Rationale for the use of combination angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker therapy in heart failure.

BACKGROUND: Heart failure (HF) is a major cause of morbidity and mortality in the United States. The renin-angiotensin system (RAS) plays a major role in its pathophysiology, and angiotensin-converting enzyme (ACE) inhibitors are the cornerstone of therapy. However, HF continues to progress despite this therapy, perhaps because of production of angiotensin II by alternative pathways, which lead to direct stimulation of the angiotensin II receptor. Angiotensin II receptor blocker (ARB) therapy alone or in combination with the ACE inhibitor is a promising approach to block the RAS and slow HF progression more completely. METHODS: The current medical literature on the pathophysiology of HF and the use of ACE inhibitors and ARBs was extensively reviewed. RESULTS: Evidence from basic science, experimental animals, and clinical trials provides data on the safety and efficacy of RAS inhibition with ACE inhibitors and ARBs as monotherapy and in combination. Data from the Evaluation of Losartan in the Elderly (ELITE) II trial indicate that ARBs alone do not appear to be more effective than ACE inhibitors in HF, but studies evaluating their use in combination are currently ongoing. CONCLUSIONS: The addition of an ARB offers more complete angiotensin II receptor blockade of the RAS than can be obtained by ACE inhibitors alone. Combination therapy preserves the benefits of bradykinin potentiation offered by ACE inhibitors while providing potential antitrophic influences of AT(2) receptor stimulation and may play an increased role in the treatment of chronic HF in the future.

The HF epidemic: the need for new treatment strategies.

The incidence of heart failure is increasing, particularly in older patients. Clinical trials often do not reflect community practice where patients are older and have more co-morbid conditions. Therapeutic agents need to be at least neutral in their effects on these other conditions. Current therapy in heart failure includes angiotensin-converting enzyme (ACE) inhibitors, beta-blockers and diuretics, with advanced heart failure patients receiving spironolactone and possibly digitalis. Ongoing clinical trials are testing more effective inhibition of the renin-angiotensin-aldosterone system (RAAS) with highly selective angiotensin II (Ang II) receptor blockers (ARBs) such as valsartan. Future trials should study diverse racial groups and the elderly, particularly those with preserved systolic function. These should ideally be large multicentre studies with internal substudies to examine mechanisms of heart failure.

Lack of effect of increased inspired oxygen concentrations on maximal exercise capacity or ventilation in stable heart failure.

Recent uncontrolled studies have suggested improved maximal exercise capacity and decreased exercise ventilation in heart failure after administration of increased inspired oxygen concentrations. To study the responses further, 16 patients performed staged, symptom-limited cycle ergometry with humidified 21% and 60% inspired oxygen concentrations using a randomized, double-blind, crossover study design. Serial measurements of minute ventilation, heart rate, blood pressure, leg blood flow, and arterial and venous lactate and oxygen content were obtained. Exercise time did not change between the 2 tests (595 +/- 179 seconds and 602 +/- 181 seconds for 21% and 60% oxygen concentrations, respectively). Similarly, measurements of the ventilatory response to exercise and of leg blood flow were not different between the 2 oxygen concentrations. Although hemoglobin oxygen saturation increased from 96.7 +/- 2.1% to 97.9 +/- 1.5% at rest, at both rest and maximal exercise there was no statistically significant difference in arterial or venous oxygen content. This study failed to demonstrate any physiologic or functional benefit from the administration of increased oxygen concentrations to patients with stable heart failure.

Beta blocker treatment in heart failure.

The sympathetic nervous system occupies a prominent role in heart failure both as a marker of severity of disease and also as an important factor in its progression. Beta blocker therapy, once thought heretical in heart failure, has consistently improved cardiac function and slowed progression of disease. Large clinical trials of mild to moderate heart failure show improved survival as well as reduction in hospitalization. Beta blockers now have stronger data in heart failure than converting enzyme inhibitors, and should be considered standard therapy in mild-moderate heart failure. Ongoing trials are addressing beta blocker therapy in advanced heart failure and comparisons between agents.

Racial differences in the outcome of left ventricular dysfunction.

