THE LANCET
`
`No. 8034
`
`Hos roN, MASS. ANDtONDON • SATURDAY 20 AUGUST 1977 (cid:9)
`
`VOL. II FOR 1977
`
`ORIGINAL ARTICLES
`Dissolution of Cholesterol Gallstones by Ursodeoxycholic Acid
`Prof. Schoichi Nakagawa, M.D., Isao Makino, M.D., Takashi Ishizaki, M.D.,
`Ichiro Dohi, M.D.
`
`Fibrinolytic Response to Surgery (cid:9)
`M. T. N. Knight, F.H.C.S., Robin Dawson, B.SC., Prof. D. G. Melrose, F.R.C.S.
`
`367
`
`370
`
`Low Levels of Eosinophil Cationic Proteins in Patients with Asthma (cid:9)
`373
`P. Venge, M.D., 0. Zetterstrom, M.D., R. Dahl, M.D., L.-E. Roxin, FIL.KAND., I. OISSOD, M.D.
`
`'„1-Adrenergic Agonist Resistance in Normal Human Airw
`S. T. Holgate, M.R.C.P., C. J. Baldwin, B.sc., A. E. Tattersfre (cid:9)
`Y.R.C.P.
`
`Pattern of Maternal F-cell Production-During Pregnancy
`N. Popat, M.B., W. G. Wood, PH.D., Prof. D. J. Weatherall, F.R.C.P., F.A.S.,
`Prof. A. C. Turnbull, F.R.C.O.G.
`Defective Neutrophil Mipporenidal
`do ' lqm
`R. W. Gange, M.R.C.P., M...4. a , M.R.C.P., Pa.,
`ringtoMIR. McKerron, M.I.S.T.
`
`375 (cid:9)
`
`377
`
`379 (cid:9)
`
`;Eh 4
`
`PRELIMINARY
`COMMUNICATIONS
`Levamisole in the Treat
`Crohn's Disease
`A. W. Segal, M.R.C.P.,
`A. J. Levi, F.R.C.P.,
`G. Loewi, F.R.C.PATH.
`Alanine Inhibition of Pyruvate
`Kinase in Gliomas and
`Meningiomas
`C. W. M. van Veelen, M.D.,
`G. E. J. Staal, PH.D.,
`H. Verbiest, M.D.,
`A. M. C. Vlug
`
`REVIEWS
`Notice of Books
`
`CHILD HEALTH
`After Court
`E. D. Alberman, M.D.,
`Prof. J. N. Morris, F.R.C.P.,
`P. 0. D. Pharoah, M.D
`
`382
`
`384
`
`385 (cid:9)
`
`393 (cid:9)
`
`CHEMOTHERAPY OF CANCER
`Multimodal Therapy for Histological
`396
`Stage-II Breast Cancer (cid:9)
`Multicentre Breast Cancer Chemotherapy
`Group
`
`OBITUARY
`Lord Cohen of Birkenhead
`Lord Adrian
`Peter Duncan Scott
`Patrick Wimberley Dill-Russell
`
`413 (cid:9)
`414 (cid:9)
`415 (cid:9)
`415 (cid:9)
`
`NOTES AND NEWS
`416
`Hemostatic Agents (cid:9)
`Handbook for the Handicapped Family
`416
`416
`416
`416
`
`Approved Names 1977 (cid:9)
`Coronary Heart-disease (cid:9)
`Antivenons (cid:9)
`
`Cancer and Vitamin K
`Dr Hilgard
`Netherton Syndrome, Enteropathic
`Acrodermatitis, and Zinc
`Dr J. A. Q. Bustos,
`Dr M. Benito Gonzalez
`Cholera and Blood-groups
`Dr Amit Chaudhuri,
`Dr S. De
`HBsAg, Alcohol, and Syphilis
`Dr Tatsuya Motoki,
`Prof. Satoru Murao
`Ratios and Proportions
`Dr J. H. Renwick
`Fatal Atheromatous Emboli to the
`Kidneys after Left-heart
`Catheterisation
`Dr Knut Gjesdal and others
`Thalidomide-type Malformations and
`Subsequent Osteosarcoma
`Dr L. Teppo and others
`Serum-bile-acids in Inflammatory
`Bowel Disease
`Dr A. A. Mihas and others
`Astroviruses Detected by
`Immunofluorescence
`Mr T. W. Lee, F.I.M.L.S.,
`Dr J. B. Kurtz
`Cardiotoxicity of 5-fluorouracil
`Mr D. Lang tevens, F.R.C.S., and others
`Standard Rehydration Fluids (cid:9)
`Mr H. L. Shapiro, M.P.S.
