Volume 116 Number 1
We conclude that, in the age range studied, a single maintenance dose of digoxin is equivalent to a twice-daily dosage regimen in maintaining therapeutic serum concentrations of digoxin. REFERENCES
1. Behrman RE, Vaughan NC. Nelson textbookof pediatrics. 3rd ed. Philadelphia: WB Saunders, 1987:102. 2. Adams FH, Emmanovilides GC. Moss' heart disease in infants, children and adolescents. 3rd ed. Baltimore: Williams & Wilkins, 1983:782. 3. Dungam WT, Doherty JE, Harvey C, et al. Tritiated digoxin XVIII: studies in infants and children. Circulation 1972;46:983-8. 4. Wettrell G. Distribution and elimination of digoxin in infants. Eur J Clin Pharmacol 1977;11:329-35.
Clinical and laboratory observations
139
5. Gorodiseher R. Cardiac drugs. In: Yaffe SJ, ed, Pediatric pharmacology. New York: Grune & Stratton, 1980:286. 6. Collins-Nakai RL, Schiff O, Ng PK. Pharmacokinetics of digoxin in low birth weight infants. Dev Pharmacol Ther 1982;5:86-97. 7. Wettrell G, Andersson KE. Clinical pharmocokinetics of digoxin in infants. Clin Pharmacol 1977;2:17-31. 8. Koren G, Parker R. Interpolation of excessive serum concentration of digoxin in children. Am J Cardiol 1985;55: 1210-4. 9. Roberts RJ. Drug therapy in infants. Philadelphia: WB Saunders, 1984:22. 10. Porter AMW. Drug defaulting in a general practice. Br Med J 1969;1:218-22. 11. Weintraub M, William YWA, Lasagna L. Compliance as a determinant of serum digoxin concentration. JAMA 1973; 224:481-5.
Increased incidence of epistaxis in adolescents with familial hypercholesterolemia treated with fish oil J. T. R. C l a r k e , MD, PhD, G. C u l l e n - D e a n , RN, BScN, E. R e g e l i n k , RN, BSN, L. C h a n , RPDt, a n d V. Rose, MD From the Divisionsof Clinical Genetics and Cardiology, Department of Pediatrics, The Hospital for Sick Children and University of Toronto, Toronto, Ontario, Canada
The results of nutritional and epidemiologic studies of Greenland Eskimos, in whom the incidence of coronary atherosclerosis and myocardial infarction is very low, led some years ago to the suggestion that the nature of dietary fat may be important in the prevention of these conditions.l, 2 Subsequent studies confirmed an association between the ingestion of fish oil and decreased mortality rates for coronary artery disease and favorable changes in plasma lipids, notably decreases in levels of triglycerides and very low density lipoprotein.3 The results of these studies suggested that the beneficial effect of diets containing fish was likely due to the presence of a high proportion of polyunsaturated fatty acids of the omega-3 series, principally eicosapentaenoie acid, in fish oil. This conclusion led to extensive use of commercially developed preparations of refined marine oils as dietary supplements. The mechanism of the beneficial effect of dietary omega3 fatty acids is still unclear. The most consistent and positive effect has been the observation that plasma levels of triglycerides and very low density lipoprotein are lowered. Potentially hazardous side effects of diets enriched in omeSubmitted for publication Feb. 13, 1989; accepted July 5, 1989. Reprint requests: J. T. R Clarke, MD, Divisionof Clinical Genetics, Hospital for Sick Children, 555 University Ave., Toronto, Ontario M5G IX8, Canada. 9/26/15112
ga-3 polyunsaturated fatty acids include problems related to the effect on platelet function. High dietary omega-3 fatty acid intake causes changes in the fatty acid composition of platelet membranes and a reduction of platelet aggregation and thrombogenesis in vivo.4-6 These side effects may limit the usefulness of currently available fish oil preparations in the treatment of hyperlipidemia. The purpose of the study reported here was to evaluate FHL
Familial hyperlipoproteinemia
the potentially beneficial effect of dietary fish oil supplementation on plasma lipid levels in a small group of adolescent patients with familial hyperlipoproteinemia type II, and to note possible undesirable side effects. METHODS We studied seven female and four male adolescents, 11 to 21 years of age, with FHL type II. The diagnosis of each case was based on a positive family history, typical abnormalities of plasma lipid levels, and absence of evidence of any other condition to account for the lipid abnormalities. All subjects were apparently heterozygous for FHL type lI; five were classified as having FHL type IIa and six, type IIb, on the basis of plasma triglyceride levels. All subjects were maintained on their usual modified low cholesterol-low saturated fat diet throughout the study; two also received
14 0
Clinical and laboratory observations
Table. Effect of fish oil treatment on plasma lipid levels
Lipid Triglycerides Cholesterol LDL-C HDL-C
Type of FHL lla lib lla lib IIa lib IIa IIb
Before treatment (mmol/L)
After treatment (retool/L)
1.12 _+ 0.30 (15) 0.96 ___0.34 (27) 2.91 _ 1.29 (18) 2.14 _+ 1.08 (35) 8.55 _+ 1.61 (15) 9.03 _+ 2.40 (27) 7.67 _+ 1.77 (18) 7.63 _+ 2.06 (35) 6.80 _+ 1.31 (15) 7.47 _+ 2.36 (27) 5.39 _+ 1.93 (18) 5.68 + 2.01 (34) 1.19 + 0.28 (15) 1.15 + 0.29 (27) 2.91 + 1.29 (18) 2.14 _+ 1.08 (35)
Valuesrepresentthe means_+SD, with the numberof observationsin parentheses. LDL-C, Low-densitylipoproteincholesterol;HDL-C. high-densitylipoprotein eholesterol.
