T
`
`No. 7956
`
`BOSTON, MASS. AND LONDON • SATURDAY 21 FEBRUARY 1976
`
`VOL. I FOR 1976
`
`ORIGINAL ARTICLES
`Regional Immunotherapy of Lung Cancer with Intrapleural B.C.G. (cid:9)
`M. F. McKneally, M.D., Carole Mayer, B.s., H. W. Kausel, M.D.
`A 5-year Controlled Study of B.C.G. and Radiotherapy for Inoperable
`Lung Cancer
`A. Pines, F.R.C.P.E.
`Levamisole in Prevention of Recurrent Upper-respiratory-tract
`Infections in Children (cid:9)
`M. Van Eygen, M.D., P. Y. Znamensky, M.D., E. Heck, M.D., I. Raymaekers, M.D.
`Cigarette Smoking in Pregnancy: Associations with Maternal Weight
`Gain and Fetal Growth (cid:9)
`385
`D. P. Davies, M.R.C.P., Prof. 0. P. Gray, F.R.C.P., P. C. Ellwood, F.F.c.m., M. Abernethy
`Menstrual Blood-loss with Intrauterine Devices (cid:9)
`387
`John Guillebaud, M.R.C.O.G., Prof. John Bonnar, F.R.C.O.G., Jean Morehead, n.sc.,
`Anne Matthews, m.sc.
`
`377
`
`380
`
`382
`
`401
`
`Brain Damage in Sport (cid:9)
`Coronary Heart-disease in
`Edinburgh and Stockholm 402
`The Least Bad Treatment
`403
`for Achalasia (cid:9)
`Pituitary Tumours and Pregnancy 404
`404
`Microbiological Safety (cid:9)
`Does Clindamycin Produce
`Viral Colitis? (cid:9)
`The Ballot (cid:9)
`
`405
`405
`
`426
`
`426
`
`427
`
`427
`
`427
`427
`
`428
`
`428
`
`428
`
`429
`
`429
`
`429
`
`429
`
`430
`
`430
`
`430
`
`431
`
`431
`
`432
`
`433
`
`433
`
`433
`
`433
`
`434
`
`434
`
`434
`
`435
`
`435
`
`435
`
`435
`435
`436
`436
`
`Age Dependence of T Lymphocytes (cid:9)
`Dr C. Alexopoulos, Dr P. Babitis
`Buffer Therapy and Intraventricular
`Hemorrhage
`Dr J. M. Anderson and others
`Hairy Cells
`Dr A. I. Spriggs
`Salbutamol in Hyperkahemic Familial
`Periodic Paralygis
`Dr D. M. Harris
`Injecting the Painful Shoulder
`Dr C. E. Quin
`Screening for Breast Cancer
`Mrs Anne Scott, F.R.C.S.E.
`Manifestations of Immunological
`Diseases in the Child (cid:9)
`Dr P. Dalen, Dr H. Kjellbo
`Coagulation Disorders and Abortion
`Using Hypertonic Solutions
`Dr Ian Craft,
`Mr Peter Bowen-Simpkins, M.R.C.O.G.
`D-penicillamine and Hemolytic Anemia
`Dr W. H. Lyle (cid:9)
`428
`Treatment of Inoperable Carcinoma of
`Bronchus (cid:9)
`Dr A. H. Laing and others
`Lecithin/sphingomyelin Ratios in
`Oropharyngeal Fluid (cid:9)
`Prof. B. Salvadori and others
`Pericarditis in Acute Myocardial
`Infarction
`Dr L. Guillevin, Dr P. E. Valere
`Ageing and Cancer (cid:9)
`Dr L. M. Franks
`Fatal Mexiletine Overdose (cid:9)
`Dr Peter Jequier and others
`Decision Pathways in the N.H.S. (cid:9)
`Mr B. Le G. Petfield, F.H.A.
