113
high-flux membrane. Before discontinuing ACE inhibitor therapy or haemodialysis with high-flux membranes in patients having anaphylactoid reactions, conversion to polysulfone high-flux membranes might be considered. Department of Nephrology, Streekziekenhuis Hilversum, and Dialysis Centre t Gooi, 1212 VH Hilversum, Netherlands
A. VAN Es F. C. HENNY S. LOBATTO
al that cyproterone antibodies played a part in the thrombotic event in their patient. INSERM U32, Hôpital Henri Mondor, 94010 Creteil, France
VIOLETTE BEAUMONT JEAN-LOUIS BEAUMONT
JL, Lemort N. Oral contraceptive, pulmonary artery thrombosis and antiethinyloestradiol monoclonal IgG. Clin Exp Immunol 1976; 24: 455-63. 2. Beaumont V, Lemort N, Beaumont JL. Oral contraception, circulating immune complexes, antiethinylestradiol antibodies and thrombosis. Am J Reprod Immunol 1. Beaumont
1982; 2: 8-12.
1. Bommer J, Becker KP, Urbascheck R, Ritz E, Urbascheck B. No evidence for endotoxin transfer across high-flux polysulfone membranes. Clin Nephrol 1987; 27: 278-82. 2 Schindler R, Dinarello CA A method for removing interleukin- 1 and tumor necrosis factor-inducing substances from bacterial cultures by ultrafiltration with polysulfone. J Immunol Methods 1989; 116: 159-65.
3. Beaumont V, Lemort N, Beaumont JL. Oral contraceptives, sex steroid induced antibodies and thrombosis: results from 1318 cases Eur Heart J (in press). 4. Lille P, Abbou CC, Beaumont V, Chopin D, Bottine Y, Auvert J. Mise en evidence d’anticorps specifiques antidiethylstilbestrol au cours du traitement du cancer de la prostate. Ann Urol 1986; 20: 113-16.
Erythromycin-induced hearing loss
Genetic predisposition to coronary heart disease and gene for apolipoprotein-CIII
SIR,-Dr Sacristan and colleagues (Oct 27, p 1080) comment that hearing loss "is one of the less known adverse effects of erythromycin". If this is so, it is useful for doctors to be fully informed of this effect. The Australian Therapeutic Goods Administration receives voluntary reports of suspected adverse reactions to drugs, forwarded by general practitioners, hospital staff, pharmacists, dentists, and other health professionals. These reports are reviewed by the Adverse Drug Reactions Advisory Committee (ADRAC), a subcommittee of the Australian Drug Evaluation Committee. In 1984 ADRAC published an article on erythromycin ototoxicity.1 Reports of hearing loss associated with erythromycin numbered 38 as at August, 1990. Erythromycin was the sole suspected drug in 20 reports. Hearing loss appeared 1-12 days after the start of therapy (median 35 days). 30 reports had noted recovery between 1 and 21 days after the cessation of erythromycin (median 4.1 days). Renal disease was recorded in 14. A high dosage of 4 g or more in 24 h was noted in 28 reports. The drug was administered intravenously in 31 cases and orally in 6. Tinnitus was also present in 7 reports. Our reports are consistent with the observations made by your correspondents and others. 1-3 Erythromycin-induced hearing loss is usually observed when high doses are used and in patients with renal insufficiency or with intravenous administration, but it can occur in other circumstances. Drug Reactions Section, Therapeutic Goods Administration, Woden, ACT 2606, Australia
Adverse
IAN BOYD
1. Adverse Drug Reactions Advisory Committee. Erythromycin ototoxicity. Aust Adverse Drug Reactions Bull 1984 (Feb). 2. Cramer R. Erythromycin ototoxidty. Drug Intell Clin Pharm 1986;; 20: 764-65. 3. Brummett RE, Fox KE. Vancomycin- and erythromycin-induced hearing loss in humans Antimicrob Agents Chemother 1989; 33: 791-96.