colestipol, 10 gin/day. Fasting plasma cholesterol, triglyceride, and high-density lipoprotein cholesterol levels were measured, 7 and low-density lipoprotein cholesterol levels were calculated 8 monthly for at least 3 months before the start of therapy, throughout the treatment period, and for 1 month after fish oil treatment was stopped. After 3 months of pretreatment observation, each subject was given a commercial fish oil supplement (in the form of MaxEPA, a commercially available preparation of fish oils containing 18% eicosapentaenoic acid, 12% other omega-3 fatty acids, and vitamin E) in a dosage started at t gin/day and increased by 1 gm/day at monthly intervals to a total of 5 gm/day for the fifth and sixth months of therapy. Treatment was monitored by monthly clinical review and measurements of plasma lipids, platelet count, bleeding time, prothrombin time, partial thromboplastin time, liver function, and serum calcium and phosphorus concentrations. The stools were tested for occult blood. A record was also maintained of nosebleeds or any other evidence of a bleeding diathesis. The effect of fish oil supplementation on plasma lipid levels was analyzed by one-way analysis of variance. RESULTS There was no overall statistically significant effect of treatment on plasma lipid levels in either group (Table). On the other hand, 8 of the 11 subjects had a total of nine episodes of epistaxis during 62 subject-months of fish oil treatment; no subject reported any nosebleeds during 43 subject-months of pretreatment and posttreatment observation (chi-sqnare value = 5.92, p
We conclude that, in the age range studied, a single maintenance dose of digoxin is equivalent to a twice-daily dosage regimen in maintaining therapeutic serum concentrations of digoxin. REFERENCES
1. Behrman RE, Vaughan NC. Nelson textbookof pediatrics. 3rd ed. Philadelphia: WB Saunders, 1987:102. 2. Adams FH, Emmanovilides GC. Moss' heart disease in infants, children and adolescents. 3rd ed. Baltimore: Williams & Wilkins, 1983:782. 3. Dungam WT, Doherty JE, Harvey C, et al. Tritiated digoxin XVIII: studies in infants and children. Circulation 1972;46:983-8. 4. Wettrell G. Distribution and elimination of digoxin in infants. Eur J Clin Pharmacol 1977;11:329-35.
Clinical and laboratory observations
139
5. Gorodiseher R. Cardiac drugs. In: Yaffe SJ, ed, Pediatric pharmacology. New York: Grune & Stratton, 1980:286. 6. Collins-Nakai RL, Schiff O, Ng PK. Pharmacokinetics of digoxin in low birth weight infants. Dev Pharmacol Ther 1982;5:86-97. 7. Wettrell G, Andersson KE. Clinical pharmocokinetics of digoxin in infants. Clin Pharmacol 1977;2:17-31. 8. Koren G, Parker R. Interpolation of excessive serum concentration of digoxin in children. Am J Cardiol 1985;55: 1210-4. 9. Roberts RJ. Drug therapy in infants. Philadelphia: WB Saunders, 1984:22. 10. Porter AMW. Drug defaulting in a general practice. Br Med J 1969;1:218-22. 11. Weintraub M, William YWA, Lasagna L. Compliance as a determinant of serum digoxin concentration. JAMA 1973; 224:481-5.