BACKGROUND: Population-based studies have found that black patients with congestive heart failure have a higher mortality rate than whites with the same condition. This finding has been attributed to differences in the severity, causes, and management of heart failure, the prevalence of coexisting conditions, and socioeconomic factors. Although these factors probably account for some of the higher mortality due to congestive heart failure among blacks, we hypothesized that racial differences in the natural history of left ventricular dysfunction might also have a role. METHODS: Using data from the Studies of Left Ventricular Dysfunction (SOLVD) prevention and treatment trials, in which all patients received standardized therapy and follow-up, we conducted a retrospective analysis of the outcomes of asymptomatic and symptomatic left ventricular systolic dysfunction among black and white participants. The mean (+/-SD) follow-up was 34.2+/-14.0 months in the prevention trial and 32.3+/-14.8 months in the treatment trial among the black and white participants. RESULTS: The overall mortality rates in the prevention trial were 8.1 per 100 person-years for blacks and 5.1 per 100 person years for whites. In the treatment trial, the rates were 16.7 per 100 person-years and 13.4 per 100 person-years, respectively. After adjustment for age, coexisting conditions, severity and causes of heart failure, and use of medications, blacks had a higher risk of death from all causes in both the SOLVD prevention trial (relative risk, 1.36; 95 percent confidence interval, 1.06 to 1.74; P=0.02) and the treatment trial (relative risk, 1.25; 95 percent confidence interval, 1.04 to 1.50; P=0.02). In both trials blacks were also at higher risk for death due to pump failure and for the combined end point of death from any cause or hospitalization for heart failure, our two predefined indicators of the progression of left ventricular systolic dysfunction. CONCLUSIONS: Blacks with mild-to-moderate left ventricular systolic dysfunction appear to be at higher risk for progression of heart failure and death from any cause than similarly treated whites. These results suggest that there may be racial differences in the outcome of asymptomatic and symptomatic left ventricular systolic dysfunction.

Effect of amlodipine on mode of death among patients with advanced heart failure in the PRAISE trial. Prospective Randomized Amlodipine Survival Evaluation.

Investigations of calcium antagonists in patients with advanced heart failure have raised concern over an increased risk of worsening heart failure and heart failure deaths. We assessed the effect of amlodipine on cause-specific mortality in such patients enrolled in a randomized, double-blind, placebo-controlled trial. In total, 1,153 patients in New York Heart Association class IIIb or IV heart failure were randomized to receive amlodipine or placebo, along with angiotensin-converting enzyme inhibitors, diuretics, and digitalis. Over a median 14.5 months of follow-up, 413 patients died. Cardiovascular deaths accounted for 89% of fatalities, 50% of which were sudden deaths and 45% of which were due to pump failure, with fewer attributed to myocardial infarction (3.3%) or other cardiovascular causes (1.6%). Amlodipine treatment resulted in a greater relative reduction in sudden deaths (21%) than in pump failure deaths (6.6%) overall. When patients were classified by etiology of heart failure (ischemic or nonischemic), cause-specific mortality did not differ significantly between treatment groups in the ischemic stratum. In the nonischemic stratum, however, sudden deaths and pump failure deaths were reduced by 38% and 45%, respectively, with amlodipine. Thus, when added to digitalis, diuretics, and angiotensin-converting enzyme inhibitors in patients with advanced heart failure, amlodipine appears to have no effect on cause-specific mortality in ischemic cardiomyopathy, but both pump failure and sudden deaths appear to be decreased in nonischemic heart failure patients treated with amlodipine.

Prevalence and significance of nonsustained ventricular tachycardia in patients with premature ventricular contractions and heart failure treated with vasodilator therapy. Department of Veterans Affairs CHF STAT Investigators.

OBJECTIVES: This study sought to determine the prevalence and significance of nonsustained ventricular tachycardia (NSVT) in patients with premature ventricular contractions (PVCs) and heart failure treated with vasodilator therapy. BACKGROUND: Heart failure patients with ventricular arrhythmia and NSVT have a significantly increased risk of premature cardiac death. Recently there has been the question of whether these arrhythmias are expressions of a severely compromised ventricle or are they independent risk factors. We, therefore, determined the prevalence and significance of NSVT in patients with PVCs and heart failure and on vasodilator therapy. METHODS: Twenty-four hour ambulatory recordings were done at randomization, at 2 weeks, at months 1, 3, 6, 9 and 12 and then every 6 months in 674 patients with heart failure and on vasodilator therapy. The median period of follow-up was 45 months (range 0 to 54). RESULTS: Nonsustained ventricular tachycardia was present in 80% of all patients. Patients without (group 1) and with (group 2) NSVT were balanced for variables: age, etiology of heart disease, New York Heart Association (NYHA) functional class, use of amiodarone and diuretics and left ventricular diameter by echocardiogram. However, group 1 patients had significantly less beta-adrenergic blocking agent use and higher ejection fraction (EF) (p < 0.002 and p < 0.001, respectively). Survival analysis for all deaths showed a greater risk of death among group 2 patients (p=0.01). Similarly, sudden death was increased in group 2 patients (p=0.02, risk ratio 1.8). After adjusting for the above variables, only EF (p=0.001) and NYHA class (p=0.01) were shown to be independent predictors of survival. Nonsustained ventricular tachycardia showed a trend (p=0.07) as an independent predictor for all-cause mortality but not for sudden death. Only EF was an independent predictor for sudden death. CONCLUSIONS: Nonsustained ventricular tachycardia is frequently seen in patients with heart failure and may be associated with worsened survival by univariate analysis. However, after adjusting other variables, especially for EF, NSVT was not an independent predictor of all-cause mortality or sudden death. These results have serious implications in that suppression of these arrhythmias may not improve survival.

