1420
`
`THE LANCET
`
`EC50 (nmol/L) AND Emax EXPRESSED AS PERCENTAGE OF
`MAXIMUM CONTRACTILE RESPONSE TO POTASSIUM,
`100 mmol/L*
`
`*Mean (SE) shown, n=6-11, tsubcutaneous.
`
`The recommended dose of subcutaneously administered
`ergotamine is 10 to 48 times lower than for subuctaneous
`sumatriptan2-4 (table). However, the 100-fold higher potency,
`combined with the 2-fold higher maximum effect, as well as the
`much longer duration of action of ergotamine, suggests that, in
`general, the cardiac liability of ergotamine is higher than that of
`sumatriptan. Both drugs are contraindicated in patients with known
`coronary artery disease. Possibly, the oral administration of
`sumatriptan-if feasible-would lead to a less rapid rise in plasma
`concentrations, which could be safer in patients who may be at risk
`from coronary side-effects.
`
`Department of Pharmacology,
`Faculty of Medicine and Health Sciences,
`Erasmus University Rotterdam,
`3000 DR Rotterdam, Netherlands
`
`WILLEM A. BAX
`PRAMOD R. SAXENA
`
`1101
`
`Contractile effect of sumatriptan in absence of U46619 (open
`circles, n = 4), and in presence of EC,o concentration (filled
`circles, n = 4), EC,o concentration (open triangles), or ECso
`(filled
`triangles)
`concentration
`of U46619 on non-
`atherosclerotic epicardial coronary arteries.
`Specimens were obtained from 4 patients aged 25, 29, 43, and
`receiving
`54 years,
`heart
`for cardiomyopathy.
`transplantation
`Experiments were done in duplicate in vessels from each patient.
`(Initial response U46619concentrations shown by different starting
`points for each curve on the y axis.) M = mol/L.
`
`of abrogated nitric oxide release. These mechanisms could be of
`pathophysiological importance in vessels affected by atherosclerotic
`disease, since we have shown that areas immediately distal to
`atheromas are hyperreactive to sumatriptan.1 The possibility exists
`that some patients receiving sumatriptan could have newly formed
`yet undetected atheroma, with an associated area of vascular
`hyperreactivity. Care should be taken when giving this drug to
`patients with coronary risk factors.
`The physiological role of 5-HT1-like receptors remains unclear,
`but in certain circumstances these receptors might mediate
`pathophysiological events in the coronary circulation.
`Department of Cardiothoracic Surgery,
`National Heart and Lung Institute,
`Heart Science Centre,
`Harefield Hospital,
`Middlesex UB9 6JH, UK
`
`A. H. CHESTER
`G. S. O’NEIL
`M. H. YACOUB
`
`1. Chester AH, Martin GR, Bodelsson, et al. 5-hydroxytryptamine receptor profile in
`healthy and diseased human epicardial coronary arteries. Cardiovasc Res 1990; 24:
`932-37.
`2. Chester AH, Allen SP, Tadjkarimi S, Yacoub MH. Interaction between thromboxane
`A2 and 5-hydroxytryptamine receptor subtypes in human coronary arteries.
`Circulation 1993; 87: 874-80.
`
`SIR,-Dr Ottervanger and colleagues prudently advise caution in
`the use of sumatriptan in patients with chest pain or "tightness of
`the chest" after use of sumatriptan. As they mention, myocardial
`ischaemia and infarction have also been recorded after ergotamine,l
`an antimigraine drug that has been used for many decades.
`However, the fact that their particular patient had not shown signs
`of myocardial ischaemia after ergotamine, prompts us to put in a
`word of caution.
`We compared the contractile effects in the human isolated
`coronary artery of sumatriptan and the non-selective 5-HT-
`receptor agonist ergotamine, and also of serotonin. The right
`coronary artery segments were obtained from 16 heart-beating
`organ donors who died of non-cardiac disorders (9 male, 7 female;
`aged 1-49 years). Hearts were provided by the Rotterdam Heart
`Valve Bank (Bio Implant Services Foundation/Eurotransplant
`Foundation) after removal of the aortic and pulmonary valves for
`homograft
`transplantation.
`Tension
`recorded
`valve
`was
`isometrically in organ baths containing oxygenated Kreb’s solution.
`The ECo and maximum effect (Emax) ofthe two antimigraine drugs
`and of serotonin show (table) that ergotamine was about 100 times
`more potent than sumatriptan. Moreover, the Emax of ergotamine
`was twice that of sumatriptan.
`
`1. Galer BS, Lipton RB, Solomona S, et al. Myocardial ischemia related to ergot
`alkaloids: a case report and literature review. Headache 1991; 31: 446-50.
`2. Perrin VL. Clinical pharmacokinetics of ergotamine in migraine and cluster headache.
`Clin Pharmacokin 1985; 10: 334-52.
`3. Farmacotherapeutisch
`Kompas
`1992.
`Ziekenfondsraad, 1992: 288-301.
`4. The Subcutaneous Sumatriptan International Study Group. Treatment of migraine
`attacks with sumatriptan. N Engl J Med 1991; 325: 316-21.
