The present disclosure provides macrocyclic compounds inspired by the immunophilin ligand family of natural products FK506 and rapamycin. The generation of a Rapafucin library of macrocyles that contain FK506 and rapamycin binding domains should have great potential as new leads for developing drugs to be used for treating diseases.

The present disclosure provides macrocyclic compounds inspired by the immunophilin ligand family of natural products FK506 and rapamycin. The generation of a Rapafucin library of macrocyles that contain FK506 and rapamycin binding domains should have great potential as new leads for developing drugs to be used for treating diseases.

The present invention relates to a novel cocrystal, a pharmaceutical composition comprising same and a preparation method therefor. By using the cocrystal of the present invention, cancers, inflammatory diseases, or viral infection diseases may be effectively prevented and/or treated.

Provided are therapeutic combinations or formulations of drugs comprising triple monoamine reuptake inhibitors, melanin concentrating hormone receptor 1 (MCHRT) antagonists and diazoxide or its formulations and various combinations thereof, these in combination with other drugs or active agents. Provided are methods for the treatment of various conditions, including genetic confirmed syndromes, and diseases, using therapeutic combinations and formulations of drugs as provided herein. Provided are methods for administering triple monoamine reuptake inhibitors (TRIs), melanin concentrating hormone receptor 1 (MCHRT) antagonists and diazoxide or diazoxide or its formulations, whose dosages are determined using a method as provided herein including empirical methods for safe and predictable titration and to determine the initial therapeutic dose; model-based methods for safe and predictable titration and to determine the initial therapeutic dose and to determine the lowest therapeutic dose or to determine an optimal effective dose, including use of Bayesian pharmacometric models.

The present disclosure is directed to bifunctional small molecules which contain a circulating protein binding moiety (CPBM) linked through a linker group to a cellular receptor binding moiety (CRBM) which is a membrane receptor of degrading cell such as a hepatocyte or other degrading cell. In certain embodiments, the (CRBM) is a moiety which binds to asialoglycoprotein receptor (an asialoglycoprotein receptor binding moiety, or ASGPRBM) of a hepatocyte. In additional embodiments, the (CRBM) is a moiety which binds to a receptor of other cells which can degrade proteins, such as a LRP1, LDLR, FcγRI, FcRN, Transferrin or Macrophage Scavenger receptor.

The present disclosure is directed to bifunctional small molecules which contain a circulating protein binding moiety (CPBM) linked through a linker group to a cellular receptor binding moiety (CRBM) which is a membrane receptor of degrading cell such as a hepatocyte or other degrading cell. In certain embodiments, the (CRBM) is a moiety which binds to asialoglycoprotein receptor (an asialoglycoprotein receptor binding moiety, or ASGPRBM) of a hepatocyte. In additional embodiments, the (CRBM) is a moiety which binds to a receptor of other cells which can degrade proteins, such as a LRP1, LDLR, FcγRI, FcRN, Transferrin or Macrophage Scavenger receptor.

Provided herein are methods for the production of native and reconstituted hyaluronan (HA) complexes containing pentraxin-3 (PTX3) and heavy chain 1 (HC1) of inter alpha inhibitor (IαI). Compositions containing the complexes and therapeutic methods using the complexes are provided. Combinations and kits for use in practicing the methods also are provided.

Provided herein are methods for the production of native and reconstituted hyaluronan (HA) complexes containing pentraxin-3 (PTX3) and heavy chain 1 (HC1) of inter alpha inhibitor (IαI). Compositions containing the complexes and therapeutic methods using the complexes are provided. Combinations and kits for use in practicing the methods also are provided.

The present disclosure provides methods and formulations for treating a patient suffering from one or more of chronic inflammatory injury, metaplasia, dysplasia or cancer of esophageal tissue and gastric tissue, which method comprises administering to the patient an agent that selectively kills or inhibits the proliferation or differentiation of pathogenic Barrett's Esophagus stem cells (BESCs) or Gastric Intestinal Metaplasia stem cells (GIMSCs) relative to normal regenerative esophageal stem cells or gastric stem cells in the tissue in which the BESCs or GIMSCs are found.

The present disclosure provides methods and formulations for treating a patient suffering from one or more of chronic inflammatory injury, metaplasia, dysplasia or cancer of esophageal tissue and gastric tissue, which method comprises administering to the patient an agent that selectively kills or inhibits the proliferation or differentiation of pathogenic Barrett's Esophagus stem cells (BESCs) or Gastric Intestinal Metaplasia stem cells (GIMSCs) relative to normal regenerative esophageal stem cells or gastric stem cells in the tissue in which the BESCs or GIMSCs are found.