`Intraosseous Fluid Administration (cid:9)
`Prof. G. H. Valentine
`Dietary Fibre in Scandinavia (cid:9)
`Dr K. W. Heaton
`Dietary Fibre in Perspective
`Dr Kenneth Vickery
`Choice of Antibiotic in Prevention
`of Wound Sepsis
`Mr A. V. Pollock, F.R.C.S.,
`Mary Evans
`Circulating Immune Complexes and
`Multiple Sclerosis
`Dr C. Jacque and others
`Patients Without Basophils
`Dr S. J. Galli and others
`Increased Intracellular Growth
`Activity of Tubercle Bacilli
`Excreted during Treatment
`Dr L. B. Hejfec and others
`Effect of Polyunsaturated Fatty Acids on
`Lymphoid Cell Survival in vitro (cid:9)
`Dr P. Frost and others
`Complete Recovery of Thyroid Function
`after Apparent Radiodestruction (cid:9)
`Dr J. G. Turner and others
`Piracetam and Acetamide in Sickle-cell
`Disease
`Dr J. T. de Araujo,
`Dr G. S. Nero
`Intraocular Lenses
`Mr S. P. B. Percival, F.R.C.s.
`Open Heart Surgery Complicated by
`Postoperative Malaria
`Dr Susannah Eykyn,
`Mr M. V. Braimbridge, F.R.C.S.
`Treatment of Erythromelalgia with
`Propranolol
`Dr J. L. Bada
`Peripheral Gangrene Complicating
`Beta-blockade
`Dr J. A. Vale and others
`Prevention of Rickets and
`Osteomalacia in Asians
`Dr M. G. Dunnigan,
`Dr J. A. Ford
`
`403
`
`403
`
`404
`
`404
`
`404
`
`405
`
`405
`
`405
`
`406
`
`406
`
`407
`
`407
`
`407
`
`408
`
`408
`
`408
`
`409
`
`409
`
`410
`
`410
`
`411
`
`411
`
`411
`
`412
`
`412
`
`a•
`
`412 z
`
`Acceptance of Measles Vaccine
`387
`388
`
`44111111iisAiro * sinophils Do
`Membrane Oxygenation in
`Pulmonary Failure
`Are There Boundaries
`to Experiment?
`Treatment of Ewing's
`Sarcoma
`Bone-marrow Transplantation in
`Leukxmia
`
`390
`
`391
`
`391
`
`392
`
`398 (cid:9)
`
`398 (cid:9)
`
`399
`
`LETTERS TO THE EDITOR
`Surapubic Aspiration in
`eneral Practice
`Dr D. Brooks
`Antipsychotic Effect of
`Opiate Agonists
`Dr M. S. Gold and others
`B-cell Suspensions for Typing
`in 90 Minutes
`Dr N. Suciu-Foca,
`Dr P. Rubinstein
`Enzyme Immunoassay for Demonstration
`of Rabies-virus Antibodies
`after Immunisation
`Dr Olaf Thraenhart,
`Prof. E. K. Kuwert
`Lactic Acidosis
`Dr Robert Matz
`Liver Damage from Long-term
`Methyltestosterone
`Mr D. A. Bird, F.R.C.S.,
`Mr K. D. J. Vowles, F.R.C.S.
`Symptom-free Hypertension
`Dr J. \X'. Todd
`Re-heating Corn Oil Does Not Saturate
`its Double Bonds
`Dr J. I. Mann and others
`Hiemoglobin Measurement in
`Developing Countries
`Dr Henry Foy,
`Dr Athena Kondi
`Drugs and Gallstones
`Dr F. Begemann and others
`Hysocalciemia and Thyroid Surgery
`r F. Escobar-Jimenez and others
`Interferon Skin Reactivity and
`Pyrexial Reactions
`Dr G. M. Scott and others
`
`399 (cid:9)
`
`400 (cid:9)
`
`400
`
`401
`
`401 (cid:9)
`
`401 (cid:9)
`
`402 (cid:9)
`
`402 (cid:9)
`
`402 (cid:9)
`
`Editorial Office: 7 Adam Street, London WC2N 6AI),
`American Edition published weekly by Little, Brown a
`34 Beacon St., Boston, Mass. 02106. In U.S. and Cs
`subscription $30.00; resident and intern rate $21.5(
`$4.00. Second class postage paid at Boston, Mass., anc
`mailing offices. c The I.ancet Ltd., 20 August 197.