Thrombosis and antibodies to cyproterone acetate
SIR,-Dr Leroy and colleagues report (Aug 25, p 509) deep-vein thrombosis associated with antibodies to cyproterone acetate in a 19-year-old woman with no risk factors other than oral contraception with ’Diane’ (cyproterone acetate 2 mg, ethinyloestradiol 35 g). We have previously shown1 that oral contraception (OC) may induce antibodies to the synthetic hormones they contain. In women on oestrogen-progestagen pills the antibodies detected by
radioimmunoassay
were
SIR,-A single nucleotide substitution in the 3’-untranslated region of the gene for apolipoprotein-CIII (apo-CIII) has been associated with hypertriglyceridaemial and coronary heart disease (CHD)2 in caucasian people in southern England. In several other populations, however, the allele of apo-CIII having this substitution (S2) showed no relation with CHD.3-S These discordant findings have been interpreted’as suggesting that the S2 allele is not an aetiological agent but may be linked to an atherogenic mutation in English people and not in those populations without such a relation. Another possibility is that the S2 allele (or a linked mutation) alone has mild phenotypic effects CHD in combination with additional environmental/genetic risk factors that prevail variably in different ethnic groups. I have found evidence supporting this latter and
may
lead
to
possibility. Apo-CIII genotyping’ of 79 randomly sampled Arab patients (mean age 56, 78% males) with proven myocardial infarction (MI) showed an S2 gene frequency of 0.25. This gene frequency was 0-01 (p < 0-01) in 34 healthy normotriglyceridaemic Arabs (mean age 50, 65% males) and 0- 11(p < 0.005) in 75 age and sex matched controls selected randomly** from healthy Arabs having routine check-ups. Two major risk factors for CHD, cigarette smoking and diabetes mellitus (all type-11), co-existed in a significantly greater proportion of the MI patients with the S 1 S2 than with the S 1 Sgenotype (table, S1 represents the common allele). Conversely, the S 1 S2 genotype was rare in non-smoker and non-diabetic patients with MI whereas it was found in nearly half the MI patients who were smoker and/or diabetic (p < 0-05). Since diabetes mellitus per se showed no association with the gene for apo-CIII (data not shown), these findings are interpreted to mean that the S2 allele predisposes genetically to CHD but that development of overt disease requires exposure to additional risk factors including cigarette smoking and diabetes mellitus. The S2 allele has been shown before to cause hypertriglyceridaemia and a rise in very-low-density lipoproteins, as well as a decrease in high-density lipoproteins in a gene dosage dependent manner.6 Plasma lipoproteins of the MI patients with the S2 allele also showed similar changes. How these atherogenic plasma lipoprotein changes arise is not clear. However, circumstantial evidence suggests that the single nucleotide substitution in the 3’-untranslated region of the gene for apo-CIII CLINICAL CHARACTERISTICS IN MI PATIENTS OF DIFFERENT APO-CIII GENOTYPES
usually against ethinyloestradiol. They
observed in 25% of otherwise healthy users of oral contraception and in 80% of users with thrombosis.2,3 We have also used the tritiated cyproterone acetate antibody assay (provided by Schering) to test 47 women who had thrombosis while taking diane. 21 women (45%) had antibodies to cyproterone acetate alone (7) or with ethinyloestradiol antibodies (14). An association between thrombosis and antibodies to synthetic sex hormones has been observed not only for ethinyloestradiol in oral contraceptives but also for diethylstilboestrol in patients treated for prostatic cancer.4 Our results support the hypothesis of Leroy et were
women (62), S1 S2, 28 men (53), 5 women (70); S2S2 2 men (54), 1 woman (61) †Between 15-60 cigarettes per day (mean 32 [SD 18]) for 12-40 years (23 [8]) ‡S1S2 genotype more frequent in cigarette smoker diabetics than non-smoker non-diabetics (p=0016, Fisher’s exact text) §S1S2 genotype less frequent in non-smoker, non-diabetics than smoker and/or diabetic
*S1S1,32 men (mean age 54), 11
patients (p
high-flux membrane. Before discontinuing ACE inhibitor therapy or haemodialysis with high-flux membranes in patients having anaphylactoid reactions, conversion to polysulfone high-flux membranes might be considered. Department of Nephrology, Streekziekenhuis Hilversum, and Dialysis Centre t Gooi, 1212 VH Hilversum, Netherlands
A. VAN Es F. C. HENNY S. LOBATTO
al that cyproterone antibodies played a part in the thrombotic event in their patient. INSERM U32, Hôpital Henri Mondor, 94010 Creteil, France
VIOLETTE BEAUMONT JEAN-LOUIS BEAUMONT
JL, Lemort N. Oral contraceptive, pulmonary artery thrombosis and antiethinyloestradiol monoclonal IgG. Clin Exp Immunol 1976; 24: 455-63. 2. Beaumont V, Lemort N, Beaumont JL. Oral contraception, circulating immune complexes, antiethinylestradiol antibodies and thrombosis. Am J Reprod Immunol 1. Beaumont
1982; 2: 8-12.
