Grapefruit juice alters the systemic bioavailability and cardiac repolarization of terfenadine in poor metabolizers of terfenadine.

A prospective cohort study was conducted to examine the effects of double-strength grapefruit juice on the pharmacokinetics and electrocardiographic repolarization pharmacodynamics of terfenadine in poor metabolizers of terfenadine. Six healthy volunteers who were previously found to be poor metabolizers of terfenadine were studied, with each participant serving as his or her own control. In phase I of the study, terfenadine was given to participants at recommended dosages until steady state was achieved (60 mg twice daily for 7 days). In phase II, participants began receiving concomitant twice-daily, double-strength servings of grapefruit juice for 7 days. Serial pharmacokinetic and pharmacodynamic determinations were made after each phase of the study. The main outcome measures were serum concentrations of terfenadine and terfenadine acid metabolite, and corrected QT intervals as determined by 12-lead electrocardiogram. Significant changes occurred in time to maximum concentration (t(max)) and area under the concentration-time curve (AUC) of terfenadine and terfenadine acid metabolite after addition of grapefruit juice. All participants had detectable concentrations of unmetabolized terfenadine at the end of Phase I, which were quantified in three of the six participants. Further, all participants had increased and quantifiable levels of unmetabolized terfenadine after addition of grapefruit juice that were associated with prolongation of the QT interval relative to the baseline control period without terfenadine. Grapefruit juice did not alter the elimination half-life (t1/2) of terfenadine acid metabolite. Because of the intraindividual variability in the pharmacokinetics of terfenadine, further study is needed to confirm these results.

Spring coil embolization of a patent ductus arteriosus in an adult.

To date, coil embolization has been reserved for occlusion of the small patent ductus arteriosus (PDA) because of potential dislodgement of the coils. We report a case of a larger, hemodynamically significant PDA in an adult which was successfully closed by two spring coils using a "crossed catheter" technique for coil delivery.

Morphologic characteristics of lesion formation and time course of smooth muscle cell proliferation in a porcine proliferative restenosis model.

OBJECTIVES: This study was performed to define the evolution of lesion morphology and its relation to thrombus formation and smooth muscle cell proliferation after experimental coronary stent placement. BACKGROUND: Restenosis after percutaneous revascularization may develop because of thrombus accumulation and smooth muscle cell proliferation. In animal models of restenosis, thrombus may assume a significant role in neointimal formation by providing an absorbable matrix into which smooth muscle cells proliferate. METHODS: Twenty-eight oversized stents were placed in the coronary arteries of 23 juvenile domestic pigs. The histologic degree of vessel injury, lesion morphometry and smooth muscle cell proliferation measured by immunolocalization with a monoclonal antibody to proliferating cell nuclear antigen (PCNA) were assessed at 24 h and 7, 14 and 28 days after stent placement. RESULTS: The area of thrombus was minimal at 24 h ([mean +/- SE] 0.44 +/- 0.12 mm2). Neointimal area at 7 days (0.72 +/- 0.20 mm2) was similar to the area of thrombus, followed by a significant increase at 14 days (3.15 +/- 0.39 mm2) and 28 days (3.30 +/- 0.28 mm2) (p < 0.0036, 24 h and 7 days vs. 14 and 28 days). At 14 and 28 days, neointimal thickness correlated with the histologic degree of vessel injury (p < 0.003). In arteries with severe injury, the increase in neointimal thickness is accounted for by replacement of the damaged media. The smooth muscle cell proliferation index was 18.6 +/- 3.5% at 7 days compared with 9.6 +/- 1.3% by 14 days (p = 0.0247) and declined to 1.1 +/- 0.97% by 28 days (p < 0.008, 7 and 14 days vs. 28 days). CONCLUSIONS: Early thrombus formation is minimal, and thrombus accounts for a small portion of subsequent neointimal formation. Smooth muscle cell proliferation and matrix formation are the major factors relating to neointimal formation in this proliferative model of restenosis. The evolution of neointimal formation after coronary stenting shows maximal smooth muscle cell proliferation at 7 days, with a decline to low levels by 28 days. Therefore, these data may be useful for developing effective therapies for restenosis.

