1420
`
`THE LANCET
`VOL 341: MAY 29, 1993
`
`max
`EXPRESSED AS PERCENTAGE OF
`EC,0 (nmol/L) AND E
`MAXIMUM CONTRACTILE RESPONSE TO POTASSIUM,
`100 mmol/L*
`
`
` 158 (33)
`0-12’5—0-5‘:3
`4 (2)
`Ergotamine
`63A
`Sumatriptan
`631 (128)
`
`*Mean (SE) shown, n =6—1 1, tsubcutaneous.
`
`The recommended dose of subcutaneously administered
`er'gotamine is 10 to 48 times lower than for subuctaneous
`sumatriptan“ (table). However, the IOO-fold higher potency,
`combined with the 2-fold higher maximum effect, as well as the
`much longer duration of action of ergotarnine, suggests that, in
`general, the cardiac liability of ergotamine is higher than that of
`sumau'iptan. 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.
`Depanment of Pharmacology,
`Faculty of Medicine and Health Scrences,
`Erasmus University Rotterdam.
`3000 DR Rotterdam, Netherlands
`
`WILLEM A. BAX
`PRAMOD R. SAXENA
`
`140
`
`120
`
`ss§#Responseof90mMKCL 8
`
`Log—1°[aumatrlptan] (M)
`
`Contractile effect of sumatriptan in absence of U4661 9 (open
`circles, n=4), and in presence of EC.o concentration (filled
`circles, n=4), EC“ concentration (open triangles). or E0“
`concentration (filled triangles) of U46619 on non-
`atherosclerotic epicardial coronary arteries.
`Specimens were obtained from 4 patients aged 25, 29, 43, and
`54 years,
`receiving heart
`transplantation for cardiomyopathy.
`Experiments were done in duplicate in vessels from each patient.
`(Initial response U46619 concentrations shown by different starting
`points for each curve on the y axis.) M = moi/L.
`
`of abrogated nitric oxide release. These mechanisms could be of
`pathophysiological importance in vessels affected by atheroscleroiic
`disease, since we have shown that areas immediately distal to
`atheromas are hyperreactive to sumatriptarr.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 U89 6JH. UK
`
`A. H. CHESTER
`,
`G- S- O NEIL
`M, H. YAOOUB
`
`1. Grester 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, Tadikarimi S, Yacoub MH. Interaction between Lhromboxane
`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 sumauiptan. As they mention, myocardial
`ischaemia and infarction have also been recorded after ergotamine,1
`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 ergotarnine, 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/Eurou'ansplant
`Foundation) after removal of the aortic and pulmonary valves for
`recorded
`homograft
`valve
`transplantation. Tension was
`isometrically in organ baths containing oxygenated Kreb’s solution.
`The EC” and maximum effect (Emu) ofthe two anu'migraine drugs
`and of serotonin show (table) that ergotamine was about 100 times
`more potent than surnatriptan. Moreover, the Emax of ergotamine
`was twice that of sumaniptan.
`
`l. Galer BS, Lipton RB, Solomons S, et a]. Myocardial ischemia related to ergot
`alkaloids: a case report and literanrre review. Headache 1991; 31: 4146-50.
`2. Pen-in VL. Clinical pharmacokinetics ofergotamine in migraine and cluster headache.
`Ch'n Pharmacoler'n 1985; 10:334—52.
`3. Famracotherapeutisch
`Kompas
`1992.
`Ziekenfondsraad, 1992: 288—301.
`4. The Subcutaneous Sumatriptan International Study Group. Treatment of migraine
`attacks with sumatriptan.NErglj‘Med19913325z316—21t
`
`The
`
`Neuter-lands:
`
`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},2 The ligand may belong to a family of proteins called
`heregulins.3 HER2 protein overexpression in breast cancers is
`associated with poor prognosis.“ 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.5 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
`which,
`being
`quantitative, may
`be
`preferable
`to
`immunohistochemistry
`or western
`blotting, which
`are
`semiquamitative.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-
`Whimey U, figure). The 10 women with family history were
`predominantly post-menopausal (mean age 644 [SE 31] v5 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 [008] vs 128 [012]). 0fthe 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, BRCAl, has been
`localised to the long arm of chromosome 177*3 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
`.