`on Form 3579 is to be mailed to The Lancet, 34 Beacc
`ton, Mass. 02106.
`THE WHOLE OF THE LITERARY MATTER IN THE LANCET
`
`North
`
`zB 01/77 12/77 LI 140958W 204
`LIBRARY OF CONGRESS
`ORDER DIVISION
`CONTINUATIONS UNIT
`WASHINGTON (cid:9)
`
`DC 20540
`
`Ex. 1089 - Page 1
`
`(cid:9)
`

`

`FT
`
`No. 8034
`
`,LANCET
`
`BOSON,MASS. AND NDON • SATURDAY 20 AUGUST 1977 (cid:9)
`
`VOL. II FOR 1977
`
`ORIGINAL ARTICLES
`Dissolution of Cholesterol Gallstones by Ursodeoxycholic Acid
`Prof. Schoichi Nakagawa, M.D., Isao Makino, M.D., Takashi Ishizaki, M.D.,
`Ichiro Dohi, M.D.
`
`Fibrinolytic Response to Surgery
`M. T. N. Knight, F.H.c.s., Robin Dawson, B.SC., Prof. D. G. Melrose, F.R.C.S.
`
`367
`
`370
`
`Low Levels of Eosinophil Cationic Proteins in Patients with Asthma (cid:9)
`373
`P. Venge, M.D., 0. Zetterstrdm, M.D., R. Dahl, M.D., L.-E. Roxin, FIL.KAND., I. Olsson, M.D.
`
`ii-Adrenergic Agonist Resistance in Normal Human Airw
`S. T. Holgate, M.R.C.P., C. J. Baldwin, B.sc., A. E. Tattersfre (cid:9)
`Y.R.C.P.
`
`Pattern of Maternal F-cell Production4Du• t•ing Pregnancy
`N. Popat, M.B., W. G. Wood, PH.D., Prof. D. J. Weatherall, F.R.C.P., F.R.S.,
`Prof. A. C. Turnbull, F.R.C.O.G.
`
`Defective Neutrophil Mi
`R. W. Gange, M.R.C.P., M.
`
`irs
`•
`M.R.C.P., . irringtoff . McKerron, M.I.S.T.
`
`7
`
`375 (cid:9)
`
`377
`
`379 (cid:9)
`
`PRELIMINARY
`COMMUNICATIONS Pgn"
`Levamisole in the Treatmentof;.
`Crohn's Disease
`A. W. Segal, M.R.C.P.,
`A. J. Levi, F.R.C.P.,
`G. Loewi, F.R.C.PATH.
`Alanine Inhibition of Pyruvate
`Kinase in Gliomas and -
`Meningiomas
`C. W. M. van Veelen, M.D.,
`G. E. J. Staal, PH.D.,
`H. Verbiest, M.D.,
`A. M. C. Vlug
`
`'1"*C14
`
`-382
`
`384
`
`REVIEWS
`Notice of Books
`
`CHILD HEALTH
`After Court
`E. D. Alberman, M.D.,
`Prof. J. N. Morris, F.R.C.P.,
`P. O. D. Pharoah, M.D
`
`385 (cid:9)
`
`393 (cid:9)
`
`CHEMOTHERAPY OF CANCER
`Multimodal Therapy for Histological
`396
`Stage-H Breast Cancer (cid:9)
`Multicentre Breast Cancer Chemotherapy
`Group
`
`OBITUARY
`Lord Cohen of Birkenhead
`Lord Adrian
`Peter Duncan Scott •
`Patrick Wimberley Dill-Russell
`
`413 (cid:9)
`414 (cid:9)
`415 (cid:9)
`415 (cid:9)
`
`NOTES AND NEWS
`416
`Haemostatic Agents (cid:9)
`Handbook for the Handicapped Family
`416'
`416
`416
`416
`
`Approved Names 1977 (cid:9)
`Coronary Heart-disease (cid:9)
`Antivenons (cid:9)
`
`Acceptance of Measles Vaccine
`387
`At. (cid:9)
`.4
`388
`vaghae4ilosmophils Do
`Membrane Oxygenation in
`Pulmonary Failure
`Are There Boundaries
`to Experiment?
