The present application relates to compositions and methods for treating a proliferative disorder by administering to a subject a pharmaceutical composition of a dual kinase inhibitor metabolite. Catecholic butane metabolites can serve as dual kinase inhibitors for purposes of methods described herein.

Embodiments of the invention involve treating ophthalmology conditions by the topical or oral use of acetylcholinesterase inhibitors. By effectively reducing or eliminating the population of demodex mites in affected areas and areas where demodex mites may exist, this treatment achieves a more complete remission of clinical signs and symptoms of the ophthalmological afflictions than any previously described method. Embodiments of the invention are useful for treating ocular afflictions caused by demodex-induced inflammatory eye conditions, including meibomian gland dysfunction, conjunctivitis, keratoconjunctivitis, hyperemia, blepharitis and dry eye disease.

Embodiments of the invention involve treating ophthalmology conditions by the topical or oral use of acetylcholinesterase inhibitors. By effectively reducing or eliminating the population of demodex mites in affected areas and areas where demodex mites may exist, this treatment achieves a more complete remission of clinical signs and symptoms of the ophthalmological afflictions than any previously described method. Embodiments of the invention are useful for treating ocular afflictions caused by demodex-induced inflammatory eye conditions, including meibomian gland dysfunction, conjunctivitis, keratoconjunctivitis, hyperemia, blepharitis and dry eye disease.

The present disclosure is directed to compounds and methods for the treatment of disorders associated with fluid retention or salt overload, such as heart failure (in particular, congestive heart failure), chronic kidney disease, end-stage renal disease, liver disease, and peroxisome proliferator-activated receptor (PPAR) gamma agonist-induced fluid retention. The present disclosure is also directed to compounds and methods for the treatment of hypertension. The present disclosure is also directed to compounds and methods for the treatment of gastrointestinal tract disorders, including the treatment or reduction of pain associated with gastrointestinal tract disorders. The methods generally comprise administering to a mammal in need thereof a pharmaceutically effective amount of a compound, or a pharmaceutical composition comprising such a compound, that is designed to be substantially active in the gastrointestinal (GI) tract to inhibit NHE-mediated antiport of sodium ions and hydrogen ions therein. More particularly, the method comprises administering to a mammal in need thereof a pharmaceutically effective amount of a compound, or a pharmaceutical composition comprising such a compound, that inhibits NHE-3, -2 and/or -8 mediated antiport of sodium and/or hydrogen ions in the GI tract and is designed to be substantially impermeable to the layer of epithelial cells, or more specifically the epithelium of the GI tract. As a result of the compound being substantially impermeable, it is not absorbed and is thus essentially systemically non-bioavailable, so as to limit the exposure of other internal organs (e.g., liver, heart, brain, etc.) thereto. The present disclosure is still further directed to a method wherein a mammal is administered such a compound with a fluid-absorbing polymer, such that the combination acts as described above and further provides the ability to sequester fluid and/or salt present in the GI tract.

Disclosed are compounds of Formula 1, ##STR00001##
stereoisomers thereof and pharmaceutically acceptable salts of the compounds and stereoisomers, wherein R.sup.1 and R.sup.2 are defined in the specification. This disclosure also relates to materials and methods for preparing compounds of Formula 1, to pharmaceutical compositions which contain them, and to their use for treating obesity and related diseases, disorders, and conditions associated with MetAP2.

Disclosed are compounds of Formula 1, ##STR00001##
stereoisomers thereof and pharmaceutically acceptable salts of the compounds and stereoisomers, wherein R.sup.1 and R.sup.2 are defined in the specification. This disclosure also relates to materials and methods for preparing compounds of Formula 1, to pharmaceutical compositions which contain them, and to their use for treating obesity and related diseases, disorders, and conditions associated with MetAP2.

Cancer stem cells are responsible for tumor recurrence, distant metastasis and drug-resistance, in the vast majority of cancer patients. There exists an urgent need to identify new mitochondrial inhibitor drugs that can target and eradicate CSCs, and companion diagnostics to identify candidates for mitochondrial inhibition therapy. In 3D mammospheres, 25 mitochondrial-related proteins were over 100-fold over-expressed in a large collection of transcriptional profiling data from ER(+) breast cancer patients. These 25 proteins may be used to derive short gene signatures to predict the likelihood of distant metastasis and tumor recurrence. For example, the 4-gene signature of ACLY, VDAC3, HADH2, and COX6B1 may be used for predicting the likelihood of distant metastasis, with a hazard ratio of 1.91-fold (P=2.2e−08). A pharmaceutically effective amount of a mitochondrial inhibitor may be administered to a candidate having elevated expression of the genes in a gene signature. Five example mitochondrial inhibitors showed preferential and selective inhibition of tumor cell metastasis, without causing significant toxicity. Mechanistically, all five mitochondrial inhibitors have been previously shown to induce ATP-depletion in cancer cells. Gene signatures composed of 6-9 large mitochondrial ribosomal proteins also show prognostic value in predicting distant metastasis, tumor recurrence, and Tamoxifen resistance, in both ER(+) and ER(−) breast cancer patients. The disclosed gene signatures may be used as companion diagnostics to assess which patients may benefit most from mitochondrial inhibition therapy.

Pharmaceutical compositions and methods of their use are provided for reducing inflammation in a subject, blocking leukocyte recruitment, inhibiting tumor metastasis, treating sepsis and preventing/reducing acute kidney injury.

Pharmaceutical compositions and methods of their use are provided for reducing inflammation in a subject, blocking leukocyte recruitment, inhibiting tumor metastasis, treating sepsis and preventing/reducing acute kidney injury.

The present invention relates to a combination product and its use in therapy.