DEUTERATED PHARMACEUTICAL COMPOSITIONS AND METHODS OF TREATING CARDIOVASCULAR DISEASES
Provided herein is a pharmaceutical composition comprising (i) a phosphodiesterase inhibitor or an adenosine receptor antagonist, (ii) a calcium channel blocker, (iii) a histamine H 1 -receptor agonist, a histamine H 2 -receptor agonist, or a histamine H 3 -receptor antagonist, and (iv) a β 2 -adrenoreceptor agonist; wherein at least one of two or more active pharmaceutical compounds is deuterium enriched. Also provided herein is a pharmaceutical composition comprising at least one of two or more deuterated compounds which increase pharmacokinetic half-life (increasing the duration of action) and reduce side effects by allowing for reduction of the dose levels. A method of use thereof pharmaceutical composition for treating, preventing, or ameliorating a cardiovascular disease.
1 . The pharmaceutical composition, for treating or ameliorating bradycardia or cardiovascular disease with active pharmaceutical ingredients, comprising:
(i) theophylline or aminophylline 3.2-192 mg/dose, a subtherapeutically effective amount;
(ii) nifedipine, a subtherapeutically effective amount;
(iii) betahistine, a subtherapeutically effective amount;
(iv) levalbuterol or albuterol, a subtherapeutically effective amount;
wherein theophylline is deuterium-enriched no less than 50%.
2 . The pharmaceutical composition of claim 1 , wherein nifedipine 0.16-38.4 mg/dose, a subtherapeutically effective amount.
3 . The pharmaceutical composition of claim 1 , wherein betahistine 0.4-120 mg/dose, a subtherapeutically effective amount.
4 . The pharmaceutical composition of claim 1 , wherein levalbuterol or albuterol 0.03-9 mg/dose, a subtherapeutically effective amount.
5 . The pharmaceutical composition of claim 2 , wherein betahistine 0.4-120 mg/dose, a subtherapeutically effective amount.
6 . The pharmaceutical composition of claim 2 , wherein levalbuterol or albuterol 0.03-9 mg/dose, a subtherapeutically effective amount.
7 . The pharmaceutical composition, for treating or ameliorating bradycardia or cardiovascular disease with active pharmaceutical ingredients, comprising:
(i) theophylline or aminophylline 3.2-192 mg/dose, a subtherapeutically effective amount;
(ii) nifedipine 0.16-38.4 mg/dose;
(iii) betahistine 0.4-120 mg/dose;
(iv) levalbuterol or albuterol 0.03-9 mg/dose;
wherein theophylline is deuterium-enriched.
8 . The pharmaceutical composition of claim 7 , wherein nifedipine 0.16-2.88 mg/dose, a subtherapeutically effective amount.
9 . The pharmaceutical composition of claim 7 , wherein betahistine 0.4-10.8 mg/dose, a subtherapeutically effective amount.
10 . The pharmaceutical composition of claim 7 , wherein levalbuterol or albuterol 0.03-1.08 mg/dose, a subtherapeutically effective amount.
11 . The pharmaceutical composition of claim 8 , wherein betahistine 0.4-10.8 mg/dose, a subtherapeutically effective amount.
12 . The pharmaceutical composition of claim 8 , wherein levalbuterol or albuterol 0.03-1.08 mg/dose, a subtherapeutically effective amount.
13 . The pharmaceutical composition, for treating or ameliorating bradycardia or cardiovascular disease with active pharmaceutical ingredients, comprising:
(v) theophylline or aminophylline 3.2-192 mg/dose, a subtherapeutically effective amount;
(vi) nifedipine, a subtherapeutically effective amount;
(vii) betahistine, a subtherapeutically effective amount;
(viii) levalbuterol or albuterol, a subtherapeutically effective amount;
wherein theophylline is deuterium-enriched.
14 . The pharmaceutical composition of claim 13 , wherein nifedipine 0.16-38.4 mg/dose, a subtherapeutically effective amount.
15 . The pharmaceutical composition of claim 13 , wherein betahistine 0.4-120 mg/dose, a subtherapeutically effective amount.
16 . The pharmaceutical composition of claim 13 , wherein levalbuterol or albuterol 0.03-9 mg/dose, a subtherapeutically effective amount.
17 . The pharmaceutical composition of claim 14 , wherein betahistine 0.4-120 mg/dose, a subtherapeutically effective amount.
18 . The pharmaceutical composition of claim 14 , wherein levalbuterol or albuterol 0.03-9 mg/dose, a subtherapeutically effective amount.
19 . The pharmaceutical composition of claim 1 , further comprising said composition formulated in extended-release dosage forms.
20 . The pharmaceutical composition of claim 13 , further comprising said composition formulated in extended-release dosage forms.