`Treatment of Ewing's
`Sarcoma
`Bone-marrow Transplantation in
`Leulmmia
`
`391
`
`391
`
`392
`
`390
`
`398 (cid:9)
`
`398 (cid:9)
`
`399 (cid:9)
`
`LETTERS TO THE EDITOR
`Suzrapubic Aspiration in
`eneral Practice
`Dr D. Brooks
`Antipsychotic Effect of
`Opiate Agonists
`Dr M. S. Gold and others
`B-cell Suspensions for Typing
`in 90 Minutes
`Dr N. Suciu-Foca,
`Dr P. Rubinstein
`Enzyme Immunoassay for Demonstration
`of Rabies-virus Antibodies
`399 (cid:9)
`after Immunisation
`Dr Olaf Thraenhart,
`Prof. E. K.Kuwert
`Lactic Acidosis
`Dr Robert Matz
`Liver Damage from Long-term
`Methyltestosterone
`Mr D. A. Bird, F.R.C.S.,
`Mr K. D. J. Vowles, F.R.C.S.
`Symptom-free Hypertension
`Dr J. W. Todd
`Re-heating Corn Oil Does Not Saturate
`its Double Bonds
`Dr J. I. Mann and others
`Haemoglobin Measurement in
`Developing Countries
`Dr Henry Foy,
`Dr Athena Kondi
`Drugs and Gallstones
`Dr F. Begemann and others
`Hysocalciernia and Thyroid Surgery
`r F. Escobar-Jimenez and others
`Interferon Skin Reactivity and
`Pyrexial Reactions
`Dr G. M. Scott and others
`
`400 (cid:9)
`
`400 (cid:9)
`
`401 (cid:9)
`
`401 (cid:9)
`
`401
`
`402
`
`402
`
`402
`
`ICI
`
`Cancer and Vitamin K
`(cid:9) Dr P. Hilgard
`Netherton Syndrome, Enteropathic
`Acrodermatitis, and Zinc
`Dr J. A. Q. Bustos, •
`Dr M. Benito Gonzalez
`Cholera and Blood-groups
`Dr Amit Chaudhuri,
`Dr S. De
`HBsAg, Alcohol, and Syphilis
`Dr Tatsuya Motoki,
`Prof. Satoru Murao
`Ratios and Proportions
`Dr J. H. Renwick •
`Fatal Atheromatous Emboli to the
`Kidneys after Left-heart
`Catheterisation
`Dr Knut Gjesdal and others
`Thalidomide-type Malformations and
`Subsequent Osteosarcoma
`Dr L. Teppo and others
`Serum-bile-acids in Inflammatory
`Bowel Disease
`Dr A. A. Mihas and others
`Astroviruses Detected by
`Immunofluorescence
`Mr T. W. Lee,
`Dr J. B. Kurtz •
`Cardiotoxicity of 5-fluorouracil
`Mr D. Lang tevens, F.R.C.S., and others
`Standard Rehydration Fluids (cid:9)
`Mr Fl. L. Shapiro, M.P. s.
`Intraosseous Fluid Administration (cid:9)
`Prof. G. H. Valentine
`Dietary Fibre in Scandinavia (cid:9)
`Dr K. W. Heaton
`Dietary Fibre in Perspective
`Dr Kenneth Vickery
`Choice of Antibiotic in Prevention
`of Wound Sepsis
`Mr A. V. Pollock, F.R.C.S.,
`Mary Evans
`Circulating Immune Complexes and
`Multiple Sclerosis
`(cid:9) and others
`Dr C.
`Patients Without Basophils
`Dr S. J. Galli and others
`Increased Intracellular Growth
`Activity of Tubercle Bacilli
`Excreted during Treatment
`Dr L. B. Hejfec and others
`Effect of Polyunsaturated Fatty Acids on
`Lymphoid Cell Survival in vitro (cid:9)
`Dr P. Frost and others
`Complete Recovery of Thyroid Function
`after Apparent Radiodestruction
`Dr J. G. Turner and others
`Piracetam and Acetamide in Sickle-cell
`Disease
`Dr J. T. de Araujo,
`Dr G. S. Nero
`Intraocular Lenses
`Mr S. P. B. Percival, F.R.C. s.
`Open Heart Surgery Complicated by
`Postoperative Malaria
`Dr Susannah Eykyn,
`Mr M. V. Braimbridge, F.R.C.S.