Design and baseline characteristics of the Veterans Affairs Non-Q-Wave Infarction Strategies In-Hospital (VANQWISH) trial. VANQWISH Trial Research Investigators.

OBJECTIVES: The Veterans Affairs Non-Q-Wave Infarction Strategies In-Hospital (VANQWISH) trial was designed to compare outcomes of patients with a non-Q wave myocardial infarction (NQMI) who were randomized prospectively to an early "invasive" strategy versus an early "conservative" strategy. The primary objective was to compare early and late outcomes between the two strategies using a combined trial end point (all-cause mortality or nonfatal infarction) during at least 1 year of follow-up. BACKGROUND: Because of the widely held view that survivors of NQMI are at high risk for subsequent cardiac events, management of these patients has become more aggressive during the last decade. There is a paucity of data from controlled trials to support such an approach, however. METHODS: Appropriate patients with a new NQMI were randomized to an early "invasive" strategy (routine coronary angiography followed by myocardial revascularization, if feasible) versus an early "conservative" strategy (noninvasive, predischarge stress testing with planar thallium scintigraphy and radionuclide ventriculography), where the use of coronary angiography and myocardial revascularization was guided by the development of ischemia (clinical course or results of noninvasive tests, or both). RESULTS: A total of 920 patients were randomized (mean follow-up 23 months, range 12 to 44). The mean patient age was 61 +/- 10 years; 97% were male; 38% had ST segment depression at study entry; 30% had an anterior NQMI; 54% were hypertensive; 26% had diabetes requiring insulin; 43% were current smokers; 43% had a previous acute myocardial infarction; and 45% had antecedent angina within 3 weeks of the index NQMI. CONCLUSIONS: Baseline characteristics were compatible with a moderate to high risk group of patients with an NQMI.

Effect of amlodipine on morbidity and mortality in severe chronic heart failure. Prospective Randomized Amlodipine Survival Evaluation Study Group.

BACKGROUND: Previous studies have shown that calcium-channel blockers increase morbidity and mortality in patients with chronic heart failure. We studied the effect of a new calcium-channel blocker, amlodipine, in patients with severe chronic heart failure. METHODS: We randomly assigned 1153 patients with severe chronic heart failure and ejection fractions of less than 30 percent to double-blind treatment with either placebo (582 patients) or amlodipine (571 patients) for 6 to 33 months, while their usual therapy was continued. The randomization was stratified on the basis of whether patients had ischemic or nonischemic causes of heart failure. The primary end point of the study was death from any cause and hospitalization for major cardiovascular events. RESULTS: Primary end points were reached in 42 percent of the placebo group and 39 percent of the amlodipine group, representing a 9 percent reduction in the combined risk of fatal and nonfatal events with amlodipine (95 percent confidence interval, 24 percent reduction to 10 percent increase; P=0.31). A total of 38 percent of the patients in the placebo group died, as compared with 33 percent of those in the amlodipine group, representing a 16 percent reduction in the risk of death with amlodipine (95 percent confidence interval, 31 percent reduction to 2 percent increase; P=0.07). Among patients with ischemic heart disease, there was no difference between the amlodipine and placebo groups in the occurrence of either end point. In contrast, among patients with nonischemic cardiomyopathy, amlodipine reduced the combined risk of fatal and nonfatal events by 31 percent (P=0.04) and decreased the risk of death by 46 percent (P<0.001). CONCLUSIONS: Amlodipine did not increase cardiovascular morbidity or mortality in patients with severe heart failure. The possibility that amlodipine prolongs survival in patients with nonischemic dilated cardiomyopathy requires further study.