Side-branch occlusion with directional coronary atherectomy: incidence and risk factors.

Side-branch occlusion is a recognized complication of directional coronary atherectomy (DCA). To evaluate the incidence, risk factors, and clinical outcome of side-branch compromise, we analyzed our first 100 consecutive atherectomies of native coronary arteries. Seventy-eight patients had 122 side branches at risk, 21 (17%) of which demonstrated compromised flow after DCA. Origin of the side branch from the culprit atheroma and preexisting side-branch ostial stenosis were highly predictive of this complication in 20 of 55 (p < 0.05) and 14 of 31 (p < 0.05) lesions, respectively. There was one non-Q-wave myocardial infarction, no emergency surgeries, and no deaths. In conclusion, side-branch loss after DCA occurs with a frequency similar to balloon angioplasty and was well tolerated in our patient population. Side branches that originate directly from culprit lesions or that have significant ostial narrowing have a higher incidence of this complication.

Placement and angiographic patency of the Strecker coronary stent.

The Strecker stent is a newer, balloon-expandable vascular prosthesis consisting of a single tantalum filament knitted into a flexible mesh tube. To test the placement characteristics and patency of this device, we implanted 29 stents in the coronary arteries of 24 juvenile Yorkshire swine. Seventeen stents were placed in the left anterior descending artery, and 12 were placed in the left circumflex system. All stents were deployed successfully. Four animals died within the first 24 hr of anesthesia-related complications. The remaining animals were sacrificed at 24 hr, 1 week, 2 weeks, or 4 weeks. Follow-up angiography demonstrated the patency of all stents. There were no episodes of stent migration or side branch occlusion. The Strecker stent has several favorable characteristics, including its unique delivery system, ease of deployment, flexibility, radiopacity, and radial strength. There was 100% patency at up to 4 weeks in this animal model. Further studies are required to define whether the knitted mesh design offers any advantage over previous models.

Coronary artery fistula diagnosed by transesophageal echocardiography.

Coronary artery fistulas have been traditionally diagnosed by angiography. This report describes a congenital and a traumatic coronary artery fistula diagnosed by transesophageal echocardiography. Transesophageal echocardiography was superior to transthoracic echocardiography in both cases and to angiography in one case. Transesophageal echocardiography may now be the procedure of choice in diagnosing coronary fistula.

Incidence of cardiac arrhythmias during intravenous pentamidine therapy in HIV-infected patients.

STUDY OBJECTIVE: There have been 15 published cases of probable pentamidine-induced torsade de pointes (TdP). A prospective analysis of this complication of therapy is valuable considering the high frequency of Pneumocystis carinii pneumonia in the AIDS population, and the role of pentamidine in its therapy. DESIGN: Open, nonrandomized, prospective study of HIV-infected patients receiving intravenous pentamidine in a 12-month period. SETTING: Walter Reed Army Medical Center, a tertiary care, referral-based facility in Washington, DC. PATIENTS: Eighteen HIV-infected patients were enrolled with informed consent; four were withdrawn from statistical analysis after receiving only one or two doses of empiric intravenously administered pentamidine. MEASUREMENTS AND RESULTS: Daily 12-lead electrocardiography, echocardiography, weekly signal-averaged electrocardiography, and weekly 24-h ambulatory electrocardiography were performed on each patient. Of the 14 subjects, 3 developed TdP. These 3 patients and 2 others developed a prolonged rate corrected, QT interval (QTc) to greater than 0.48 s (max QTc mean, 0.55 s, mean increase, 0.12 s). The QTc prolongation was noted in all five patients by the fourth daily dose (4 mg/kg/d) of pentamidine. The other 9 patients developed minimal change in QTc intervals throughout therapy (max QTc mean, 0.45 s; mean increase, 0.03 s). The maximum QTc increase was significantly different between these two cohorts (p < 0.03). The occurrence of TdP in the subgroup of patients developing prolonged QTc intervals to greater than 0.48 s (3 of 5 patients), or a change in QTc of greater than 0.08 s (3 of 4 patients) over individual baseline also was significant (p = 0.03 and p = 0.01, respectively). No baseline clinical variables associated with TdP or QTc prolongation were identified. CONCLUSION: Intravenously administered pentamidine frequently results in QTc prolongation with a subsequent risk of TdP in HIV-infected patients. All patients treated with intravenously administered pentamidine should be evaluated with baseline and daily ECGs, at least during the first week of therapy, and should be closely monitored for a change in the QT interval. An increase in QTc to above 0.48 s or greater than 0.08 s above baseline carries a significant risk for proarrhythmia, and in this instance, continuous electrocardiographic monitoring or an alternative antibiotic regimen should be considered.