`Treatment of Erythromelalgia with
`Propranolol
`Dr J. L. Bada
`Peripheral Gangrene Complicating
`Beta-blockade
`Dr J. A. Vale and others
`Prevention of Rickets and
`Osteomalacia in Asians
`Dr M. G. Dunnigan,
`Dr J. A. Ford
`
`403
`
`403
`
`404
`
`404
`
`404
`
`405
`
`405
`
`405
`
`406
`
`406
`
`407
`
`407
`
`407
`
`408
`
`408
`
`408
`
`409
`
`409
`
`410
`
`410
`
`411
`
`.411
`
`411
`
`412
`
`412
`
`412
`
`Editorial Office: 7 Adam Street, I.ondon WC2N 6AD, Eatclqnct North ..____
`American Edition published weekly by Little, Brown a (cid:9)
`--
`' Z8 0 1 / 7 7 12 / 77'14 - 140958W :204
`34 Beacon St., Boston, Mass. 02106. In U.S. and Ca (cid:9)
`subscription $30.00; resident and intern rate $21.50
`.LIBRARY'oF"CoNGRESS
`$4.00. Second class postage paid at Boston, Mass., anc (cid:9)
`to
`mailing offices. c The Lancet I.td., 20 August 197", , (cid:9) ORDER DIVISION
`on Form 3579 is to be mailed to The I.ancet, 34 Bead
`ton,
`CONTINUATIONS UNIT'
`ton, Mass. 02106. '
`THE WHOLE OF THE LITERARY MATTER IN THE LANCET ! WASHINGTON (cid:9)
`
`DC 20540
`
`
`
`
`Ex. 1089 - Page 2
`
`(cid:9)
`(cid:9)
`

`

`Preliminary Communications
`
`LEVAMISOLE IN THE TREATMENT OF
`CROHN'S DISEASE
`
`A. W. SEGAL (cid:9)
`G. LoEwI
`Clinical Research Centre, Watford Road, Harrow,
`Middlesex HAI Al
`
`A. J. LEVI
`
`Summary (cid:9)
`
`In 8 patients with active uncomplicated
`Crohn's disease who were not receiving
`any specific therapy, a clinical remission was induced
`with an elemental diet, and then an attempt was made
`to maintain this remission with levamisole. This regimen
`resulted in excellent control of the disease. A drug-
`induced arthritis developed in two patients and resolved
`spontaneously. There were no other significant side-
`effects.
`
`INTRODUCTION
`ONE of the most striking and consistent abnormalities
`in Crohn's disease is the failure of neutrophils to migrate
`in normal numbers to an area of acute inflammation.'
`This defect may be important in the pathogenesis of the
`disease, because failure of these cells to accumulate in
`sufficient numbers may delay removal from the bowel
`wall of foreign material, such as bacteria and their pro-
`ducts and ingested proteins. Delayed clearance of
`foreign material could result in granuloma formation and
`tissue damage, possibly through the accumulation of
`macrophages. These cells may release lysosomal
`enzymes' or produce tissue thromboplastin,3 which may
`lead to a local Schwartzmann phenomenon? Mucosal
`ulceration removes the barrier to the influx of further
`intestinal contents, and a vicious circle is set up.
`This hypothesis explains many of the features of
`Crohn's disease. The disease is diffuse and the whole
`bowel is involved, with histological changes in areas
`which appear macroscopically normal.' Surgical remo-
`val of obviously affected segments of bowel does not cure
`the disease, and relapses are common.' A Kveim test
`resulted in granuloma formation in some patients,6
`probably, as a result of a non-specific delay in the remo-
`val of the injected material from the injection site; it is,
`unlikely to be due to the injection of an infective agent
`
`THE LANCET, AUGUST 20, 1977
`
`common to both Crohn's disease and sarcoidosis. An in-
`teresting fact is that a severe neutrophil defect, similar
`to that in Crohn's disease, has been reported in sar-
`coidosis.7
`In addition to the primary disease there probably are
`secondary non-specific effects as a result of the pen-
`etration of the mucosa by intestinal contents, such as
`dietary proteins and bacteria and their products. These
`foreign bodies probably play a part in the constitutional
`effects seen in many ulcerative lesions of the intestine.
`The treatment used in this study was designed with
`this hypothesis in mind. An elemental, protein-free diet
`was used to induce a clinical remission and healing of
`the mucosal ulceration (possibly brought about by the
`absence of ingested protein, or by a change in the bac-
`terial flora).8 Levamisole, which has been used for the
`treatment of Crohn's disease,' was then administered to
`maintain this remission by stimulating immunity, par-
`ticularly neutrophil function,'" before resumption of a
`normal diet.