Rationale and design of the third vasodilator-heart failure trial (V-HeFT III): felodipine as adjunctive therapy to enalapril and loop diuretics with or without digoxin in chronic congestive heart failure. V-HeFT III investigators.

Therapy with angiotensin-converting enzyme inhibitors and nonselective vasodilators (hydralazine and isosorbide dinitrate) has become accepted treatment in patients with symptomatic, chronic congestive heart failure (CHF), and has been demonstrated in large clinical trials to ameliorate symptoms, improve exercise performance, and reduce cardiac mortality. Nevertheless, the management of patients with CHF remains a therapeutic challenge. The second Vasodilator-Heart Failure Trial (V-HeFT II) showed that the average 2-year mortality with enalapril (18%) was significantly lower than that with hydralazine-isosorbide dinitrate (25%) but, somewhat surprisingly, the nonspecific vasodilators produced significantly more improvement in exercise performance and left ventricular function. Such data suggest that improvement in symptoms, hemodynamics, and survival may not be afforded by the use of a single class of vasodilator therapy, but might be optimized by the combined use of different agents. This report describes the rationale and design of V-HeFT III, a multicenter, prospective, randomized, double-blind, placebo-controlled trial comparing the effects of chronic oral extended-release felodipine (felodipine ER) 2.5 to 5 mg twice daily, when added to a stable regimen of enalapril and loop diuretics, with or without digoxin, on exercise performance, morbidity, and mortality in patients with New York Heart Association functional class II to III CHF followed for a minimum of 12 weeks. Felodipine is a second-generation dihydropyridine calcium antagonist with a high degree of vascular selectivity which, in the doses used in this study, exerts its systemic arterial effect by decreasing peripheral vascular resistance without producing negative inotropic effects. The results of V-HeFT III may shed important light on the role of additive vasodilator therapy in the management of patients with CHF.

Interaction of baseline characteristics with the hazard of encainide, flecainide, and moricizine therapy in patients with myocardial infarction. A possible explanation for increased mortality in the Cardiac Arrhythmia Suppression Trial (CAST).

BACKGROUND: The Cardiac Arrhythmia Suppression Trial (CAST) was designed to test the hypothesis that suppression of ventricular ectopy with antiarrhythmic drugs after a myocardial infarction reduces the incidence of sudden arrhythmic death. Patients in whom ventricular ectopy could be suppressed with encainide, flecainide, or moricizine were randomly assigned to receive either active drug or placebo. The encainide and flecainide arms of the study were discontinued in 1989 (CAST-I) and the moricizine arm in 1991 (CAST-II) because of excess mortality. To explore the mechanisms of these adverse outcomes, we examined the interaction of baseline characteristics with the hazard of therapy with encainide, flecainide, or moricizine compared with their respective placebos. METHODS AND RESULTS: CAST-I comprised 755 patients assigned to flecainide or encainide and 743 patients assigned to placebo, whereas in CAST-II, 502 patients received moricizine and 491 patients received placebo. Clinical and laboratory baseline variables of patients receiving active drug and those receiving placebo were similar. In CAST-I patients, there was a significant interaction of active therapy with both all-cause death/cardiac arrest and arrhythmic death/cardiac arrest for non-Q-wave myocardial infarction (total mortality hazard ratios, 1.8 versus 7.9 for Q-wave versus non-Q-wave infarction, P = .03). Ventricular premature depolarization (VPD) frequency > or = 50/h and heart rate > or = 74 beats per minute each interacted significantly with total mortality/cardiac arrest only. In the sicker CAST-II patients (ejection fraction < or = 40%), only diuretic use at baseline interacted significantly with moricizine use for both all-cause death/cardiac arrest and arrhythmic death/cardiac arrest (total mortality hazard ratios, 1.9 versus 0.7 for diuretic use versus no use, P = .01). CONCLUSIONS: Although active treatment in CAST-I was associated with greater mortality than placebo with respect to almost all baseline variables, the therapeutic hazard was more than expected in patients with non-Q-wave myocardial infarction and (for total mortality) frequent premature VPDs and higher heart rates, suggesting that the adverse effect of encainide or flecainide therapy is greater when ischemic and electrical instability are present. The relative hazard of therapy with moricizine in the sicker CAST-II population was greater in those using diuretics. Thus, although these drugs have the common ability to suppress ventricular ectopy after myocardial infarction, their detrimental effects on survival may be mediated by different mechanisms in different populations, emphasizing the complex, poorly understood hazards associated with antiarrhythmic drug treatment.

