The present invention relates to an in vitro method for evaluating the anti- or pro-arrhythmic potential, cardiotoxicity and/or modulation capacity of cardiomyocyte function of compound(s). The present invention also relates to compound(s) identified or evaluated in the method of the invention for use in the treatment of a heart disease. The present invention further relates to the use of the density change of cardiac Nav 1.5 sodium channels in intercalated discs of cardiomyocytes as marker and/or diagnostic for the anti- or pro-arrhythmic potential of a compound, the cardiotoxicity of a compound or modulation capacity of cardiomyocyte function by said compound, and/or in preclinical assessment for cardiac liability of compounds and cardio-safety assessment. The present invention further relates to a kit for evaluating the anti- or pro-arrhythmic potential, cardiotoxicity and/or modulation capacity of cardiomyocyte function of compound(s).

A methylphenidate, particularly including dextro-threo-methylphenidate, is administered to a subject to treat a speech, gait or limb impairment secondary to a genetically acquired pre-frontal cortex processing disease or disorder, particularly including multiple sclerosis, cerebral palsy, Angelman syndrome, Rett syndrome and Fragile-X syndrome.

There is described, inter alia, a coated bead comprising: (a) a granule; (b) a first layer coated over the granule, the first layer comprising a first amount of an active pharmaceutical ingredient comprising a central nervous system stimulant; and (c) a second layer coated over the first layer, the second layer being present in an amount sufficient to substantially delay release of the active pharmaceutical ingredient in the first layer until after the coated bead reaches a distal intestine portion of a subject to whom the coated bead is administered; and (d) the third layer coated over the second layer, the third layer comprising a second amount of the active pharmaceutical ingredient, the third layer being configured to permit substantially immediate release of the active pharmaceutical ingredient comprised therein. Embodiments related to a solid oral pharmaceutical composition are also described.

There is described, inter alia, a coated bead comprising: (a) a granule; (b) a first layer coated over the granule, the first layer comprising a first amount of an active pharmaceutical ingredient comprising a central nervous system stimulant; and (c) a second layer coated over the first layer, the second layer being present in an amount sufficient to substantially delay release of the active pharmaceutical ingredient in the first layer until after the coated bead reaches a distal intestine portion of a subject to whom the coated bead is administered; and (d) the third layer coated over the second layer, the third layer comprising a second amount of the active pharmaceutical ingredient, the third layer being configured to permit substantially immediate release of the active pharmaceutical ingredient comprised therein. Embodiments related to a solid oral pharmaceutical composition are also described.

In various aspects and embodiments, the present invention provides abuse deterrent pharmaceutical formulations, and methods of making the same. The abuse deterrent formulations can comprise a CNS stimulant (particularly one that is addictive or prone to be abused) and an opioid receptor antagonist. These agents are bound by one or more pharmaceutically acceptable resins (e.g., ion exchange resins) to limit their potential to be separated by a potential abuser.

In various aspects and embodiments, the present invention provides abuse deterrent pharmaceutical formulations, and methods of making the same. The abuse deterrent formulations can comprise a CNS stimulant (particularly one that is addictive or prone to be abused) and an opioid receptor antagonist. These agents are bound by one or more pharmaceutically acceptable resins (e.g., ion exchange resins) to limit their potential to be separated by a potential abuser.

In various aspects and embodiments, the present invention provides abuse deterrent pharmaceutical formulations, and methods of making the same. The abuse deterrent formulations can comprise a CNS stimulant (particularly one that is addictive or prone to be abused) and an opioid receptor antagonist. These agents are bound by one or more pharmaceutically acceptable resins (e.g., ion exchange resins) to limit their potential to be separated by a potential abuser.

The invention provides combination therapies that include an agent that shifts cellular metabolism from fatty acid oxidation to glucose oxidation and an inhibitor of pyruvate dehydrogenase kinase. The combination therapies are useful for treating a variety of diseases, disorders, and conditions, including diabetes, cancer, and cardiovascular conditions. The invention also provides methods of treating such conditions using the combination therapies provided herein.

The invention provides combination therapies that include an agent that shifts cellular metabolism from fatty acid oxidation to glucose oxidation and an inhibitor of pyruvate dehydrogenase kinase. The combination therapies are useful for treating a variety of diseases, disorders, and conditions, including diabetes, cancer, and cardiovascular conditions. The invention also provides methods of treating such conditions using the combination therapies provided herein.

The invention provides combination therapies that include an agent that shifts cellular metabolism from fatty acid oxidation to glucose oxidation and an inhibitor of pyruvate dehydrogenase kinase. The combination therapies are useful for treating a variety of diseases, disorders, and conditions, including diabetes, cancer, and cardiovascular conditions. The invention also provides methods of treating such conditions using the combination therapies provided herein.