`
`PATIENTS AND METHODS
`
`Details of the patients studied appear in the accompanying
`table. The study received the approval of the ethical committee
`and all the patients gave informed consent. All the patients
`were acutely ill and pyrexial when their treatment was started.
`Five of the patients had had previous treatment. Patients 1
`and 2 had clinical remission after "bowel sterilisation"" and
`patient 3 after treatment with an elemental diet. These pa-
`tients relapsed 2, 10, and 3 months after their treatment was
`stopped. Patient 4 had been treated with metronidazole," but
`had failed to respond; patient 5 had been treated with predni-
`sone and azathioprine, but her symptoms had never been ade-
`quately controlled and she had not taken these drugs in the
`year before starting on treatment.
`
`Treatment Regimen
`The diet produced approximately 150 kJ/kg optimum calcu-
`lated body-weight/day. 8000-10 000 kJ/day were supplied by
`the elemental diet (`Vivonex', Eaton Laboratories). Additional
`energy was supplied by clear carbohydrate-rich, protein-free,
`drinks and confectionery. The elemental diet was given accord-
`ing to the manufacturers' directions. All the patients were
`treated in hospital except for patient 2 who managed the diet
`at home.
`14 days after the start of the elemental diet, levamisole was
`administered in a dose of 50 mg (25 mg for patient no. 4)
`8-hourly for 3 consecutive days every 2 weeks. After the second
`course of levamisole treatment the elemental diet was stopped
`and a normal diet resumed.
`Supportive therapy, in the form of codeine phosphate or
`
`Patient
`no.
`
`1
`
`2
`3
`4
`5
`
`6
`
`7
`8
`
`Age
`(yr)
`
`28
`
`30
`32
`13
`35
`
`21
`
`56
`71
`
`Sex
`
`F
`
`F
`M
`F
`F
`
`M
`
`M
`F
`
`DETAILS OF PATIENTS
`
`Duration •
`of
`symptoms
`(mo)
`
`- Radiological
`extent of
`disease
`
`4
`
`11
`10
`16
`108
`
`2
`
`1
`1
`
`Distal ileum to
`sigmoid colon
`Pancolitis
`Distal ileum .
`Distal ileum
`Terminal ileum to
`tranverse colon
`Distal ileum. cmcum.
`descending colon
`l'ancolitis
`Cmcum to,sigmoid
`colon
`
`Duration of
`therapy with
`levamisole
`(mo)
`
`12
`
`3
`12
`12
`11
`
`-'
`
`8
`
`7
`6
`
`Complications
`of
`therapy
`
`—
`
`Arthritis
`—
`
`—
`
`Arthritis
`
`—
`—
`
`Ex. 1089 - Page 3
`
`

`

`THE LANCET, AUGUST 20,1977
`
`Tomotil' (diphenoxylate with atropine) for diarrhcea, an iron
`preparation, and analgesics, was prescribed or continued
`where necessary.
`
`Neutrophil Migration
`Neutrophil migration into skin windows' was examined at
`the midpoint of the interval between courses of levamisole
`therapy, 3-12 months after the start of the regimen.
`
`RESULTS
`The diet is unpleasant but is well tolerated within a
`week. Improvement started 3-10 days after beginning
`the diet and the patients generally became apyrexial
`during this period.
`All the patients responded to the treatment, and seven
`are free of symptoms and leading normal lives.
`Arthritis was a side-effect in two of the patients (2 and
`6), and levamisole had to be withdrawn." Patient 2
`remains completely symptom-free. Patient 6, an atypical
`case of Crohn's disease with IgA deficiency and spleno-
`megaly," responded to treatment initially, but had a
`recurrence of his bowel symptoms when the arthritis de-
`veloped. He has subsequently failed to respond to sys-
`temic immunoglobulins or prednisone and azathioprine.
`The only other side-effects of levamisole were light-
`headedness and a loss of taste in patient 1.
`
`Elemental
`diet (cid:9)
`
`Levamisole
`t (cid:9) I (cid:9) I
`1 (cid:9) 1 (cid:9)
`1 (cid:9) I (cid:9) l (cid:9) I (cid:9)
`
`Weight
`change (kg)
`
`10
`50 —
`
`Serum-
`albumin (VI) 40 —
`
`30 —
`15 —
`
`13 —
`
`11 —
`7 —
`
`5 —
`
`Hcemoglobin (cid:9)
`(g/dl)
`
`Serum-
`cholesterol (cid:9)
`(mmol/t)
`
`3 —
`Erythrocyte- 80
`60
`sedimentation
`40
`rate (mm) (cid:9)
`20
`
`
`I (cid:9) "1 (cid:9)
`6-12
`4 (cid:9)
`
`0 (cid:9)
`
`2 (cid:9)
`
`3 (cid:9)
`Months
`Fig. 1—Effect of treatment on various indices of disease activity
`and patient wellbeing.
