The present invention provides bicyclic heterocyclyl kinase enzyme inhibitor compounds of formula (I), which are therapeutically useful as kinase inhibitors, particularly IRAK4 inhibitors. ##STR00001##
wherein A, Y, Z, X.sub.1, X.sub.2, X.sub.3, R.sub.1, R.sub.3, ‘m’, ‘n’ and ‘p’ have the meanings given in the specification and pharmaceutically acceptable salt or stereoisomer thereof that are useful in the treatment and prevention of diseases or disorder, in particular their use in diseases or disorder mediated by kinase enzyme, particularly IRAK4 enzyme. The present invention also provides pharmaceutical composition comprising at least one of the compounds of compound of formula (I) together with a pharmaceutically acceptable carrier, diluent or excipient therefor.

The present invention provides compounds that inhibit Factor XIa or kallikrein and pharmaceutically acceptable salts thereof and compositions thereof. The present invention also provides methods of using these compounds and compositions.

High penetration compositions (HPC) of a parent compound, which are capable of crossing biological barriers with high penetration efficiency. The HPCs are capable of being converted to parent drugs or parent drug-related compounds such as metabolites after crossing one or more biological barriers and thus can render treatments for the conditions that the parent drugs or parent drug-related compounds can. Additionally, the HPCs are capable of reaching areas that their parent drugs or parent drug-related compounds may not be able to access or to render a sufficient concentration at the target areas HPCs of NSAIA, for example, have demonstrated indications such as treating hair loss. A HPC can be administered to a subject through various administration routes, e.g., locally delivered to an action site of a condition with a high concentration or systematically administered to a biological subject and enter the general circulation with a faster rate.

Compounds and pharmaceutical compositions that modulate kinase activity, including PI3 kinase activity, and compounds, pharmaceutical compositions, and methods of treatment of diseases and conditions associated with kinase activity, including PI3 kinase activity, are described herein.

Disclosed is a pharmaceutical composition or food composition for the treatment or prevention of hypertension, containing a peptide isolated from a fraction of a flounder surimi hydrolysate as an active ingredient and is based on the finding that the flounder surimi has an effect of reducing blood pressure, and the hydrolysate of the flounder surimi, the fraction of the hydrolysate of the flounder surimi and peptides isolated from the fraction of the hydrolysate of the flounder surimi have an inhibition activity against an angiotensin I converting enzyme (ACE). Thus, peptides isolated from the fraction of the hydrolysate of the flounder surimi can be used for pharmaceutical compositions or food compositions for treating or preventing hypertension. Also, the present invention is based on the finding that the hydrolysate of the flounder surimi and peptides isolated therefrom have radical scavenging effect and a protective effect against oxidative stress and are thus capable of inhibiting ROS production, lipid peroxidation and apoptosis. Accordingly, peptides isolated from fractions of the hydrolysate of the flounder surimi can be used for food compositions for antioxidation.

Disclosed is a pharmaceutical composition or food composition for the treatment or prevention of hypertension, containing a peptide isolated from a fraction of a flounder surimi hydrolysate as an active ingredient and is based on the finding that the flounder surimi has an effect of reducing blood pressure, and the hydrolysate of the flounder surimi, the fraction of the hydrolysate of the flounder surimi and peptides isolated from the fraction of the hydrolysate of the flounder surimi have an inhibition activity against an angiotensin I converting enzyme (ACE). Thus, peptides isolated from the fraction of the hydrolysate of the flounder surimi can be used for pharmaceutical compositions or food compositions for treating or preventing hypertension. Also, the present invention is based on the finding that the hydrolysate of the flounder surimi and peptides isolated therefrom have radical scavenging effect and a protective effect against oxidative stress and are thus capable of inhibiting ROS production, lipid peroxidation and apoptosis. Accordingly, peptides isolated from fractions of the hydrolysate of the flounder surimi can be used for food compositions for antioxidation.

Compounds of the general formula

##STR00001##

are disclosed with activity towards treating diseases related to inflammation, such as cancer, neurodegenerative and cardiovascular diseases. Pharmaceutical compositions and methods of use are also described.

The present invention aims to provide a preparation containing a compound of the formula [I] or a pharmaceutically acceptable salt thereof or a hydrate thereof having improved pharmacokinetics, and a manufacturing method thereof. The present invention relates to a solid dispersion containing (1) an amorphous compound represented by the following formula [I]:

##STR00001##

or a pharmaceutically acceptable salt thereof or a hydrate thereof, and

(2) one to four kinds of pharmaceutically acceptable polymers selected from the group consisting of hydroxypropylmethylcellulose acetate succinate, methylcellulose, hypromellose and polyvinyl alcohol, and a manufacturing method thereof.

Compositions and methods are provided for metabolically degrading ADMA. In one embodiment a device is provided for reducing a patients ADMA levels in their blood wherein the device comprises a biologically active dimethylarginine dimethylaminohydrolase (DDAH) polypeptide covalently linked to a solid support. In one embodiment a method for reducing ADMA levels in a patients blood comprises the step of contacting the patients blood or a blood fraction with an immobilized biologically active DDAH polypeptide, wherein contact of the patients blood with said DDAH polypeptide results in degradation of ADMA present in the patients blood.

Compositions and methods are provided for metabolically degrading ADMA. In one embodiment a device is provided for reducing a patients ADMA levels in their blood wherein the device comprises a biologically active dimethylarginine dimethylaminohydrolase (DDAH) polypeptide covalently linked to a solid support. In one embodiment a method for reducing ADMA levels in a patients blood comprises the step of contacting the patients blood or a blood fraction with an immobilized biologically active DDAH polypeptide, wherein contact of the patients blood with said DDAH polypeptide results in degradation of ADMA present in the patients blood.