George K. Asdourian

Clinical pharmacokinetics and efficacy of amiodarone for refractory tachyarrhythmias.

Using a high-pressure liquid chromatographic assay, we measured serum amiodarone concentrations serially in 122 patients treated with amiiodarone for 1.5–53 months (mean 9.3 months) for control of refractory symptomatic atrial or symptomatic and life-threatening ventricular tachyarrhythmias. The atrial tachyarrhythmias were successfully controlled in 45 of 54 patients (83%) during a mean follow-up of 10.0 months. In the ventricular tachyarrhythmia group, which included 22 survivors of sudden cardiac death, 38 of 50 patients (76%) responded to amiodarone during a mean follow-up of 10.9 months. Although the mean serum amiodarone concentration did not differ between responders and nonresponders, eight responders relapsed when their serum concentration fell below 1.0 mg/I. Side effects resulted in withdrawal of amiodarone in only 10 of 122 patients (9%) despite a 30% overall incidence of side effects. Central nervous system and gastrointestinal side effects became more frequent with serum concentrations > 2.5 mg/l, although only central nervous system side effects achieved statistical significance. Absorption and disposition kinetics of a single oral 800-mg dose of amiodarone were studied in eight patients. Serum values were measured for 24 hours in five patients during maintenance therapy, and elimination kinetics after long-term therapy were evaluated in three patients. The tissue concentration of amiodarone was determined in two patients who died during long-term amiodarone therapy and an attempt was made in 14 patients to correlate serum concentrations with daily dosages during maintenance therapy. The pharmacokinetics of oral amiodarone support the practice of using high loading dosages until arrhythmia suppression or apparent steady state is achieved (usually 2–4 weeks), followed by low-dose maintenance therapy (200400 mg once a day) for treatment of symptomatic atrial and ventricular tachyarrhythmias.

Efficacy and safety of long-term amiodarone in treatment of cardiac arrhythmias: Dosage experience

Abstract The efficacy and safety of long-term oral amiodarone was assessed in 173 patients with symptomatic tachyarrhythmias: 96 with life-threatening ventricular tachycardia and fibrillation (VT-VF), of whom 40 had survived sudden cardiac death (SCD), and 77 with atrial tachyarrhythmias (AT), predominantly atrial fibrillation and flutter, that had been refractory to conventional antiarrhythmic agents in therapeutic dosages. Amiodarone administration consisted of a high-dose loading phase (800 to 1600 mg/day in divided doses) for 8 days to 4 weeks, followed by a low-dose maintenance phase (200 to 400 mg once a day). The regulation of the maintenance dose was aided by frequent monitoring of serum amiodarone concentrations, clinical response, and development of side effects. Amiodarone had long-term effectiveness (mean follow-up 10.1 months; range 1.5 to 62 months) in 139 of 173 patients (79%). It was effective in 82 of 96 patients (83%) with symptomatic VT-VF (35 of 40 survivors [86%] of SCD), whose mean follow-up was 10.3 months. In the 77 AT patients there were 57 long-term responders (74%; mean follow-up 9.1 months; range 1.5 to 60 months). The maintenance (apparent steady-state) serum amiodarone concentrations ranged from 0.6 to 2.8 μg/ml (mean 1.6 μg/ml) in 139 of the 173 responders and were lower than those in the nonresponders (mean 1.9 μg/ml). These differences were not significant. There was a wide intersubject variation of serum levels for a given dose of amiodarone. Arrhythmia relapses occurred in nine patients when their serum concentrations fell to ≤1.0 μg/ml. In eight of these patients, reinstitution of higher amiodarone dosages and elevation of serum amiodarone concentrations restored control of their tachycardia. Side effects occurred in 44 of 173 patients (25%) but precluded long-term use in only 18 patients (10%). Although side effects were generally more common when serum amiodarone concentrations exceeded 2.5 μg/ml, even serious ones occurred over a wide range (0.6 to 4.4 μg/ml) of serum drug concentrations. Important drug interactions occurred with warfarin and class I antiarrhythmic agents.

CTC1 Mutations in a patient with dyskeratosis congenita

Dyskeratosis congenita (DC) is a rare inherited bone marrow failure syndrome caused by mutations in seven genes involved in telomere biology, with approximately 50% of cases remaining genetically uncharacterized. We report a patient with classic DC carrying a compound heterozygous mutation in the CTC1 (conserved telomere maintenance component 1) gene, which has recently implicated in the pleiotropic syndrome Coats plus. This report confirms a molecular link between DC and Coats plus and expands the genotype–phenotype complexity observed in telomere‐related genetic disorders. Pediatr Blood Cancer 2012;59:311–314.

