L-Sotalol

Eckardt, L., Haverkamp, W., Mertens, H., Johna, R., Clague, J.R., Borggrefe, M., and Breithardt, G., Drug-related torsades de pointes in the isolated rabbit heart comparison of clofilium, d,l-sotalol, and erythromycin, /. Cardiovasc. Pharmacol., 32, 425-434,1998. 

Pacifico, A., et al.. Prevention of implantable-defibrillator shocks by treatment with sotalol. d,l-Sotalol Implantable Cardioverter-Defibrillator Study Group. New Engl J Med, 1999. 340(24) p. 1855-62. 

Deneer VHM, Drese GB, Roemele PEH, Verhoef JC, Lie-A-Huen L, Kingma JH, Brouwers JRBJ, Junginger HE (2002) Buccal transport of flecainide and sotalol Effect of a bile salt and ionization state. Int J Pharm 241 127-134... 

Sotalol (13) is a racemic mixture, and its two enantiomers have been studied extensively [47-51]. As expected from studies with other ff-blocking agents, the Class II activity resides predominantly in only one enantiomer [(-)-sotalol] while the Class III activity can be found equally in both enantiomers. Therefore, the (-I-)-enantiomer, which is essentially devoid of P-blocking activity, has been studied as one of the few early examples of a selective Class III agent. Both sotalol [52-55] and its enantiomer, (-l-)-sota-lol [56-58], have been shown to be clinically effective in the prevention of ventricular arrhythmias. The efficacy rate for suppression of inducible ventricular tachycardia during programmed electrical stimulation for both... 

In addition to the amiodarone-related compounds, (81) and (82), described above, BASF has been exploring some novel heterocyclic compounds as Class III antiarrhythmic agents. A series of imidazo[l,2-c]pyrro-lo[l,2-a]quinazoline derivatives have been patented which are several times more potent than (-I- )-sotalol in lengthening QT interval of the electrocardiogram in the anaesthetized guinea-pig model [230], One of the most potent compounds is (85), which was 17-times more potent than the standard. These compounds represent one of the unique Class III structural types described to date. 

Blockers are antiarrhythmics of class II according to the Vaughan-Williams classification, effective in the treatment of both supraventricular and ventricular tachyarrhythmias. These drugs can also reduce ectopic beats, especially if they are a result of sympathetic activity. Sotalol is a racemic mixture of the -blocking L-isomer and the class III antiarrhythmic D-isomer. This racemic mixture as well as D-sotalol are used as class Ill-antiarrhythmic. 

Hirvonen, J., Kontturi, K., Murtom i, L., Paronen, P., and Urtti, A. Transdermal iontophoresis of sotalol and salicylate The effect of skin charge and penetration enhancers. J. Controlled Rel. 26 109, 1993. 

Julian DG, Prescott RJ, Jackson FS, Szekely P. Controlled trial of sotalol for one year after myocardial infarction. Lancet 1982 l(8282) 1142-7. 

Boriani G, Biffi M, De Simone N, Bacchi L, Martignani C, Bitonti F, Zannoli R, Butrous G, Branzi A. Repolarization changes in a double-blind crossover study of dofetilide versus sotalol in the treatment of ventricular tachycardia. Pacing Clin Electrophysiol 2000 23(11 Pt 2) 1935-8. 

Boriani G, Biffi M, Bacchi L, Martignani C, Zannoli R, Butrous GS, Branzi A. A randomised cross-over study on the haemodynamic effects of oral dofetilide compared with oral sotalol in patients with ischaemic heart disease and sustained ventricular tachycardia. Eur J Clin Pharmacol 2002 58(3) 165-9. 

Sotalol (-)-Sotalol (3-adrenoceptor biocker (-l-)-Sotaioi antiarrythmic agent Drayer ... 

Despite the discouraging results of the CAST, post-MI patients with complex ventricular ectopy remain at risk for death. Other drugs besides type Ic drugs have been studied, including sotalol. Sotalol is marketed as a racemic mixture of a D- and L-isomer both are type in potassium blockers, but the L-isomer has /3-blocking actions. Chronic therapy with D-sotalol was studied in patients with remote MI complicated by complex ectopy in the Survival With Oral D-Sotalol (SWORD) trial. Unlike in the CAST, D-sotalol treatment was not designed to cause PVC suppression, yet (as in the CAST) the trial was halted prematurely because of excessive mortality in the treatment arm. Again, the presumed reason for this observation was D-sotalol-related pro arrhythmia. Currently, only two antiarrhythmic... 

Urech, R. Chan, L. Duffy, P. High-performance liquid chromatographic assay of sotalol improved procedure and investigation of peak broadening. J.Chromatogr., 1990, 534, 271-278... 

N-[4-[l-Hydroxy-2-[(l-methylethyl)amino]ethyl]phenyl]-methanesulfonamide 4 -[ 1 -hydroxy-2-(isopropylamino)ethyl]-methanesulfonanilide (1,2) MJ-1999 (2). Chemical abstracts registry no. 3930-20-9, sotalol 959-24-0. sot ol hydrochloride (2). 

The infrared spectrum of sotalol hydrochloride is depicted in Figure 4. The spectrum was obtained on a KBr disk using a Nicolet 20 SX Fourier Transform infrared spectrometer. Diagnostic peaks were observed at 3570 cm (secondary alcohol, free) 3410 cm l (secondary alcohol, H-bonded) 2700-2800 cm l and 2950-3200 cm l (hydrochloride) 1325 cm (S=0 asymmetric stretch) 1154 cm l (S=0 symmetric stretch). The peaks are presented in Table I. 

The water/n-octanol partition coefficient (log P value) has been reported to be 0.24 (7). Using octan-l-ol/phosphate buffer (pH 7,4) at 37 C, sotalol was reported to have a partition coefficient of 0.09 (8). 

Sotalol is excreted by glomerular filtration with approximately 75% of the drug being excreted within 72 hours (29). The reported elimination half-life ranges from 7-18 hours (29). As expected, reduced renal function (i.e., reduced creatinine clearance) results in reduced renal clearance values of sotalol. For example, renal clearance has been reported (34) to be reduced from a mean of 4.99 L/h (creatinine clearance > 80 ml/min) to a mean of 0.27 L/h (creatinine clearance < 10 ml/min). In fact, after chronic administration of sotalol, the serum half-life was reported to be 69 hours in an anuric patient (35). Although there is no difference in the enantiomeric clearance of sotalol (31), it has been suggested that the clearance of (-i-)-sotalol after administration of such may be reduced (36) as compared to its clearance when administered with an equal proportion of (-)-sotalol (i.e., when administered as racemate). 

Le Garrec L, Delee E, Pascal J-C Direct separation of d- and 1-sotalol mandelate and hydrochloride salts by high performance liquid chromatography. 7. L/. Chromatogr. 1987 10 3015-3023. 

Waldo, A.L. Camm, A.J. de Ruyter, H. Friedman, P.L. MacNiell, D.J. Pauls, J.F. Pitt, B. Pratt, C.M. Schwartz, P.J. Veltri, E.P. Effect of d-sotalol on mortality in patients with left ventricular dysfunction after recent and remote myocardial infarction. Lancet 1996, 348, 7-12. 

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