Provided are biphenyl derivatives having the structure of Formula 1: ##STR00001##
stereoisomers thereof, and pharmaceutically acceptable salts thereof, wherein R.sub.1 is hydrogen, halogen, hydroxy, substituted or unsubstituted C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6 alkoxy; R.sub.2, R.sub.3 and R.sub.4 are each independently hydrogen, halogen, substituted or unsubstituted amino, nitro, cyano, hydroxy, substituted or unsubstituted C.sub.1-C.sub.6 alkyl, substituted or unsubstituted C.sub.1-C.sub.6 alkoxy, or —C(O)R.sub.6; R.sub.5 is hydrogen or C.sub.1-C.sub.6 alkyl; n is 0 or 1; and R.sub.6 is hydrogen or amino, methods for preparing the same, and a pharmaceutical composition containing the same. The biphenyl derivatives having the structure of Formula 1 act as muscarinic M3 receptor antagonists, and thus are useful for the prevention or treatment of a disease selected from among chronic obstructive pulmonary disease, asthma, irritable bowel syndrome, urinary incontinence, rhinitis, spasmodic colitis, chronic cystitis, Alzheimer's disease, senile dementia, glaucoma, schizophrenia, gastroesophageal reflux disease, cardiac arrhythmia, and hyper-salivation syndromes.

Pharmaceutical compositions that stabilize a Clostridial toxin active ingredient are described. The compositions can be liquid or solid compositions, and comprise a surfactant and an antioxidant. In some embodiments, the compositions comprise a surfactant selected from a poloxamer and a polysorbate; an antioxidant selected from methionine, N-acetyl cysteine, ethylenediaminetetraacetic acid and combinations thereof; and, optionally, a tonicity agent and/or a lyoprotector selected from, for example, trehalose and sucrose.

Pharmaceutical compositions that stabilize a Clostridial toxin active ingredient are described. The compositions can be liquid or solid compositions, and comprise a surfactant and an antioxidant. In some embodiments, the compositions comprise a surfactant selected from a poloxamer and a polysorbate; an antioxidant selected from methionine, N-acetyl cysteine, ethylenediaminetetraacetic acid and combinations thereof; and, optionally, a tonicity agent and/or a lyoprotector selected from, for example, trehalose and sucrose.

The invention provides novel adrenomedullin analogs that exhibit high biological stability in administering to subjects while maintaining pharmacological effects of the parent compound adrenomedullin. An aspect of the invention relates to a compound or a salt thereof, or a solvate thereof, wherein the compound is a peptide selected from the group consisting of: (a) a peptide consisting of an amino acid sequence of SEQ ID NO: 3 wherein one to three amino acid residues are substituted or deleted; (b) a peptide having a disulfide bond formed by cysteine residues at positions 4 and 9 of the peptide of (a); (c) a peptide wherein the disulfide bond of the peptide of (b) is substituted with an ethylene group; (d) a peptide wherein one to three amino acid residues of any of the peptides of (a) to (c) are deleted or added; (e) a peptide wherein any of the peptides of (a) to (d) is amidated at the C-terminus thereof; and (f) a peptide wherein any of the peptides of (a) to (d) has a glycine residue added to the C-terminus thereof. Another aspect of the invention relates to a method for producing the compound or the like, and a medicament and agent for prevention or treatment each comprising the compound or the like as an active ingredient.

The invention provides compounds which are selective PDE2 inhibitors for use in the treatment of tachycardia or tachyarrhythmia. Such compounds are particularly suitable for use in the treatment of any of the following conditions: atrial tachycardia, atrial fibrillation, atrial flutter, paroxysmal supraventricular tachycardia, premature ventricular contractions (PVCs), ventricular fibrillation and ventricular tachycardia, and may be used alone or in combination therapy with other conventional cardiovascular drugs, e.g. beta-blockers. In particular, the invention provides compounds which are selective PDE2 inhibitors for use in the treatment of ventricular tachycardia in patients who are suffering from, or who are at risk of suffering from heart failure, CPVT or long QT syndrome.

The invention provides compounds which are selective PDE2 inhibitors for use in the treatment of tachycardia or tachyarrhythmia. Such compounds are particularly suitable for use in the treatment of any of the following conditions: atrial tachycardia, atrial fibrillation, atrial flutter, paroxysmal supraventricular tachycardia, premature ventricular contractions (PVCs), ventricular fibrillation and ventricular tachycardia, and may be used alone or in combination therapy with other conventional cardiovascular drugs, e.g. beta-blockers. In particular, the invention provides compounds which are selective PDE2 inhibitors for use in the treatment of ventricular tachycardia in patients who are suffering from, or who are at risk of suffering from heart failure, CPVT or long QT syndrome.

Methods of administering an anti-arrhythmic, such as dofetilide, to a patient in an amount effective for treating a cardiovascular condition are described. The drug can be administered intravenously for at least one hour. A loading dose of 0.1 to 12 μg/kg bodyweight over a duration of up to 60 minutes can be administered and/or a maintenance dose of 0.1 to 10 μg/kg/hr can be administered intravenously over a duration of at least 1 hour, optionally alternatively or in addition wherein the amount of the loading dose and/or the IV maintenance dose is in the range of about ±50% of a maintenance dofetilide dose. The cardiovascular condition can include atrial fibrillation or flutter, ventricular tachycardia, hemodynamically stable or unstable ventricular tachycardia, paroxysmal atrial fibrillation, ventricular fibrillation, paroxysmal supraventricular tachycardia, heart failure, coronary artery disease, or pulmonary artery hypertension. A patient's QT interval and/or a creatinine clearance can be measured, and the effective amount can be selected based on either or both of the QT interval or the creatinine clearance measurements.

Methods of administering an anti-arrhythmic, such as dofetilide, to a patient in an amount effective for treating a cardiovascular condition are described. The drug can be administered intravenously for at least one hour. A loading dose of 0.1 to 12 μg/kg bodyweight over a duration of up to 60 minutes can be administered and/or a maintenance dose of 0.1 to 10 μg/kg/hr can be administered intravenously over a duration of at least 1 hour, optionally alternatively or in addition wherein the amount of the loading dose and/or the IV maintenance dose is in the range of about ±50% of a maintenance dofetilide dose. The cardiovascular condition can include atrial fibrillation or flutter, ventricular tachycardia, hemodynamically stable or unstable ventricular tachycardia, paroxysmal atrial fibrillation, ventricular fibrillation, paroxysmal supraventricular tachycardia, heart failure, coronary artery disease, or pulmonary artery hypertension. A patient's QT interval and/or a creatinine clearance can be measured, and the effective amount can be selected based on either or both of the QT interval or the creatinine clearance measurements.

The invention relates to a new method for the prevention and treatment of wave burst arrhythmia by administering a gestagen having an androgenic effect.

The compound of the formula (I-1): ##STR00001##
wherein all the symbols have the same meanings as described in the specification, has two cyclic groups, particularly phenoxy groups at specific substitution positions and thus has high human S1P.sub.2 antagonistic activity. The compound may therefore be used as a therapeutic agent for S1P.sub.2-mediated diseases such as diseases resulting from vascular constriction, fibrosis, and respiratory diseases.