Macular and perimacular vascular remodelling sickling haemoglobinopathies.

The posterior pole vasculature of 100 patients with different sickling haemoglobinopathies was studied prospectively over a period of three years. Various abnormalities of the posterior pole vasculature were seen in 29 per cent of the patients. Continuous remodelling of the macular and perimacular vasculature occurred. Visual acuity was variably affected and sometimes remained intact.

Spontaneous Regression (Autoinfarction) of Proliferative Sickle Retinopathy

Of 45 patients with proliferative sickle retinopathy in stages III, IV, and V, nine patients (eight with hemoglobin SC disease, one with sickle cell thalassemia) showed spontaneous regression (autoinfarction) of retinal sea fans. One mechanism involved in autoinfarction of neovascular tissue is progressive, centripetal retraction of the anterior vascular arcade of the peripheral retina. In addition, vitreous traction on feeder vessels may result in sluggish blood flow and occlusion of these vessels, or may tear the sea fan completely away from its feeder vessels. In view of the many incidences of vitreous hemorrhages that occur in patients with proliferative retinopathy, however, we recommend treatment of neovascularization rather than prolonged observation.

Angioid streaks and sickle haemoglobinopathies.

Five patients had angioid streaks associated with sickle cell haemoglobinopathy. Other diseases associated with angioid streaks were ruled out, as was elastic tissue degenegation in sickle cell patients. After studying over 350 patients, we believe the incidence of angioid streaks in sickle cell disease to be between 1 and 2 per cent.

Amiodarone for tachyarrhythmias: pharmacology, kinetics, and efficacy.

Amiodarone, although widely studied in Europe, is a recent addition to the investigational antiarrhythmics being used in the U.S. Pharmacologically, its primary cardiac effects are to increase coronary artery blood flow, increase the effective refractory period, and produce an atropine-resistant bradycardia. Amiodarone is incompletely (~ 50 percent) and slowly (peak serum concentration ~ 6 h) absorbed. With chronic administration, it deposits both in adipose tissue and in organs with high blood perfusion. It has an apparent elimination half-life of 15–45 days, which presents unique dosing problems. The apparent therapeutic range is 0.6-3 μg/ml. Amiodarone is 85–95 percent effective in the treatment of atrial tachyarrhythmias and 70–80 percent effective in ventricular tachyarrhythmias. It appears to be of particular value in chronic atrial fibrillation/flutter because it may be able to maintain sinus rhythm after cardioversion. Side effects, although uncommon, may prevent the drug from becoming a standard of therapy. Drug interactions, particularly with warfarin and digoxin, as well as pulmonary fibrosis are of concern.

Evolution of the retinal black sunburst in sickling haemoglobinopathies.

In a prospective study of 38 patients, who were initially selected as being at an early stage of sickling retinopathy, three developed circular black chorio-retinal scars (black sunbursts) during a period of 6 to 24 months. These lesions appear to be the sequelae of intraretinal and subretinal haemorrhage. They occur in the fundus periphery and do not interfere with vision.

Spontaneous Remodeling of the Peripheral Retinal Vasculature in Sickling Disorders

Periodic photographic and angiographic surveys of patients with the earliest stages of sickle retinopathy showed a number of fundus findings. In seven cases (sickle cell anemia, four; sickle cell hemoglobin C, three), these findings included: (1) a variety of vascular abnormalities in the equatorial and post-equatorial retina such as segmented dilations of the vessel walls, hairpin-shaped vascular loops, hypertrophic, tortuous A-V anastomoses, intraluminal plugs, closure and loss of capillary bed, and terminal budding of capillaries; and (2) a continuous, spontaneous remodeling of the peripheral retinal vasculature due to successive closures and reopenings of equatorial retinal vessels. A centripetal recession of the peripheral retinal vasculature usually resulted. No correlation between the ophthalmoscopic and the systemic condition of the patients could be made.

Macular abnormalities in papilledema from pseudotumor cerebri

Three young women with papilledema secondary to pseudotumor cerebri evolved mottled macular pigmentation with preservation of normal visual acuity. Choroidal folds or macular star figures were observed. These macular changes could represent the sequelae of either macular edema or a mechanical disruption of the retinal pigment epithelium. The mechanism of choroidal folds in papilledema remains uncertain.