Torsades de pointes is a potentially lethal arrhythmia that occasionally appears as an adverse effect of pharmacotherapy. Recently developed understanding of the underlying electrophysiology allows better estimation of the drug‐induced risks and explains the failures of older approaches through the surface ECG. This article expresses a consensus reached by an independent academic task force on the physiologic understanding of drug‐induced repolarization changes, their preclinical and clinical evaluation, and the risk‐to‐benefit interpretation of drug‐induced torsades de pointes. The consensus of the task force includes suggestions on how to evaluate the risk of torsades within drug development programs. Individual sections of the text discuss the techniques and limitations of methods directed at drug‐related ion channel phenomena, investigations aimed at action potentials changes, preclinical studies of phenomena seen only in the whole (or nearly whole) heart, and interpretation of human ECGs obtained in clinical studies. The final section of the text discusses drug‐induced torsades within the larger evaluation of drug‐related risks and benefits. (J Cardiovasc Electrophysiol, Vol. 15, pp. 475‐495, April 2004)

We consider the problem of studying several dose combinations of two drugs for a therapeutic endpoint in a multilevel factorial clinical trial. Two test statistics are constructed to test whether there exists at least one dose combination that is more effective than its component doses. Their distributions involve nuisance parameters quantifying the mean differences among the doses of the two component drugs. It is shown that their power functions achieve maxima as all the nuisance parameters approach infinity in absolute value. The significance levels of the two tests are derived and two alpha-level tests are proposed. Tables are given to provide the alpha-level critical values for these tests and to gain insights into their power performances.

A B S T R A C T In isolated fiber bundles of external intercostal muscle from each of 13 normal volunteers and each of 6 patients with myotonia congenita, some or all of the following were measured: concentrations of Na+, K+, and Cl-, extracellular volume, water content, K+ efflux, fiber size, fiber cable parameters, and fiber resting potentials.Muscle from patients with myotonia congenita differed significantly (0.001 < P< 0.025) with respect to the following mean values (myotonia congenita vs. normal): the membrane resistance was greater (5729 vs. 2619 U. cm2), the internal resistivity was less (75.0 vs. 123.2 Q-cm), the water content was less (788.2 vs. 808.2 ml/kg wet weight), and the mean resting potential was greater (68 vs. 61 mv).No significant differences were found with respect to the following variables: K+ content (73.5 vs. 66.7 mEq/kg wet weight) and the calculated intracellular K+ concentration (215 vs. 191 mEq/liter fiber water), fiber capacitance (5.90 vs. 5.15 Mf/cm2), Na+ content (97.7 vs. 94.1 mEq/kg wet weight), 74.7 mEq/kg wet weight), mannitol extracellular volume (45.1 vs. 46.6 cc/100 g wet weight), and K+ efflux (23.2 vs. 21.5 moles X 10-12 cm-2.sec-1).These abnormalities of skeletal muscle in human myotonia congenita are like those of skeletal muscle in goats with hereditary myotonia. We tentatively conclude that a decreased Cl-permeability accounts for some of the abnormal electrical properties of skeletal muscle in myotonia congenita. We now report findings in isolated external intercostal muscle from patients with myotonia congenita and from normal volunteers. We have compared our human results with similar data we obtained in isolated external intercostal muscle from the goat (1, 2). METHODS Normal volunteers. Our normals are 13 males aged 21-33 yr with no evidence of neuropathy or myopathy. One (R. G.) had diabetes mellitus; another (T. P.) had probable pulmonary sarcoidosis (minimal pulmonary fibrosis on chest X-ray and scalene node biopsy positive for noncaseating granuloma). At the time of muscle biopsy, T. P. had no symptoms and his chest X-ray was clearer (without therapy) than 1 yr earlier. No volunteer had taken any medication for at least 5 days before the external intercostal muscle biopsy except for the patient with diabetes, who received insulin up to and including the day before biopsy. The remaining 11 subjects were healthy and the results of laboratory studies (chest X-ray, electrocardiogram, hemoglobin, hematocrit, white blood cell count and differential, urinalysis, serum urea nitrogen, fasting blood sugar, Wasserman, serum creatinine, serum ions [Na+, K+, Cl-], serum Ca and Mg, total serum proteins, serum alkaline phosphatase, serum glutamic oxalacetic transaminase, and creatinine phosphokinase) were normal. Biopsy techniques. Biopsies of the anterior border of external intercostal muscle (2.5-5 cm in length) were obtained under local anesthesia from the right eighth intercostal space. Preoperative medications were pentobarbital (from 100 to 200 mg), and morphin...