`Acrodermatitis Enteropathica, Zinc, and
`Ultrastructural Lesions in Paneth
`Cells (cid:9)
`Dr I. Polanco and others
`Daunorubicin Cardiotoxicity (cid:9)
`Dr G. Ippoliti and others
`Trisomy-20 Syndrome in Man (cid:9)
`Dr P. D. Pallister and others
`Nicotinic Acid and Myocardial Action
`Potential (cid:9)
`Dr Andrzej Beresewicz,
`Dr Jacek Wojiczak
`Chlorpheniramine-induced Bone-marrow
`Suppression (cid:9)
`432
`Dr P. M. Dennger, Dr Alice Maniatis
`Simultaneous Diagnosis and Treatment
`of Acute Adrenal Insufficiency (cid:9)
`Dr D. Mattingly, Dr P. Sheridan
`Matching Kidney Grafts
`Dr John Morton
`Pseudopolycythemia
`Prof. M. Mongin
`Arsenic and Non-cirrhotic Portal
`Hypertension (cid:9)
`Dr D. V. Datta
`Flucloxacillin and Bilirubin Binding (cid:9)
`Prof. F. Hanefeld, Prof. L. Ballowitz
`Alpha -antitrypsin Deficiency (cid:9)
`Dr J. P. Martin and others
`Evolution of X-chromosome
`Inactivation (cid:9)
`Dr Joe-Jie Hoo
`Disclosure on Abortion (cid:9)
`Prof. P. J. Huntingford, F.R.C.O.G.
`Yersinia Infection (cid:9)
`OBITUARY
`Hugh Owen Moss Bryant
`NOTES AND NEWS
`Blood-pressure in Brussels
`425 (cid:9)
`Prenatal Diagnosis of Metabolic
`425 Disorders
`A Warning from the Review Body
`426 (cid:9) Nutritional Anaemia
`Dealing with Death
`
`391
`
`393
`
`PRELIMINARY COMMUNICATIONS
`Non-invasive Quantitation of
`Corneal Copper in
`Hepatolenticular Degeneration
`(Wilson's Disease) (cid:9)
`M. Belkin, M.D., and others
`Immunostimulant Therapy with
`Levamisole for Rheumatoid
`Arthritis (cid:9)
`E. C. Huskisson, M.R.C.P., and others
`HYPOTHESIS
`Refined Carbohydrate,
`Smooth-muscle Spasm and Disease
`of the Colon (cid:9)
`D. S. Grimes, M.R.C.P.
`An Alternative Theory of
`Herpes-simplex Recurrence and a
`Possible Role for Prostaglandins (cid:9)
`T. J. Hill, PH.D.,
`W. A. Blyth, PH.D.
`COMMENTARY FROM
`WESTMINSTER
`Committee on Abortion
`
`395
`
`397
`
`406
`
`OCCASIONAL SURVEY
`Alternative Explanations of the
`Differing Behaviour of Ovarian
`and Testicular Teratomas (cid:9)
`R. P. Erickson, M.D.,
`B. Gondos, M.D.
`Multifactorial Regulation of
`Prolactin Secretion
`H. A. Zacur, M.D., and others
`NATIONAL HEALTH SERVICE
`Doctors and Administrators (cid:9)
`D. S. Grimes, M.R.C.P.
`PERSONAL PAPER
`Chronic Osteomyelitis
`Prof. Frank Falkner, F.R.C.P.
`LETTERS TO THE EDITOR
`Merrison and the Colleges (cid:9)
`Sir Martin Roth, F.R.C.PSYCH.,
`Prof. Bernard Tomlinson
`Graduate Clinical Training (cid:9)
`Dr J. R. Bennett
`Osteoporosis (cid:9)
`Dr R. Lindsay and others;
`Mr A. W. Fowler, F.R.C.S.,
`Prof. J. Grimley Evans
`Glucoreceptor Deficiency in Diabetes (cid:9)
`Dr Kjell Asplund
`Insulin Extraction and Hepatic
`Blood-flow (cid:9)
`Dr R. I. Misbin
`
`497
`
`410
`
`413
`
`415
`
`416
`
`416
`
`417
`
`418
`
`418
`
`419
`
`419
`
`419
`
`419
`
`420
`
`420
`
`Insulin in Diabetic Ketoacidosis
`Dr G. Ghirlanda and others
`Sugar-free Drugs for Diabetics
`Dr David Haler
`Re-use of Disposable Dialysers
`Dr R. Ahmad, Dr H. I. Goldsmith
`Waste Not
`Mr G. J. C. Smelt, B.sc.
`Taxes, Smoking, and Health
`Dr A. G. Freeman
`Cost of Breast-feeding
`Prof. D. B. Jelliffe,
`Mrs Patrice Jelliffe, M.P.H.