`Mean+ s.E.m. All the results refer to eight patients except those
`between 6 and 12 months (six patients).
`*Significance of difference from initial results P<0.05.
`
`1
`
`383
`
`The effects on the indices of disease activity and pa-
`tient wellbeing are shown in fig. 1. Except for the eryth-
`rocyte-sedimentation rate, which remains raised in some
`patients, there was a dramatic and sustained improve-
`ment. A mean weight-gain of approximately 10 kg, 6-12
`months after the start of the treatment, is a particularly
`dramatic indication of its success.
`Neutrophil migration into skin windows reverted to
`normal after treatment (fig. 2). The number of cells that
`entered the skin windows was different from that in un-
`treated patients with Crohn's disease (p<0.001) but not
`from that in normal controls (p>0.1) when compared by
`Student's t test.
`
`DISCUSSION
`Preliminary results indicate that this regimen offers a
`successful' alternative to the conventional treatment of
`early Crohn's disease. Immunosuppressive glucocorti-
`coids and azathioprine probably alleviate the secondary
`manifestations without affecting the primary mechan-
`ism. Relapse is common after surgical resection5—a
`removal of bowel in a disease which itself destroys
`bowel, and which may end fatally owing to malabsorp-
`tion.
`Levamisole offers an attractive alternative. It may
`exert a direct effect on the basic pathogenic mechanism
`of the disease, because it appears to correct the defect of
`neutrophil migration into areas of acute inflammation
`(fig. 2). All the patients, with one exception (an atypical
`case of Crohn's disease with hypogammaglobulinmmia
`and splenomegaly), are symptom-free and leading nor-
`
`O
`
`•
`
`••
`•
`
`1x105—
`
`•
`
`•
`
`•••••••••
`
`Fig. 2—Effect of treatment on neutrophil migration into skin
`windows (number of cells/5 h).
`Four patients were studied before and after treatment.
`
`11,4231 (cid:9)
`
`"ft1!iV1".. (cid:9)
`
`Fri.;:4
`
`Ex. 1089 - Page 4
`
`

`

`384
`
`mal lives. Three of the patients had previously relapsed
`after other forms of treatment. Most of the indices of
`disease activity have return to normal (fig. 1), with the
`exception of the erythrocyte-sedimentation rate, which
`remained raised in four patients. This may reflect in-
`complete control of the disease or may be related to the
`action of the drug. Barium studies of the bowel showed
`healing of the mucosal ulceration, although extramuco-
`sal abnormalities, such as narrowing and rigidity of the
`distal ileum, persisted-possibly as a result of irrever-
`sible fibrosis.
`Side-effects of levamisole therapy include granuloci-
`topenia and thrombocytopenia, gastrointestinal upset, a
`"flu-like" syndrome, rashes, and central-nervous-system
`upsets. Reports indicate that they affect between 3%14
`and 22%" of patients and disappear on withdrawal of
`the drug. The only adverse effects in the patients with
`Crohn's disease was a reversible drug-induced arthritis
`in two patients."
`Levamisole appears to be a useful drug in maintaining
`a clinical remission in Crohn's disease. Further studies
`are necessary to confirm these results and to determine
`the best dose and treatment regimen, duration of treat-
`ment, and long-term efficacy and toxicity.
`
`We thank Prof. C. C. Booth for allowing us to study patients under
`his care.
`Requests for reprints should be addressed to A. W. S.
`
`REFERENCES
`
`1. Segal, A. W., Loewi, G. Lancet, 1976, ii, 219.
`2. Cardella, C. J., Davies, P., Allison, A. C. Nature, 1974, 247, 46.
`3. Prytz, H., Allison, A. C. ibid. (in the press).
`4. Goodman, M. J., Skinner, J. M., Truelove, S. C. Lancet, 1976, i, 275.
`5. Lennard-Jones, J. E., Stalder, G. A. Gut, 1967,8,332.
`6. Kraft, S. C. New Engl.'. Med. 1971, 285,1259.
`7. Gange, R. W., Black, M. M. Lancet, 1977, ii, 379.
