggregation inhibitors, blood platelets, chemical structure--biological activity blood coagulation, fibrinogen, blood platelets, platelet activation, platelet aggregation, calcium flux (cellular), purine nucleotides, adenine nucleotides, amp cyclic fungi, ascomycetes, claviceps, human, clinical, human, human subjects, volunteers, physical separation, fractionation, solvent

Arterial thrombotic diseases such as myocardial infarction and stroke are the leading cause of death in the U. S. Their socioeconomic and psychological impacts are immense. As thrombosis is a crucial process in the initiation and propagation of arterial occlusive disease, there is a compelling reason to develop novel, specific anti-thrombotic drugs. Drugs that can efficaciously reduce or eliminate these diseases are of great clinical importance and should have major commercial applications. Unfortunately, efficacious drugs are quite limited. The objective of this study is to develop new pharmacologic strategies for treating thromboembolic disorders. Our pilot work from Phase I designed to characterize the inhibitory component(s) of Cordyceps sinenis revealed that the inhibitory activity could be due to at least two, low molecular weight, organic solvent extractable, active principle(s). One active principle(s) appears to be non-poplar compound; whereas, the other appears to be a polar compound. We also found that the cultured mycelia extracts had the same two active fractions. In Phase 11, we will isolate and purify both types of active principle from Cordyceps sinensis as well as its cultured mycelia (ccs-2). Once purified, we will evaluate the physicochemical and biological activities and elucidate their mechanism of action. The effects of the active principle(s) on thrombosis inhibition will be evaluated in animal models. Finally, we will attempt to synthesize these active principle(s), their analogs and assess their biological activities.Awardee's statement of the potential commercial applications of the research: There is a great need for novel anti-thrombotic agents. The compounds that are being purified from Cordyceps sinensis appear to be novel and therefore, it will have important commercial value. Phase 11 support is critical for purification, characterization and evaluation of the physicochemical and biological properties. Once the chemical structure of a given active compound is defined, it may be chemically synthesized and may be modified. We believe that the work will yield a group of new anti-thrombotic agents which are therapeutically useful, and are optimistic about their commercial potential.National Heart, Lung, and Blood Institute (NHLBI)