`
`The
`
`Netherlands:
`
`Amstelveen,
`
`Tumour HER2 protein in breast cancer and
`family history
`SiR,—The HER2 gene, located on the long arm of chromosome
`17, codes for a protein with the characteristics of a growth factor
`receptor.1,2 The ligand may belong to a family of proteins called
`heregulins.3 HER2 protein overexpression in breast cancers is
`associated with poor prognosis.4 Moreover, HER2 overexpression
`is positively correlated with inflammatory tumours, higher tumour
`mitotic activity, high tumour grade, large tumour size, and young
`age. HER2 overexpression is negatively correlated with tumour
`oestrogen and progesterone receptor content. We report that high
`tumour HER2 protein is also associated with a family history of
`breast cancer.
`We measured HER2 protein in 20 women who had breast
`cancers excised in our centre. HER2 protein in the tumours was
`measured by enzyme-linked immunosorbent assay (ELISA)6
`preferable
`which,
`quantitative,
`being
`be
`to
`may
`immunohistochemistry
`blotting,
`which
`western
`are
`or
`semiquantitative .6 All assays were done by Dianon Systems,
`Stratford, Connecticut.
`HER2 concentrations were significantly higher in women with a
`family history of breast cancer (p=00025, two-tailed Mann-
`Whitney U, figure). The 10 women with family history were
`predominantly post-menopausal (mean age 64-4 [SE 3 1] vs 57 [4-7]
`for the other 10; not significantly different, t-test). There was no
`significant difference in tumour DNA index between the two
`groups (1-13 [0’08] vs 1-28 [0-12]). Of the 10 women with a family
`history ofbreast cancer, 4 had a first-degree relative with the disease
`(mother or sister); the other 6 had a second-degree relative with
`breast cancer (aunts, cousins, or a niece).
`A familial breast-ovarian cancer gene, BRCAI, has been
`localised to the long arm of chromosome 17.7,8 This gene,
`associated with breast cancer in women under age 45, is not the
`HER2 gene.2 In addition, there is evidence implicating at least two
`genes on the short arm of chromosome 17 in breast cancer
`carcinogenesis.9 Hospira v. Genentech
`IPR2017-00737
`Genentech Exhibit 2022
`
`

`

`THE LANCET
`
`1421
`
`In African countries, low birthweight is twice as common as in
`western populations. 15% or more of infants lie below the 5th
`centile of growth, as indicated by US National Children’s Health
`Study reference standardsl-reaching 25-40% in preschool and
`schoolchildren. Nevertheless, these conditions seem to inhibit
`subsequent cardiovascular disease. In black South African adults,
`coronary heart disease (CHD) is absent in rural dwellers,
`and remains rare in urban dwellers, despite the facts that a
`quarter have raised cholesterol concentrations,over half the men
`smoke, and hypertension frequency is higher than in the white
`population. However, with the slight rise in socioeconomic
`status and its sequelae, the prevalence of diabetes, by contrast
`with its near absence in the past, is as high in elderly rural blacks
`as in whites.’ In both populations the poor and less poor are
`affected.
`Historically, in western populations up to the turn ofthe century,
`most people were very poor. Undoubtedly, low birthweight and
`malnutrition diseases such as rickets were far more common than
`now. Yet until the 1920s CHD was very uncommon: in the UK it
`was regarded as "a rare disease in hospitals".** Similarly, in the
`USA, when Paul Dudley White was young (in the 1920s), records at
`Massachusetts General Hospital did not reveal "more than a rare
`case of CHD" among poor people, although cases did occur among
`the well-to-do.6 We therefore suggest that adverse factors at birth
`and immediately after manifest their long-term pathogenicity, with
`respect to CHD and diabetes, principally in a westernised
`setting-higher energy high-fat diets, smoking practice, and
`diminished physical activity.
`What can we do toward clarification? Unfortunately, no
`anthropometric data at infancy are available for middle-aged black
`adults. As second best, we are seeking to learn from individual black
`patients with CHD and diabetes to what extent their early family life
`was very poor, average, or better off.
`
`Human Biochemistry Research Unit,
`School of Pathology,
`University of Witwatersrand;
`and the South African Institute
`for Medical Research,
`Johannesburg 2000, South Africa
`
`A. R. P. WALKER
`B. F. WALKER
`
`1. Yach D, Coetzee N, Hugo-Hamman CT, Fisher SA, Kibel MA. Identifying children
`at risk in peri-urban Cape Town. S Afr J Epidemiol Infect 1990; 5: 6-8.
`2. Walker ARP, Walker BF, Walker AJ. Slower growth and other deficits in South
`African black schoolchildren aged 12 years: is dietary supplementation mandatory?
`Int Clin Nutr Rev 1989; 9: 76-83.
`3. Walker ARP, Walker BF. Coronary disease in blacks in underdeveloped populations.
`Am Heart J 1985; 109: 1410.
`4. Walker ARP, Walker BF. Diabetes prevalence in elderly rural blacks in South Africa.
