Английская Википедия:AH-1058
Шаблон:Short description Шаблон:Infobox drug
AH-1058 is a lipophilic antiarrhythmic calcium channel blocker synthesized by the Pharmaceutical Research Laboratories of Ajinomoto Co., Inc in Kawasaki, Japan.[1] It is derived from cyproheptadine, a compound with known antiserotonic, antihistaminic and calcium channel blocking properties.[1][2] The IUPAC name of AH-1058 is: 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-[E-3-(3-methoxy-2-nitro) phenyl-2-propenyl]piperidine hydrochloride.[3]
Medical uses
AH-1058 displays characteristics of Class IV antiarrhythmics (L-type calcium channel blockers). Class I antiarrhythmic (sodium channel blocker) characteristics have also been seen, but the effect AH-1058 has on sodium channels is variable and unknown.[1] Some proposed uses for AH-1058 include the treatment of angina pectoris, stenosis of the outflow tract from obstructive hypertrophic cardiomyopathy and ventricular arrhythmias.[1][4] Treatment of these conditions (long term and short term) is possible due to the cardioselective nature of AH-1058 and the ability of AH-1058 to inhibit calcium channels and thus reduce cardiac contractility and energy consumption.[3][5]
Studies have compared AH-1058 to widely used and clinically available drugs such as verapamil (a Class IV antiarrhythmic drug)[1] and atenolol (a beta blocker)[6] to assess the efficacy of AH-1058. The effects of AH-1058 are slower to onset but longer-lasting than those of verapamil and atenolol.[7][5] In addition, the minimal effects AH-1058 has on total peripheral vascular resistance is an important advantage over atenolol and verapamil, as these drugs can be taken long term for disease management.[8] Lastly AH-1058 displays a greater selectivity for cardiac tissue over verapamil and atenolol with the same level of potency as verapamil in vitro.[8][9] AH-1058 studies have been limited to in vitro and in vivo canine and guinea-pig models,[3] with a greater potency displayed in vitro than in vivo.[7] Along with decreased potency in vivo, blood levels do not correlate with AH-1058 activity.[8]
Pharmacology
Mechanism of action
AH-1058 is a cardioselective L-type calcium channel blocker.[1][3][10] AH-1058 binds to the same sites on the alpha-1 subunit of L-type calcium channels as phenylalkylamines (ex. verapamil) and benzothiazepines; both of which are well known calcium channel blockers.[5] These sites on the alpha-1 subunit differ from the active site of the calcium channel, meaning AH-1058 binds L-type calcium channels allosterically to alter activity.[5] In addition AH-1058 appears to interact with multiple states of L-type calcium channels (i.e. resting and inactive) to suppress calcium currents.[1] A minor effect on sodium channels at higher concentrations has also been seen, but these effects appear to vary between species.[1]
Mode of action
The calcium blocking activity of AH-1058 can decrease ventricular contractility, heart rate, and conductance through the atrioventricular node.[1][3][7] In addition AH-1058 has been shown to decrease systolic blood pressure while minimally affecting total peripheral vascular resistance and leaving diastolic blood pressure unaffected.[8] The order of the potency of the effects AH-1058 has on the cardiovascular system is: ventricular contraction > coronary blood flow >> atrioventricular conduction > sinoatrial automaticity (level of sinoatrial self-activation).[7]
References
- ↑ 1,0 1,1 1,2 1,3 1,4 1,5 1,6 1,7 1,8 Шаблон:Cite journal
- ↑ Шаблон:Cite journal
- ↑ 3,0 3,1 3,2 3,3 3,4 Шаблон:Cite journal
- ↑ Шаблон:Cite journal
- ↑ 5,0 5,1 5,2 5,3 Шаблон:Cite journal
- ↑ Шаблон:Cite journal
- ↑ 7,0 7,1 7,2 7,3 Шаблон:Cite journal
- ↑ 8,0 8,1 8,2 8,3 Шаблон:Cite journal
- ↑ Шаблон:Cite journal
- ↑ Шаблон:Cite journal