Increased incidence of epistaxis in adolescents with familial hypercholesterolemia treated with fish oil J. T. R. C l a r k e , MD, PhD, G. C u l l e n - D e a n , RN, BScN, E. R e g e l i n k , RN, BSN, L. C h a n , RPDt, a n d V. Rose, MD From the Divisionsof Clinical Genetics and Cardiology, Department of Pediatrics, The Hospital for Sick Children and University of Toronto, Toronto, Ontario, Canada
The results of nutritional and epidemiologic studies of Greenland Eskimos, in whom the incidence of coronary atherosclerosis and myocardial infarction is very low, led some years ago to the suggestion that the nature of dietary fat may be important in the prevention of these conditions.l, 2 Subsequent studies confirmed an association between the ingestion of fish oil and decreased mortality rates for coronary artery disease and favorable changes in plasma lipids, notably decreases in levels of triglycerides and very low density lipoprotein.3 The results of these studies suggested that the beneficial effect of diets containing fish was likely due to the presence of a high proportion of polyunsaturated fatty acids of the omega-3 series, principally eicosapentaenoie acid, in fish oil. This conclusion led to extensive use of commercially developed preparations of refined marine oils as dietary supplements. The mechanism of the beneficial effect of dietary omega3 fatty acids is still unclear. The most consistent and positive effect has been the observation that plasma levels of triglycerides and very low density lipoprotein are lowered. Potentially hazardous side effects of diets enriched in omeSubmitted for publication Feb. 13, 1989; accepted July 5, 1989. Reprint requests: J. T. R Clarke, MD, Divisionof Clinical Genetics, Hospital for Sick Children, 555 University Ave., Toronto, Ontario M5G IX8, Canada. 9/26/15112
ga-3 polyunsaturated fatty acids include problems related to the effect on platelet function. High dietary omega-3 fatty acid intake causes changes in the fatty acid composition of platelet membranes and a reduction of platelet aggregation and thrombogenesis in vivo.4-6 These side effects may limit the usefulness of currently available fish oil preparations in the treatment of hyperlipidemia. The purpose of the study reported here was to evaluate FHL
Familial hyperlipoproteinemia
the potentially beneficial effect of dietary fish oil supplementation on plasma lipid levels in a small group of adolescent patients with familial hyperlipoproteinemia type II, and to note possible undesirable side effects. METHODS We studied seven female and four male adolescents, 11 to 21 years of age, with FHL type II. The diagnosis of each case was based on a positive family history, typical abnormalities of plasma lipid levels, and absence of evidence of any other condition to account for the lipid abnormalities. All subjects were apparently heterozygous for FHL type lI; five were classified as having FHL type IIa and six, type IIb, on the basis of plasma triglyceride levels. All subjects were maintained on their usual modified low cholesterol-low saturated fat diet throughout the study; two also received
14 0
Clinical and laboratory observations
Table. Effect of fish oil treatment on plasma lipid levels
Lipid Triglycerides Cholesterol LDL-C HDL-C
Type of FHL lla lib lla lib IIa lib IIa IIb
Before treatment (mmol/L)
After treatment (retool/L)
1.12 _+ 0.30 (15) 0.96 ___0.34 (27) 2.91 _ 1.29 (18) 2.14 _+ 1.08 (35) 8.55 _+ 1.61 (15) 9.03 _+ 2.40 (27) 7.67 _+ 1.77 (18) 7.63 _+ 2.06 (35) 6.80 _+ 1.31 (15) 7.47 _+ 2.36 (27) 5.39 _+ 1.93 (18) 5.68 + 2.01 (34) 1.19 + 0.28 (15) 1.15 + 0.29 (27) 2.91 + 1.29 (18) 2.14 _+ 1.08 (35)
Valuesrepresentthe means_+SD, with the numberof observationsin parentheses. LDL-C, Low-densitylipoproteincholesterol;HDL-C. high-densitylipoprotein eholesterol.
colestipol, 10 gin/day. Fasting plasma cholesterol, triglyceride, and high-density lipoprotein cholesterol levels were measured, 7 and low-density lipoprotein cholesterol levels were calculated 8 monthly for at least 3 months before the start of therapy, throughout the treatment period, and for 1 month after fish oil treatment was stopped. After 3 months of pretreatment observation, each subject was given a commercial fish oil supplement (in the form of MaxEPA, a commercially available preparation of fish oils containing 18% eicosapentaenoic acid, 12% other omega-3 fatty acids, and vitamin E) in a dosage started at t gin/day and increased by 1 gm/day at monthly intervals to a total of 5 gm/day for the fifth and sixth months of therapy. Treatment was monitored by monthly clinical review and measurements of plasma lipids, platelet count, bleeding time, prothrombin time, partial thromboplastin time, liver function, and serum calcium and phosphorus concentrations. The stools were tested for occult blood. A record was also maintained of nosebleeds or any other evidence of a bleeding diathesis. The effect of fish oil supplementation on plasma lipid levels was analyzed by one-way analysis of variance. RESULTS There was no overall statistically significant effect of treatment on plasma lipid levels in either group (Table). On the other hand, 8 of the 11 subjects had a total of nine episodes of epistaxis during 62 subject-months of fish oil treatment; no subject reported any nosebleeds during 43 subject-months of pretreatment and posttreatment observation (chi-sqnare value = 5.92, p