`S Afr J Food Sci Nutr 1991; 3: 68-71.
`5. McCrae T. Osler’s principles and practice of medicine. London: Appleton, 1912: 836.
`6. White PD. The cardiologist enlists the epidemiologist. Am J Public Health 1957; 47:
`1-3.
`
`SIR,-Professor Barker and colleagues, in their review of the
`effects of fetal nutrition on cardiovascular disease in adult life, risk
`seriously misleading clinicians and other non-specialists about the
`effects of maternal undemutrition in pregnancy. Their long-term,
`retrospective, epidemiological studies are a valuable stimulus to
`further reflection, but I believe that their ideas on possible
`physiological
`mechanisms
`misconceived
`and
`be
`may
`counterproductive.
`Intrauterine growth retardation may be mainly caused by
`maternal undernutrition and excessive physical labour, as well as
`closely spaced pregnancies and disease, in parts of the developing
`world, but there is no evidence that the same is true in industrialised
`countries such as the UK. The test is whether supplementary
`feeding of pregnant women in the UK increases birthweight, and it
`does not. Smallness for dates for our women has a multitude of
`causes, many of them unknown, and there are many known
`non-nutritional factors in the environment related to lifestyle--but
`undemutrition is not known to be among them.1
`Even in communities in which undemutrition is a contributing
`factor, this factor can only be shown to operate in the last trimester,
`and has not been shown in man in early embryonic life or in
`mid-pregnancy. It is not helpful to assert that embryonic and
`trophoblast growth are influenced by the concentration of nutrients,
`
`of Breast Cancer
`
`HER2 protein in tumours of women with and without family
`history of breast cancer.
`Mean (SE): 742 (113) and 2607 (776) ng/mg, respectively, n=100
`per group.
`
`The association of family history of breast cancer and raised
`tumour HER2 protein suggests that another gene, linked to
`post-menopausal familial breast cancer, may reside on the long arm
`ofchromosome 17. Since there are few mutations of the HER2 gene
`in breast cancer,s the gene in question might lie in a nearby region of
`the chromosome which affects HER2 expression. It would be
`worthwhile to try to correlate the high HER2 concentrations and
`family history with a chromosome 17 marker. Linkage studies with
`the marker might then further localise the gene.
`
`Departments of Radiation Oncology
`and Surgery,
`Mount Sinai Medical Centre,
`New York, New York 10029, USA
`
`STEVEN LEHRER
`PATRICIA LEE
`PAUL TARTTER
`STEVEN BROWER
`
`1. Hoffman M. New clue found to oncogene’s role in breast cancer. Science 1992, 256:
`1129.
`2. Roberts L. Zeroing in on a breast cancer susceptibility gene. Science 1993; 259: 622-25.
`3. Holmes WE. Sliwkowski M, Akita RW, et al. Identification of heregulin, a specific
`activator of p185-erbB2. Science 1992; 256: 1205-10.
`4. Paik S, Burkhard E, Lippman ME. Clinical significance of erbB2 protein
`overexpression. In: Dickson RB, Lippman ME, eds. Genes, oncogenes, and
`hormones. Advances in cellular and molecular biology of breast cancer. Boston:
`Kluwer Academic, 1992: 181-91.
`5. Lofts FJ, Gullick WJ. c-erbB2 amplification and overexpression in human tumors. In:
`Dickson RB, Lippman ME, eds. Genes, oncogenes, and hormones. Advances in
`cellular and molecular biology of breast cancer. Boston: Kluwer Academic, 1992:
`161-79.
`6. Carney WP, Hamer PJ, Petit D, et al. Detection and quantitation of the human neu
`oncoprotein. J Tumor Marker Oncol 1991; 6: 53-72.
`7. Hall JM, Lee MK, Newman B, et al. Linkage of early-onset familial breast cancer to
`chromosome 17q21. Science 1990; 250: 1684-89.
`8. Narod S, Feunteun J, Lynch HT, et al. Familial breast-ovarian cancer locus on
`chromosome 17q12-q23. Lancet 1991; 338: 82-83.
`9. Coles C, Thompson AM, Elder PA, et al. Evidence implicating at least two genes on
`chromosome 17p in breast carcinogenesis. Lancet 1990; 336: 761-63.
`
`Fetal nutrition and cardiovascular disease in
`adult life
`SIR,-Professor Barker and colleagues’ findings (April 10, p 938)
`indicate that babies small at birth or during infancy have increased
`rates of cardiovascular disease and diabetes as adults.
`Living in juxtaposition with Africans, traditionally living and
`transitional, we are uncertain how much of their health/ill-health is
`regulated by genetic and environmental factors, dietary and
`non-dietary. African village children, equally poor and eating the
`same limited range of foodstuffs, show wide ranges in various
`indices (anthropometrical, biochemical, haematological, faecal pH),
`which are not fully explained by carefully assessed dietary intakes.
`Doubtless, factors of genetic origin, of very early childhood
`experience, and of differing individual reactivity to environmental
`factors are in operation.
`
`