1. Bommer J, Becker KP, Urbascheck R, Ritz E, Urbascheck B. No evidence for endotoxin transfer across high-flux polysulfone membranes. Clin Nephrol 1987; 27: 278-82. 2 Schindler R, Dinarello CA A method for removing interleukin- 1 and tumor necrosis factor-inducing substances from bacterial cultures by ultrafiltration with polysulfone. J Immunol Methods 1989; 116: 159-65.
3. Beaumont V, Lemort N, Beaumont JL. Oral contraceptives, sex steroid induced antibodies and thrombosis: results from 1318 cases Eur Heart J (in press). 4. Lille P, Abbou CC, Beaumont V, Chopin D, Bottine Y, Auvert J. Mise en evidence d’anticorps specifiques antidiethylstilbestrol au cours du traitement du cancer de la prostate. Ann Urol 1986; 20: 113-16.
Erythromycin-induced hearing loss
Genetic predisposition to coronary heart disease and gene for apolipoprotein-CIII
SIR,-Dr Sacristan and colleagues (Oct 27, p 1080) comment that hearing loss "is one of the less known adverse effects of erythromycin". If this is so, it is useful for doctors to be fully informed of this effect. The Australian Therapeutic Goods Administration receives voluntary reports of suspected adverse reactions to drugs, forwarded by general practitioners, hospital staff, pharmacists, dentists, and other health professionals. These reports are reviewed by the Adverse Drug Reactions Advisory Committee (ADRAC), a subcommittee of the Australian Drug Evaluation Committee. In 1984 ADRAC published an article on erythromycin ototoxicity.1 Reports of hearing loss associated with erythromycin numbered 38 as at August, 1990. Erythromycin was the sole suspected drug in 20 reports. Hearing loss appeared 1-12 days after the start of therapy (median 35 days). 30 reports had noted recovery between 1 and 21 days after the cessation of erythromycin (median 4.1 days). Renal disease was recorded in 14. A high dosage of 4 g or more in 24 h was noted in 28 reports. The drug was administered intravenously in 31 cases and orally in 6. Tinnitus was also present in 7 reports. Our reports are consistent with the observations made by your correspondents and others. 1-3 Erythromycin-induced hearing loss is usually observed when high doses are used and in patients with renal insufficiency or with intravenous administration, but it can occur in other circumstances. Drug Reactions Section, Therapeutic Goods Administration, Woden, ACT 2606, Australia
Adverse
IAN BOYD
1. Adverse Drug Reactions Advisory Committee. Erythromycin ototoxicity. Aust Adverse Drug Reactions Bull 1984 (Feb). 2. Cramer R. Erythromycin ototoxidty. Drug Intell Clin Pharm 1986;; 20: 764-65. 3. Brummett RE, Fox KE. Vancomycin- and erythromycin-induced hearing loss in humans Antimicrob Agents Chemother 1989; 33: 791-96.
