dna polymorphisms flanking insulin gene and atherosclerosis

348

product leaflet. Professor Silverman claims that the manufacturers’information does not support the use of oxymetazoline in childrenunder two years of age, that it provides ample information about theadverse effects of oxymetazoline, and that too high doses were usedin most of the cases we described. He suggests that naphazolinewould have been a better drug to choose for comparison. Silvermanalso claims that adverse effects to phenylpropanolamine (PPA) havebeen due to overdosage of PPA, often in combination with otherdrugs, and that no side-effects of PPA have been described when it isused properly.However, manufacturers’ information in Sweden, the UK, and

Canada gives dose recommendations within the range we reported(table) and doesnot state any age limit of years. In the United Statesoxymetazoline is only available in a concentration of0’5 5 mg/ml andthe age limit is 6 years (Physicians Desk Reference 1984). Only theCanadian compendium gives adequate information about adverseeffects. Can all these sources of information be wrong? Manyphysicians rely upon them when prescribing nose-drops for

patients, including infants and small children. In Sweden theaverage number of prescriptions for oxymetazoline to children aged0-4 years was 527 per 1000 per year between 1979 and 1982.1Since adverse CNS and cardiovascular effects from naphazoline,

especially in overdoses, are well known and since nose-dropscontaining naphazoline have not been available in Sweden since1974 we did not find this substance relevant for comparison.During the 1970s PPA alone or in combination with

antihistamines became increasingly used as a systemic nasal

decongestant in Sweden. In 1978 total sales of PPA-containingdrugs were as high as 12 "defined daily doses" (DDD= 100 mg) per1000 inhabitants daily. 1 For outpatients the number of

prescriptions of single-ingredient PPA preparations varied from200 per 1000 population per year in patients aged 0-4 years down to30 in those over 65. It soon emerged that PPA alone or incombination with antihistamines could give rise to several adverseeffects even at recommended doses. In 1977, the Swedish AdverseDrug Reactions Advisory Committee (SADRAC) warned abouturinary retention and dysuria and in 1979 a warning was sent outabout mental disturbances.2,3 In 1979, 61 cases of mentaldisturbances were reported, 48 in children up to 15 years of age. Ofthese, 18 patients had taken drugs containing PPA alone. After this,the use of PPA has been reduced by half (to 5 - 6 DDD per 1000 perday in 1983).1SADRAC has on file 118 reports of adverse reactions to single-

ingredient PPA which have been classified as probable or possible.The most common symptoms are mental disturbances (62), skinreactions (27), neurological disorders (16), and micturition

problems (11). The most common psychiatric reactions consist of

DOSE RECOMMENDATIONS FOR OXYMETAZOLINE IN SWEDEN, UK,AND CANADA, FOR CHILDREN

Sources: FAS (Farmaceurzska speaalzrerer I Svenge) 1984: 575-76. British Nallo1UlIFormulary 1984 (no 7) 331 ABPI Data Sheet CompendIum 1983: 573, 745 CanadianCompendIum oj Pharmaceullcals and Speczalznes 1983: 393.

excitation with disturbed sleep, sometimes with agitation andconfusion. 30 of these 118 patients were under 5 years of age and 19between 5 and 14. 20 of the 36 cases of mental disturbance in this agegroup were at doses higher than those recommended and in 6 ofthese 20 cases another ephedrine or PPA-containingpharmaceutical was taken concomitantly. However, in 16 cases thedoses were within the recommended dose range. Also only one ofthe 4 patients previously reported who had a psychotic reaction ofsingle-ingredient PPA had taken an overdose. The fact thatSilverman et al5 could not find any significant rise in mean bloodpressure after a single 25 mg dose of PPA alone to 25 adults or incombination with 100 mg caffeine to 12 does not prove the safety ofPPA in clinical use.

Adverse Reactions Section,Department of Drugs,National Board of Health and Welfare,and Department of Clinical Pharmacology,

Huddinge University Hospital,5-141 86 Huddinge, Sweden BENGT-ERIK WIHOLM

1. Swedish statistics on medicines. Stockholm: Apoteksbolaget, 1978-83.2. Widerlov E. Psykoser av fenylpropanolamin. Lakartidningen 1979; 76: 4529-30.3. Swedish Adverse Drug Reactions Advisory Committee. Fenylpropanolamin: Psykisk

paverkån och förvirringstillstånd (bulletin no 31). Lakartidningen 1979; 76: 45314. Norvenius G, Widerlöv E, Lönnerholm G. Phenylpropanolamine and mental

disturbances. Lancet 1979; ii: 1367-68.5. Silverman HI, Kreger BE, Lewis GP, Karabelas A, Paone R, Foley M. Lack of side

effects from orally administered phenylpropanolamine and phenylpropanolaminewith caffeine: a controlled three-phase study. Curr Ther Res 1980; 28: 185-94

DNA POLYMORPHISMS FLANKING INSULIN GENEAND ATHEROSCLEROSIS

SIR,-Two recent reports have suggested that a particular allele,the U allele (to distinguish it from the L allele), in a polymorphicregion of DNA close to the human insulin gene is a genetic markerfor atherosclerosis.1,2 We have done a similar study with 100consecutive patients (84 males) who underwent coronaryangiography for suspected coronary artery disease. This group wasgenotyped and independently graded into three subgroups withminimal, intermediate, or severe atherosclerosis:

Insulin genotypeAtherosclerosis LL UL UU TotalsMinimal 19 10 4 33

Intermediate 20 14 3 37

Severe 18 12 0 30

We have not found an increased frequency of the Uallele in patientswith extensive coronary artery disease compared with subjects withangiographically normal coronary arteries, and so cannot confirmthat this allele is a genetic marker for atherosclerosis.

Full clinical and experimental details are to be published elsewhere.

Departments of Medicineand Cardiology,

St Bartholomew’s Hospital,London EC 1A 7BE

N. I. JOWETTA. REES

J. CAPLINL. G. WILLIAMSD. J. GALTON

1. Owerbach D, Billesbølle P, Schroll M, Johansen K, Poulsen S, Nerup J. Possibleassociation between DNA sequences flanking the insulin gene and atherosclerosisLancet 1982; ii: 1291-93.

2. Mandrup-Poulsen T, Martensen SA, Meinertz H et al. DNA sequences flanking theinsulin gene on chromosome 11 confer risk of atherosclerosis Lancet 1984, i.

250-52.

NORTH SEA DIVERS ARE NO FITTER THANSEDENTARY MEN

SIR,-Our measurements accord with those of Dr Thompson andcolleagues (July 14, p 107) that maximum oxygen uptake of diversaged 30 years is on average 46 ml kg- min-1. Thompson et alwould prefer a greater margin of safety and propose a minimum fordivers of 50 ml kg - min-1. We do not know of evidence to supportthis level, which exceeds that required by the Norwegians for workat great depths. Doesn’t the greater experience of older men offsettheir lower aerobic power? Many divers would have difficulty inmaintaining the proposed standard since much of their work issedentary or static and in our experience does not promote cardio-vascular fitness; in longitudinal studies diving does, however.increase the vital capacity. Men in mine rescue brigades must pass