In isolated bundles of external intercostal muscle from normal goats and goats with hereditary myotonia the following were determined: concentrations and unidirectional fluxes of Na+, K+, and C-, extracellular volume, water content, fiber geometry, and core-conductor constants. No significant difference between the two groups of preparations was found with respect to distribution of fiber size, intracellular concentrations of Na+ or Cl-, fiber water, resting membrane potential, or overshoot of action potential. The intracellular C1-concentration in both groups of preparations was 4 to 7 times that expected if C1-were distributed passively between intracellular and extracellular water. The membrane permeability to K (Ps) calculated from efflux data was (a) at 38°C, 0.365 X 10 -6 cm sec -1 for normal and 0.492 X 10-6 for myotonic muscle, and (b) at 250°C, 0.219 X 10-6 for normal and 0.199 X 10-6 for myotonic muscle. From C1-washout curves of normal muscle usually only three exponential functions could be extracted, but in every experiment with myotonic muscle there was an additional, intermediate component. From these data Pcl could be calculated; it was 0.413 X 10-6 cm sec-1 for myotonic fibers and was > 0.815 X 10-6 cm sec-1 for normal fibers. The resting membrane resistance of myotonic fibers was 4 to 6 times greater than that of normal fibers.

Diphenylhydantoin, in concentrations of Fig. 1. The lower curves show the relation of the maximal sodium current (the peak of the transient, inwardly directed current) to the membrane potentials to which the axon membrane was clamped. The upper curves show the same relation for the potassium current (the delayed, steadystate, positive current).The principal result was a reduction of the transient, sodium currents. The effects with 10 ,M diphenylhydantoin were greater than with 5 I&M (Fig. 1), and 50 p&M drug reduced the peak sodium current by about 75%. The effect was largely reversible, with "recovery" to 65-90% of the initial (control) sodium conductance upon return to control artificial sea water. In no experiment did the drug significantly change the voltage (i.e., less than 5-10 mV, representing the accuracy of the method used) at which the peak transient current occurred. Inconsistent, small (i.e., less than 0.1 msec) increases in the time to reach this peak current (for any given depolarizing step) lead us to tentatively conclude that no significant change in the time-to-peak sodium current occurred.Diphenylhydantoin had little or no effect on the resting membrane potential or on the leakage currents. Its effects are probably not on the "resting elements" of the membrane, but rather upon the ionic channels that are associated with a change from the resting to the active state of the membrane. This permeability change (activated sodium conductance) is best characterized by the empirical formulations of Hodgkin and Huxley (10) as a product of three parameters (i.e., 9Na = gNamlh). The absence of any voltage shift or delay in the time-to-peak sodium currents speak against the drug affecting the process of sodium activation (m), or sodium inactivation (h), or either of their time constants. Occasionally, small changes in the sodium reversal potential (as in Fig. 1) occurred (i.e., the potential where the sodium current is zero was shifted to the left after drug administration). Even when present, this effect was of insufficient magnitude to account for the observed decrease in the sodium current.Thus, it appears that diphenylhydantoin principally alters the sodium conductance, ONa, presumably by directly blocking the activated channels through which the sodium ions normally enter the axon. This effect (decreasing #Na, without appreciably altering m or h) is similar to the effects of saxitoxin (13) and tetrodotoxin (14,17), and is somewhat different from the effects of procaine (15). (Fig. 2). The upper section of Fig. 2 shows the peak sodium 1758