`Celltrron v. Genentech
`IPR2017-01122
`
`Genentech Exhibit 2022
`
`

`

`VOL 341: MAY 29, 1993
`
`THE LANCET
`
`1421
`
`10
`
`10
`
`HER2
`
`(ng/mg) 8
`
`No
`
`Yes
`
`Family History
`of Breast Cancer
`
`HERZ protein in tumours of women with and without family
`history of breast cancer.
`Mean (SE): 742 (113) and 2607 (776) ng/mg, respectively, n=10
`per group.
`
`The association of family history of breast cancer and raised
`tumour HERZ 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 ofthe HERZ gene
`in breast cancer,‘ the gene in question might lie in a nearby region of
`the chromosome which affects HERZ expression. It would be
`worthwhile to try to correlate the high HERZ 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 TAR'I'I'ER
`STEVEN BROWER
`
`1. Hofii'nan M New clue found to oncogene’s role in breast cancer. Science 1992; 256:
`1129.
`2. Roberts L. Zeroinginona breast amoer susceptibilitygene. Sabra; 1993;259: 622—25.
`3. Holmes WE. Sliwkowski M, Akita RW, et al. Identifimtion of hm'egulin, a specific
`activator ofplBS-erbBZ. SW 1992; 256: 1205—10.
`41 Fail: S, Burkhard E, Lippman ME. Clinical significance of erbBZ protein
`overexpression. In: Dickson RB, Lipprnan ME, eds. Genes, oncogenm, and
`hormones. Advances in cellular and molecular biology of breast cancer. Boston:
`Kluwer Academic, 1992: 181—91.
`5. Lofts FJ, Gullidr W]. c—erbBZ amplification and overexpression in human tumors. In:
`Dickson RB, Lippman ME, eds. Genes, oncoges, and hormones. Advances in
`cellular and molecular biology of breast cancer. Boston: Kluwer Academic, 1992:
`161—79.
`6. Carney WP, Hamer P], Petit D, et al. Detection and quantitation of the human neu
`oncoprotein._7 Tumor Marker Oncol 1991; 6: 53—72.
`7. Hall JM, Lee MK, Newman )3, et a1. Linkage of early—onset familial breast Queer to
`chromosome 17q21. Science 1990; 250: 1684-89.
`8. Namd S, Fcunteun ], Lynch HT, et a1. Familial breast-ovarian ancer locus on
`chromosome l7q12—q23. lancer 1991; 338: 82—83.
`9. Coles C, Thompson AM, Elda- PA, et a1. Evidence irnplimting 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)
`indimte 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
`tl’ansitional, 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
`me 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.
`
`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.2 Nevertheless, these conditions seem to inhibit
`subsequent cardiovascular disease. In black South African adults,
`coronary heart disease (CI-ID)
`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.3 However, with the slight rise in socioeconomic
`status and its sequelae, the prevalence of diabetes, by contrast
`with its near absmcc in the past, is as high in elderly rural blacks
`as in whites.4 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 birthwcight and
`mahiutrition 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”.5 Similarly, in the
`USA, when Paul Dudley White was young (in the 19203), 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.‘ 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 westemised
`setting—higher energy high—fat diets, smoking practice, and
`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 ofl‘.
`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. Yeah D, Cosme N, Hugo—Hamman CT, Fisher SA, Kibel MA. Idenlifying children
`at risk in pen—urban Cape Town. S Afrj Epider Infect 1990; 5: 6-8.
`2. Walker ARP, Walker BF, Walker A]. 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} 1985; 109: 1410.
`4. Walker ARP, Walker BF. Diabetes prevalence in elderly rural blacks in South Africa.
`SAfr] Food Sci Nurr 1991; 3: 68—71.
`5. Mche T. Osler’s principles and practice ofmedicine. London: Appleton, 1912: 836.
`6. White PD. The cardiologist enlists the epidemiologist Am 3 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 undernuttition in pregtancy. Their long-term,
`retrospective, epidemiological studies are a valuable stimulus to
`further reflection, but
`I believe that
`their ideas on possible
`physiological mechanisms may
`be misconceived
`and
`counterproductive.
`Intrauterine growth retardation may be mainly caused by
`maternal under-nutrition 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 ofpregnant women in the UK increases birthweight, and it
`does not. Smallness for dates for our women has a multitude of
`causes, Inany of them unknown, and there are many known
`non—nutritional factors in the environment related to lifestyle—but
`undernutrition 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 ofnutrients,
`
`