Thrombosis and antibodies to cyproterone acetate
SIR,-Dr Leroy and colleagues report (Aug 25, p 509) deep-vein thrombosis associated with antibodies to cyproterone acetate in a 19-year-old woman with no risk factors other than oral contraception with ’Diane’ (cyproterone acetate 2 mg, ethinyloestradiol 35 g). We have previously shown1 that oral contraception (OC) may induce antibodies to the synthetic hormones they contain. In women on oestrogen-progestagen pills the antibodies detected by
radioimmunoassay
were
SIR,-A single nucleotide substitution in the 3’-untranslated region of the gene for apolipoprotein-CIII (apo-CIII) has been associated with hypertriglyceridaemial and coronary heart disease (CHD)2 in caucasian people in southern England. In several other populations, however, the allele of apo-CIII having this substitution (S2) showed no relation with CHD.3-S These discordant findings have been interpreted’as suggesting that the S2 allele is not an aetiological agent but may be linked to an atherogenic mutation in English people and not in those populations without such a relation. Another possibility is that the S2 allele (or a linked mutation) alone has mild phenotypic effects CHD in combination with additional environmental/genetic risk factors that prevail variably in different ethnic groups. I have found evidence supporting this latter and
may
lead
to
possibility. Apo-CIII genotyping’ of 79 randomly sampled Arab patients (mean age 56, 78% males) with proven myocardial infarction (MI) showed an S2 gene frequency of 0.25. This gene frequency was 0-01 (p < 0-01) in 34 healthy normotriglyceridaemic Arabs (mean age 50, 65% males) and 0- 11(p < 0.005) in 75 age and sex matched controls selected randomly** from healthy Arabs having routine check-ups. Two major risk factors for CHD, cigarette smoking and diabetes mellitus (all type-11), co-existed in a significantly greater proportion of the MI patients with the S 1 S2 than with the S 1 Sgenotype (table, S1 represents the common allele). Conversely, the S 1 S2 genotype was rare in non-smoker and non-diabetic patients with MI whereas it was found in nearly half the MI patients who were smoker and/or diabetic (p < 0-05). Since diabetes mellitus per se showed no association with the gene for apo-CIII (data not shown), these findings are interpreted to mean that the S2 allele predisposes genetically to CHD but that development of overt disease requires exposure to additional risk factors including cigarette smoking and diabetes mellitus. The S2 allele has been shown before to cause hypertriglyceridaemia and a rise in very-low-density lipoproteins, as well as a decrease in high-density lipoproteins in a gene dosage dependent manner.6 Plasma lipoproteins of the MI patients with the S2 allele also showed similar changes. How these atherogenic plasma lipoprotein changes arise is not clear. However, circumstantial evidence suggests that the single nucleotide substitution in the 3’-untranslated region of the gene for apo-CIII CLINICAL CHARACTERISTICS IN MI PATIENTS OF DIFFERENT APO-CIII GENOTYPES
usually against ethinyloestradiol. They
observed in 25% of otherwise healthy users of oral contraception and in 80% of users with thrombosis.2,3 We have also used the tritiated cyproterone acetate antibody assay (provided by Schering) to test 47 women who had thrombosis while taking diane. 21 women (45%) had antibodies to cyproterone acetate alone (7) or with ethinyloestradiol antibodies (14). An association between thrombosis and antibodies to synthetic sex hormones has been observed not only for ethinyloestradiol in oral contraceptives but also for diethylstilboestrol in patients treated for prostatic cancer.4 Our results support the hypothesis of Leroy et were
women (62), S1 S2, 28 men (53), 5 women (70); S2S2 2 men (54), 1 woman (61) †Between 15-60 cigarettes per day (mean 32 [SD 18]) for 12-40 years (23 [8]) ‡S1S2 genotype more frequent in cigarette smoker diabetics than non-smoker non-diabetics (p=0016, Fisher’s exact text) §S1S2 genotype less frequent in non-smoker, non-diabetics than smoker and/or diabetic
*S1S1,32 men (mean age 54), 11
patients (p