`Why Do Women Stop Breast Feeding? 420
`Dr D. P. Davies, Dr C. Thomas
`Dried-milk Infant Feeds (cid:9)
`Miss V. Cooper, B.PHARM., and others
`Intensive Antenatal Plasmapheresis (cid:9)
`Dr J. M. Bowman
`Family Planning in Hospitals (cid:9)
`Mr Roger Hole, F.R.C.S.
`Intravenous Prednisolone in Asthma (cid:9)
`Dr A. E. Tattersfield, Dr S. T. Holgate
`Levels of Consciousness in Coma (cid:9)
`Dr E. N. S. Fry
`Coombs-positive Hemolytic Anemia
`Provoked by Chlorpromazine (cid:9)
`Dr Cs. Hadnagy
`Infectious-mononucleosis Rash
`after Talampicillin
`Dr John Morris
`Activities of Tobramycin and Amikacin
`against Gentamicin-resistant
`Gram-negative Bacilli
`Dr Elizabeth Houang,
`Dr Edward McKay-Ferguson
`Do Tricyclic Antidepressants Work? (cid:9)
`Dr Juhn Jaaskelainen,
`Dr N. M. A. Viukari
`Suprarenal-artery Berry Aneurysm
`Mr Martyn Waterworth, F.R.C.S.
`Severe Renal Dysfunction after
`Tobramycin/cephalothin Therapy
`Dr J. M. Whitehouse and others
`Incision of Small Vessels
`Dr R. M. Becker, Dr M. S. Chughtai
`Patient-controlled Intravenous Narcotic
`Dr J. M. Evans and others
`
`421
`
`421
`
`422
`
`422
`
`422
`
`423
`
`423
`
`423
`
`424
`
`424
`
`Editorial Office: 7 Adam Street, London WC2N 6AD, England. North
`American Edition published weekly by Little, Brown and Company,
`34 Beacon St., Boston, Mass. 02106. In U.S. and Canada, annual
`subscription $30.00; resident and intern rate $21.50; single copy
`$4.00. Second class postage paid at Boston, Mass., and at additional
`mailing offices. c The Lancet Ltd., 21 February 1976. Notification
`on Form 3579 is to be mailed to The Lancet, 34 Beacon Street, Bos-
`ton, Mass. 02106.
`THE WHOLE OF THE LITERARY MATTER IN THE LANCET IS COPYRIGHT
`
`ei
`
`zi3 0 117
`l-I i3 OF CONGRESS
`URC:ER ,DI V
`CONT I NUAT IWOUNIT.
`WASHINGTON"'
`
`2054?)
`
`Ex. 1086 - Page 1
`
`

`

`MSD
`MERCK -
`?al&
`
`MAR 4 197
`
`Cont c ey
`
`AND THROUGHOUT THE YEARS
`
`OF ANTIHYPERTENSIVE THERAPY
`
`"Required
`Reading"
`For Your
`Hypertensive
`Patients
`
` ss'Oe
`toodoe
`091"
`
`' (cid:9)
`
`Because of the importance of
`patient motivation, Merck
`Sharp & Dohme offers "High
`Blood Pressure," a concise,
`pocket-sized booklet that
`defines the patient's own role
`in the management of hyper-
`tension. This booklet is avail-
`able for you to give to your
`patients. It is designed to
`reinforce your explanation of
`hypertension and it emphasizes
`the importance of patient
`understanding in adhering to
`the regimen you prescribe.
`
`Please ask your Merck Sharp &
`Dohme Professional Represen-
`tative or write Professional
`Service Department, West
`Point, Pa. 19486 for a supply
`of this booklet.
`
`• When drug therapy is indicated in hypertension, HydroDIURIL has
`proven to be a clinically useful baseline agent
`• The antihypertensive effect of HydroDIURIL is usually maintained
`throughout long-term therapy
`• When additional therapy is warranted, HydroDIURIL may be used in
`combination with other antihypertensive agents. HydroDIURIL
`may add to or potentiate the action of other antihypertensive drugs.
`Therefore, careful observations for changes in blood pressure
`must be made.
`Contraindications include anuria and hypersensitivity to hydro-
`chiorothiazide or other sulfonamide-derived drugs. Use with caution
`in patients with severe renal disease, impaired hepatic function,
`or progressive liver disease.