Population variability in the pharmacokinetics of terfenadine: the case for a pseudo-polymorphism with clinical implications.

Terfenadine is nearly completely first pass biotransformed. Unmetabolized terfenadine plasma concentrations have been associated with altered cardiac repolarization. During previous drug interaction studies, 2 subjects were found to have quantifiable concentrations of unmetabolized terfenadine with accompanying electrocardiographic repolarization changes while on terfenadine alone. To determine whether these subjects were representative of the population, 150 healthy volunteers (109 males, 41 females, ages 19-49) were screened for their ability to metabolize terfenadine after achieving steady-state. Blood was obtained at known times of maximum terfenadine concentration after dosing. Eleven subjects had quantifiable concentrations of terfenadine demonstrating wide intersubject variability in terfenadine metabolism. Further studies to determine whether such subjects are more susceptible to untoward terfenadine-associated events are underway.

Itraconazole affects single-dose terfenadine pharmacokinetics and cardiac repolarization pharmacodynamics.

The object of this study was to examine prospectively the effects of itraconazole on the pharmacokinetics and electrocardiographic repolarization pharmacodynamics (QTc intervals) of single-dose terfenadine in six healthy volunteers. It was designed as a prospective cohort study with each subject serving as his own control, set in an outpatient cardiology clinic. The participants were six healthy volunteers (two men, four women; ages 24-35) not taking any prescription or over-the-counter medications. Single-dose terfenadine administration (120 mg) was accompanied by pharmacokinetic profiles and serial determination of the QTc interval for 12 hours. The subjects then began daily oral itraconazole (200 mg each morning) for 7 days. Repeat pharmacokinetic and pharmacodynamic determinations were made after administration of a second dose (120 mg) of terfenadine while receiving itraconazole. The main outcome measures were terfenadine and acid metabolite serum concentrations; corrected QT intervals as determined by 12-lead electrocardiogram (ECG); and presence or absence of late potentials as determined by signal-averaged ECGs over 150 cardiac cycles. There were significant changes in the pharmacokinetic parameters of acid metabolite after treatment with itraconazole. All subjects had detectable levels of unmetabolized terfenadine after addition of itraconazole, which was associated with QT prolongation. There was no evidence of late depolarization as manifested by an increase in QRS duration found using signal-averaged electrocardiography. Itraconazole influences the metabolism of terfenadine in normal volunteers and results in the accumulation of unmetabolized parent drug associated with altered cardiac repolarization. This drug combination should be avoided.

The heart in polymyositis: a prospective evaluation of 26 patients.