Effects of vesnarinone on morbidity and mortality in patients with heart failure. Vesnarinone Study Group.

BACKGROUND: Inotropic therapy, other than with digitalis glycosides, has had limited success in patients with chronic congestive heart failure. We investigated whether vesnarinone, a new positive inotropic agent, reduces morbidity and mortality and improves the quality of life of patients with symptomatic heart failure. METHODS: Patients receiving concomitant therapy with digoxin (87 percent) and an angiotensin-converting-enzyme inhibitor (90 percent) who had ejection fractions of 30 percent or less were randomly assigned to receive double-blinded therapy with 60 mg of vesnarinone per day, 120 mg of vesnarinone per day, or placebo. Afer 253 patients had been enrolled, randomization to the 120-mg vesnarinone group had to be stopped because of a significant increase in early mortality in this group. Thereafter, patients were randomly assigned only to 60 mg of vesnarinone per day (a total of 239 patients) or placebo (a total of 238 patients). RESULTS: Significantly fewer patients in the group receiving 60 mg of vesnarinone than in the group receiving placebo (26 vs. 50 patients; P = 0.003) died or had worsening heart failure during the six-month study period. The reduction in risk was 50 percent (95 percent confidence interval, 20 to 69 percent). Similarly, there was a 62 percent reduction (95 percent confidence interval, 28 to 80 percent) in the risk of dying from any cause among the patients receiving vesnarinone. Furthermore, quality of life improved to a greater extent in the vesnarinone group than in the placebo group over 12 weeks (P = 0.008). The principal side effect associated with vesnarinone was reversible neutropenia, which occurred in 2.5 percent of the patients. CONCLUSIONS: Six months of therapy with 60 mg of vesnarinone per day resulted in lower morbidity and mortality and improved the quality of life of patients with congestive heart failure. However, a higher dose of vesnarinone (120 mg per day) increased mortality, suggesting that this drug has a narrow therapeutic range; the long-term effects of vesnarinone are unknown.

The influence of atrial fibrillation on prognosis in mild to moderate heart failure. The V-HeFT Studies. The V-HeFT VA Cooperative Studies Group.

BACKGROUND: Atrial fibrillation occurs commonly in heart failure; however, its importance in terms of prognosis is controversial. METHODS AND RESULTS: We assessed the relation of atrial fibrillation on first Holter monitor to morbidity and mortality in mild to moderate heart failure in 632 patients in the Veterans Affairs Vasodilator-Heart Failure Trial (V-HeFT) I and 795 patients in V-HeFT II: Ninety-nine patients in atrial fibrillation and 533 patients in sinus rhythm were followed for a mean of 2.5 years (range, 6 months to 5.7 years) in V-HeFT I; 107 patients in atrial fibrillation and 688 patients in sinus rhythm in V-HeFT II were followed for a mean of 2.5 years (range, 6 months to 5.0 years). V-HeFT I compared treatment with prazosin, hydralazine-isosorbide dinitrate, and placebo, whereas V-HeFT II compared hydralazine-isosorbide dinitrate with enalapril. Follow-up evaluations included serial Holter monitors, serial metabolic exercise testing, hospitalization data, and clinical examinations. In V-HeFT I, cumulative mortality at 2 years was 0.34 for patients with atrial fibrillation and 0.30 for patients in sinus rhythm (p = 0.25). Overall cumulative mortality was 0.54 for atrial fibrillation patients and 0.64 for sinus rhythm patients (p = 0.86). In V-HeFT II, cumulative mortality at 2 years was 0.20 for patients with atrial fibrillation and 0.21 for patients with sinus rhythm (p = 0.68), and overall cumulative mortality was 0.46 for atrial fibrillation patients and 0.52 for those in sinus rhythm (p < 0.46). Sudden death was not increased with atrial fibrillation in V-HeFT I patients (p = 0.64) or in V-HeFT II (p = 0.68). By multivariate analysis, the relative mortality risk for atrial fibrillation was 0.95 in V-HeFT I and 0.76 in V-HeFT II: Metabolic exercise testing, showed no significant difference in mean change in peak oxygen consumption between patients with atrial fibrillation and those with sinus rhythm in V-HeFT I and a slight decrease late in V-HeFT II: Hospitalization rate for heart failure was not increased in either study. The embolic event rate was not increased for atrial fibrillation patients: 3% versus 4.9% of patients in sinus rhythm (p = 0.41) in V-HeFT I and 4.0% versus 6.0% in V-HeFT II patients (p = 0.44). A secondary analysis compared mortality of patients in atrial fibrillation with that of patients in sinus rhythm on all Holters: Mortality was not increased overall (p = 0.72 in V-HeFT I and p = 0.35 in V-HeFT II). CONCLUSIONS: Atrial fibrillation does not increase major morbidity or mortality in mild to moderate heart failure.