`
`MSD
`cK
`
`RP%
`nH
`HME
`
`RA
`
`TABLETS, 25 mg, 50 mg, and 100 mg
`
`arro[0111
`(Hydrochlorothiazide MSD)
`highly effective,
`single-entity
`antihypertensive
`
`For a brief summary of prescribing information, please see following page. (cid:9)
`
`Ex. 1086 - Page 2
`
`

`

`"Required
`Reading"
`For Your
`Hypertensive
`Patients
`
`Because of the importance of
`patient motivation, Merck
`Sharp & Dohme offers "High
`Blood Pressure," a concise,
`pocket-sized booklet that
`defines the patient's own role
`in the management of hyper-
`tension. This booklet is avail-
`able for you to give to your
`patients. It is designed to
`reinforce your explanation of
`hypertension and it emphasizes
`the importance of patient
`understanding in adhering to
`the regimen you prescribe.
`
`Please ask your Merck Sharp &
`Dohme Professional Represen-
`tative or write Professional
`Service Department, West
`Point, Pa. 19486 fora supply
`of this booklet.
`
`p6 MAR 4 1976
`
`Cont (..‘itdy
`
`AND THROUGHOUT THE YEARS
`
`OF ANTIHYPERTENSIVE THERAPY
`
`• When drug therapy is indicated in hypertension, HydroDIURIL has
`proven to be a clinically useful baseline agent
`• The antihypertensive effect of HydroDIURIL is usually maintained
`throughout long-term therapy
`• When additional therapy is warranted, HydroDIURIL may be used in
`combination with other antihypertensive agents. HydroDIURIL
`may add to or potentiate the action of other antihypertensive drugs.
`Therefore, careful observations for changes in blood pressure
`must be made.
`Contraindications include anuria and hypersensitivity to hydro-
`chlorothiazide or other sulfonamide-derived drugs. Use with caution
`in patients with severe renal disease, impaired hepatic function,
`or progressive liver disease.
`
`TABLETS, 25 mg, 50 mg, and 100 mg
`
`HydroDIURIL
`(Hydrochlorothiazide MSD)
`highly effective,
`single-entity
`antihypertensive
`
`MM
`
`SD
`
`MERCK
`RII
`For a brief summary of prescribing information, please see following page. uOHME
`
`Ex. 1086 - Page 3
`
`

`

`THE LANCET, FEBRUARY 21, 1976
`
`IMMUNOSTIMULANT THERAPY WITH
`LEVAMISOLE FOR RHEUMATOID ARTHRITIS
`
`E. C. HUSKISSON
`P. A. DIEPPE
`JANE SCOTT
`JANE TRAPNELL
`H. W. BALME
`D. A. WILLOUGHBY
`Department of Rheumatology and Experimental Pathology,
`St. Bartholomew's Hospital, London EC1
`
`Summary (cid:9)
`
`In a controlled study involving thirty-
`four patients levamisole was shown to be
`as effective as D-penicillamine and more effective than
`placebo in the treatment of rheumatoid arthritis. Its
`action was slow and was accompanied by a reduction in
`erythrocyte sedimentation-rate, rheumatoid factor, and
`technetium index. These properties indicate that it has
`a specific action like that of D-penicillamine. Stimulation
`of cell-mediated immunity was evident in patients
`treated with levamisole, and there was a correlation
`between such changes and pain relief. Animal models
`confirmed the absence of anti-inflammatory effect and
`provided some evidence of enhancement of cell-mediated
`immunity and macrophage stimulation.
`
`INTRODUCTION
`
`STIMULATION of some aspect of the immune response
`by levamisole might be beneficial in several diseases.'
`Enthusiastic statements made about the effects of this
`compound in uncontrolled trials in various diseases, in-
`cluding rheumatoid arthritis,2 have been followed by
`demands for controlled studies. We report the results of
`such a controlled study of levamisole in rheumatoid
`arthritis.