Although cardiac abnormalities have been reported in patients with idiopathic polymyositis-dermatomyositis (PM), the nature and extent of these abnormalities have varied. The purpose of this study was to determine the prevalence and to obtain a better description of the spectrum of cardiac abnormalities in a cohort of patients with PM by use of a thorough noninvasive cardiac evaluation. Accordingly, we studied 26 patients with a history of PM and clinically inactive myositis (22 polymyositis, 4 dermatomyositis) between June 1984 and June 1991. Examination included history, physical examination, 12-lead electrocardiography, 24-h ambulatory electrocardiographic monitoring, chest radiography, transthoracic echocardiography, and radionuclide ventriculography. Of the patients studied, 77% were taking corticosteroid medications at a mean dose of 39 +/- 27 mg at the time of their evaluation. All 26 patients were identified as having two or more cardiac abnormalities. Cardiac symptoms and signs were common (62 and 81%, respectively), but were generally nonspecific. Electrocardiographic findings were most common (in 85% of cases), followed by findings on ambulatory monitoring (77%), echocardiography (42%), and radionuclide ventriculography (15%). The prevalence of mitral valve prolapse (8%) and hyperkinetic left ventricular contraction (12%) was significantly lower than previously reported. A secondary aim of this study was to determine associations between demographic variables including age, disease duration, cardiovascular symptoms, immunosuppressive therapy, autoantibody status, and creatinine phosphokinase level, and the presence of cardiac abnormalities. Of these patient variables, only increasing patient age was associated with an increased likelihood of cardiac abnormalities on noninvasive testing.(ABSTRACT TRUNCATED AT 250 WORDS)

Transcoronary cardiac pacing during myocardial ischemia.

Severe bradyarrhythmias are a rare but potentially life threatening complication of percutaneous transluminal coronary angioplasty (PTCA). Previous work has outlined a technique for coronary pacing using the angioplasty guidewire. To examine the effectiveness of this technique during severe ischemia, seven swine underwent placement of an unmodified 0.014 inch angioplasty guidewire and 3.0 mm balloon catheter in the left anterior descending (LAD) artery. Baseline pacing thresholds were obtained. Pacing was begun at twice diastolic threshold and ischemia was produced by balloon inflation. Repeat capture thresholds were obtained after 1 and 8 minutes of ischemia. Transcoronary pacing was successfully performed in all seven animals and was continued for a mean of 13.8 +/- 1.5 minutes. The baseline capture threshold was 4.0 +/- 0.5 mA. The mean capture threshold was 3.3 +/- 0.3 mA and 4.5 +/- 0.9 mA at 1 and 8 minutes of ischemia, respectively. We conclude that transcoronary pacing using the angioplasty guidewire can be successfully performed during myocardial ischemia and may serve as a reliable backup system during interventional procedures complicated by bradyarrhythmias.

Terfenadine-ketoconazole interaction. Pharmacokinetic and electrocardiographic consequences.

OBJECTIVE: To examine prospectively the effects of ketoconazole on the pharmacokinetics and electrocardiographic repolarization pharmacodynamics (corrected QT intervals) of terfenadine in men and women. DESIGN: Prospective cohort study with each subject serving as his or her own control. SETTING: Outpatient cardiology clinic and inpatient telemetry unit for monitoring period. PARTICIPANTS: Six healthy volunteers (four men and two women, aged 24 to 35 years) not taking any prescription or over-the-counter medications. INTERVENTION: After achieving a steady state while taking terfenadine (60 mg every 12 hours for 7 days), daily concomitant oral ketoconazole (200 mg every 12 hours) was added to the subjects' regimen. Pharmacokinetic profiles were obtained while subjects were taking terfenadine alone and after the addition of ketoconazole. Electrocardiograms were obtained at baseline, after 1 week of taking terfenadine alone, and at the time of the second pharmacokinetic profile after the addition of ketoconazole to the regimen. MAIN OUTCOME MEASURES: Terfenadine and its acid metabolite serum concentrations and corrected QT intervals. RESULTS: All subjects had detectable levels of unmetabolized terfenadine after the addition of ketoconazole, which was associated with QT prolongation. Only two of the six subjects could complete the entire course of ketoconazole coadministration. Four subjects received a shortened duration of ketoconazole therapy because of significant electrocardiographic repolarization abnormalities. There was a significant change in the area under the curve of the acid metabolite of terfenadine after the addition of ketoconazole administration. CONCLUSIONS: Ketoconazole alters the metabolism of terfenadine in normal men and women and results in the accumulation of unmetabolized parent drug, which is associated with significant prolongation of the corrected QT interval. This drug combination should be avoided.

Increased risk of coronary artery dissection during coronary angiography with 6F catheters.