Incidence of thromboembolic events in congestive heart failure. The V-HeFT VA Cooperative Studies Group.

BACKGROUND: The incidence of thromboembolism and the benefit of anticoagulation in congestive heart failure are controversial. METHODS AND RESULTS: The data base provided by the Veterans Affairs Vasodilator-Heart Failure Trials (V-HeFT I and II) was examined retrospectively to address these issues. In V-HeFT I, 642 men with heart failure were followed an average of 2.28 years, providing 1,464 patient-years of follow-up. In V-HeFT II, 804 men were followed an average of 2.56 years, with 2,061 patient-years of follow-up. Mean left ventricular ejection fraction was 30% in V-HeFT I and 29% in V-HeFT II: Functional capacity was at the interface of classes II and III with a peak exercise oxygen consumption of 14.7 mL.kg-1 x min-1 in V-HeFT I and 13.7 mL.kg-1 x min-1 in V-HeFT II: Warfarin and antiplatelet agents were administered at the discretion of individual investigators. The incidence of all thromboembolic events during 1,068 patient-years without warfarin in V-HeFT I was 2.7/100 patient-years and during 1,188 patient-years in V-HeFT II was 2.1/100 patient-years and was not reduced in patients treated with warfarin. Patients experiencing events had a lower peak exercise oxygen consumption (p < 0.03 in V-HeFT I and p < 0.001 in V-HeFT II) and a lower mean ejection fraction (p = 0.10 in V-HeFT I and p = 0.07 in V-HeFT II). Atrial fibrillation was not associated with an increased risk of thromboembolic events. CONCLUSIONS: The incidence of thromboembolism and stroke in class II or III congestive heart failure is not high and may not be significantly reduced with warfarin treatment. Routine use of anticoagulants in patients with heart failure may not be justified.

Severe bradycardia following electrical cardioversion for atrial tachyarrhythmias in patients with acute myocardial infarction.

Bradycardia following electrical cardioversion is an uncommon complication. The present report describes three patients who developed life-threatening bradycardia following electrical cardioversion for atrial tachyarrhythmias in the setting of an acute myocardial infarction. All three patients had multivessel coronary artery disease with a totally occluded right coronary artery and a possibility of ischemic sinus node dysfunction. When electrical cardioversion is undertaken for new onset of atrial tachyarrhythmia in the setting of an acute myocardial infarction, measures for immediate, temporary pacing should be easily available.

Biotransformation of primaquine in vitro with human K562 and bone marrow cells.

Although the antimalarial activity, hemolytic and methemoglobinemic side effects, and detoxification of primaquine are all thought to depend on various biotransformation products of the drug, their site and mechanism of formation and degradation are unknown and their specific biologic effects remain very poorly understood, particularly in humans. We have therefore explored the feasibility of studying primaquine metabolism in cultured human cells. We found that the biotransformation of primaquine can be investigated in vitro in serum-supplemented liquid cultures of partially synchronized and exponentially growing human erythroleukemic K562 cells. Further, these cells can be replaced by cells present in normal bone marrow. Primaquine is rapidly and predominantly converted in vitro into carboxyprimaquine (CPQ) in a quantitative manner and without further modification. In addition to CPQ, a compound Xc that is not 6-methoxy-8-aminoquinoline, and is not derived from CPQ, appears in minor amounts in a delayed fashion. With the K562 as well as with the bone marrow cells the formation of CPQ from primaquine can be totally blocked by large concentrations of the nitrosourea, 1,3-bis-(2-chloroethyl)-nitrosourea (BCNU). With bone marrow, increasing blockade of CPQ formation by BCNU leads invariably to a progressive and striking accumulation of Xc. The availability of reproducible, quantitative, and practical new tools for the study of primaquine metabolism in vitro raises a number of challenging questions and may improve understanding of the mode of action, toxicology, and pharmacogenetics of 8-aminoquinolines.