`8. Winitz, M., Adams, R. F., Seedman, D. A., Davis, P. N., Jayko, L. G.,
`Hamilton, J. A. Am. 1. clin. Nutr. 1970, 23, 546.
`9. Bertrand, J., Renoux, G., Renoux, M., Palat, A. Nouv. Presse med. 1974,
`3,2265.
`10. Anderson, R., Glover, A., Koornhof, H. J., Rabson, A. R. J. Immun. 1976,
`117,428.
`11. Kane, S. P. Proc. R. Soc. Med. 1976, 69, 266.
`12. Ursing, B., Kamme, C. Lancet, 1975,1, 775.
`13. Segal, A. W., Pugh, S. F., Levi, A. J., Loewi, G. Br. med. y. (in the press).
`14. Rosenthal, M., Breysse, Y., St. J. Dixon, A., et al. Lancet, 1977, i, 904.
`15. Parkinson, D. R., Cano, P. O., Jerry, L. M., Capek, A., Shibata, H. R., Man-
`sell, P. W., Lewis, M. G., Marquis, G. ibid. p. 1129.
`
`THE LANCET, AUGUST 20, 1977
`
`INTRODUCTION
`WHEN gliomas are removed, the limits of the tumour
`may be difficult to estimate during surgery, since mac-
`roscopically normal brain tissue may still harbour
`tumour cells. Intraoperative methods of microscopical
`examination of biopsy specimens have not so far proved
`helpful in detecting residual cancer tissue.
`There is growing evidence that enzyme composition
`in cancer tissues differs from that found in normal tis-
`sues.' In particular, key enzymes of glucose metabolism
`may be altered. One of these-pyruvate kinase (E.C.
`2.7.1.40)-occurs in different molecular forms, the two
`main ones being a liver type (L) and a muscle type (M).
`The M type can be further divided into subtypes MI and
`Mu, which can be easily distinguished by their behav-
`iour in the presence of alanine. The MI type is little, if
`at all, inhibited by alanine, whereas the Mil type is
`strongly inhibited. MI is predominant in normal brain
`tissue. Weber,2 Weinhouse et al.,' and Ibsen' have
`demonstrated a shift from the normal MI type to the Mn
`type in tumours.
`We have found a shift from MI to Mir pyruvate kinase
`in various brain tumours. Examination of this iso-
`enzyme shift during the operation may be useful as a
`diagnostic aid in the surgery of gliomas.
`
`100 (cid:9)
`
`
`
`701
`
`..-'
`
`-
`
`o
`
`ca, so_
`"8
`o 40-
`
`30-
`
`ALANINE INHIBITION OF PYRUVATE
`KINASE IN GLIOMAS AND MENINGIOMAS
`
`A DIAGNOSTIC TOOL IN SURGERY FOR GLIOMAS?
`
`C, W. M. VAN VEELEN
`G. E. J. STAAL
`H. VERBIEST
`A. M. C. VLUG
`Departments of Neurosurgery and Medical Enzymology, State
`University Hospital, Utrecht, The Netherlands
`
`Summary (cid:9)
`
`In gliomas a shift was found in the'com-
`position of enzymes, manifested by
`abnormal inhibition of pyruvate kinase by alanine. This
`study demonstrates the appearance of the Mu-type iso-
`enzyme in various gliomas. This Mu' type is also found
`in meningiomas but not in normal brain tissue. The
`method of enzyme examination described may be valu-
`able as a diagnostic aid in the surgery of gliomas.
`
`3
`4
`5
`
`10
`
`4
`
`1 (cid:9)
`2
`Alanine concentration (almot/l)
`
`Alanine inhibition of pyruvate kinase in centre of brain tumours
`(at 25°C, pH 8.2, adenosine diphosphate 0.2 nunolilf
`phosphoenolpyruvate 1 mmo1/I).
`
`1=Oligodendroglioma (age 48).
`2=Astrocytoma grade 4 (age 42).
`3=Medulloblastoma (age 27).
`4=Medulloblastoma (age 8).
`5=Oligodendroglioma (age 16).
`6=Astrocytoma grade iv (age 54).
`7=Glioblastoma multiforme (age 55).
`8=Glioblastoma gigantocellulare (age 51).
`9=Glioblastoma multiforme (age 37).
`10=Astrocytoma grade (cid:9)
`(age 43).
`
`Ex. 1089 - Page 5
`
`(cid:9)
`(cid:9)
`(cid:9)
`