The use of smaller sized catheters for coronary angiography (CA) is increasing, but little is known about the safety of CA with 6F catheters. The authors reviewed all cases of CA in which 6F and 8F catheters were used in adult patients between 1988 and June, 1990. There were 597 patients in the 6F group and 2,409 patients in the 8F group. Cases of CA with 6F catheters were more likely to be elective (95% vs 87%), to have no coronary disease (35% vs 24%), and to be performed by nonfirst-year fellows (70% vs 54%) when compared with CA with 8F catheters. There were 5 cases of coronary artery dissection. The incidence of dissections was significantly higher (p = .007) in the 6F group (0.67%) than in the 8F group (0.04%). The incidence of dissections was highest for first-year fellows using 6F catheters (1.7%), which was significantly higher (p = .008) than for first-year fellows using 8F catheters. The incidence of major vascular complications tended to be lower (p = .068) in the 6F group (0.17%) than in the 8F group (0.95%). In summary, CA with 6F catheters is associated with an increased risk of coronary artery dissection, particularly with less experienced operators, but tends to be associated with a lower risk of major vascular complications.

Effect of concomitant administration of cimetidine and ranitidine on the pharmacokinetics and electrocardiographic effects of terfenadine.

Terfenadine is a widely prescribed non-sedating antihistamine which undergoes rapid and almost complete first pass biotransformation to an active carboxylic acid metabolite. It is unusual to find unmetabolised terfenadine in the plasma of patients taking the drug. Terfenadine in vitro is a potent blocker of the myocardial potassium channel. Overdose, hepatic compromise and the coadministration of ketoconazole and erythromycin result in the accumulation of terfenadine, which is thought to be responsible of QT prolongation and Torsades de Pointes ventricular arrhythmia in susceptible individuals. Cimetidine and ranitidine are two popular H2 antagonists which are often taken with terfenadine. The effects of cimetidine and ranitidine on terfenadine metabolism were studied in two cohorts of 6 normal volunteers given the recommended dose of terfenadine (60 mg every 12 h) for 1 week prior to initiation of cimetidine 600 mg every 12 h or ranitidine 150 mg every 12 h. Pharmacokinetic profiles and morning pre-dose electrocardiograms were obtained whilst the patients were on terfenadine alone and after the addition of cimetidine or rantidine. One of the subjects in each cohort had a detectable plasma level of parent compound after 1 week of terfenadine therapy alone; it did not accumulate further after addition of the H2 antagonist. The pharmacokinetics of the carboxylic acid metabolite of terfenadine (Cmax, tmax, AUC) were not significantly changed after co-administration of either H2 antagonist. None of the remaining 5 subjects in either cohort demonstrated accumulation of unmetabolised terfenadine after addition of the respective H2 antagonist and electrocardiographic QT intervals and T-U morphology in them was not changed during the course of the study.(ABSTRACT TRUNCATED AT 250 WORDS)

Coronary arterial ectasia: increased prevalence in patients with abdominal aortic aneurysm as compared to occlusive atherosclerotic peripheral vascular disease.

Coronary artery ectasia (CAE) is the saccular or fusiform dilatation of a coronary artery. CAE is found in 1.2% to 4.9% of patients at autopsy or during angiographic studies, with a similar prevalence of CAE found in patients with atherosclerotic peripheral vascular disease (PVD). Abdominal aortic aneurysm (AAA) and CAE are similar in pathogenesis and histology. To determine whether CAE occurs more frequently in patients with AAA than in occlusive forms of atherosclerotic PVD, a review of coronary angiograms was performed in patients who underwent cardiac catheterization and vascular reconstruction for AAA or occlusive atherosclerotic PVD of the lower extremities. Of 72 patients with AAA, 15 had CAE (20.8%) compared with only 2 of 69 patients with atherosclerotic PVD (2.9%) (p < 0.003). CAE was predominantly discrete, located in the left coronary system, and associated with significant coronary atherosclerosis. CAE may be more prevalent in patients with AAA resulting from a similar pathogenetic process.