`
`METHODS
`Clinical assessment.-Thirty-four patients with definite or
`classic rheumatoid arthritis by the American Rheumatism As-
`sociation criteria were studied, twelve receiving at least 6
`months' treatment with levamisole, twelve with penicillamine,
`and ten with placebo. All patients had active disease which had
`not responded to or progressed despite anti-inflammatory
`drugs. At the start of the study they were stabilised on an opti-
`mum anti-inflammatory regimen which remained constant
`during the study. After an initial clinical assessment, levamis-
`ole, penicillamine, or placebo was added to the anti-inflamma-
`tory regimen. Levamisole was used in a dose of 50 mg three
`times daily, placebo three tablets daily, and penicillamine 250
`mg daily for 2 weeks, increasing thereafter at fortnightly inter-
`vals by 250 mg daily up to a total daily dose of 1 g. The treat-
`ments were not identical in appearance. The patients were
`assessed by a single observer who was unaware of their treat-
`ment and with whom side-effects were not discussed. Measure-
`ments made before the start of the treatment and again after
`3 and 6 months included pain (visual analogue scale), duration
`of morning stiffness, articular index,; proximal interphalan-
`geal joint circumference, erythrocyte sedimentation-rate
`(E.S.R.), rheumatoid factor titre using the latex test, immuno-
`globulins (IgG, IgM and IgA), and complement. The techne-
`tium index was measured in patients receiving n-penicillamine
`or levamisole before treatment and again after 6 months, using
`the method described by Berry and Huskisson.• Weekly
`measurements of pain relief were made by the patients, using
`a visual analogue pain-relief scale.
`Immunological assessment.-Before treatment and again
`after 3 months, delayed hypersensitivity was assessed by skin
`tests and leucocyte migration inhibition in patients receiving
`levamisole or placebo. Skin testing was carried out with intra-
`dermal injections of 0.1 ml of 1/1000 P.P.D., the diameter of
`erythema and degree of induration, measured with skin cal-
`
`393
`
`lipers, were recorded 48 hours after injection. Leucocyte mi-
`gration was assessed according to the method of Rosenberg and
`David,' the percentage inhibition induced by tuberculin
`antigen being recorded.
`Laboratory assessment.-The effect of levamisole on acute
`inflammation was tested using carrageenan-induced pleurisy in
`male Wistar rats.6 The volume of exudate and total number of
`cells recovered were recorded at 6 and 24 hours after injection
`of carrageenan, one group of animals being orally pre-treated
`for 1 week with 5 mg/kg levamisole. Adjuvant arthritis was in-
`duced in male Wistar rats. Foot oedema was measured by a
`mercury displacement method daily for 21 days after injection
`of adjuvant. Levamisole (5 mg kg-' day-') was administered
`orally throughout the experiment. The effect on macrophage
`activity was assessed by the implantation of glass coverslips in
`mice;' the area of glass covered with cells and percentage of
`giant cells formed were recorded 4, 7, and 10 days after im-
`plantation, with and without daily oral doses of 5 mg/kg
`levamisole.
`Statistical methods-Student's t test was used to compare
`differences between changes in the thiee treatment groups. In
`the case of technetium index, the paired t test was used. Corre-
`lation coefficients were sought between clinical and immunolo-
`gical measurements.
`
`RESULTS
`After 3 months' treatment both penicillamine and
`levamisole produced statistically significant improve-
`ment in pain scores when compared with placebo
`(t=2.72, P<0.02 for levamisole; t=2.18, P<0.05 for
`penicillamine). Other clinical measurements showed a
`similar trend, which did not necessarily achieve statisti-
`cal significance. There was a statistically significant
`reduction in E.S.R. on both drugs (t=2.73, P<0.02 for
`levamisole; t=4.35, P<0.01 for penicillamine).
`The results after 6 months' treatment are shown in
`tables t and II. Levamisole produced a statistically sig-
`nificant or highly significant improvement in pain,
`duration of morning stiffness, proximal interphalangeal
`joint circumference, E.S.R., latex titre, and IgG concen-
`tration, when compared with patients on placebo.
`D-penicillamine was similarly effective. D-penicillamine
`was more effective than levamisole in reducing the
`duration of morning stiffness, and this difference was of
`borderline statistical significance (0.1>p>0.05); in none
`of the other measurements was there any statistically
`significant difference between the changes produced by
`D-penicillamine and levamisole. There was a statistically
`
`TABLE I-CHANGES IN CLINICAL MEASUREMENTS AFTER 6 MONTHS'
`TREATMENT WITH LEVAMISOLE, D-PENICILLAMINE, OR PLACEBO
`
`Duration
`of morning
`stiffness
`(min)
`
`-
`
`Pain
`
`Joint
`Articular
`size
`index
`(mm)
`-4.0
`-25.9t
`-13.5t
`-50t
`Levamisole
`-9.9t
`-12.5`
`-7.9•
`-19.3
`-129t
`-5.3•
`Penicillamine
`..
`-3.1
`-8.8
`-9
`+0.3
`Placebo
`Significance of differences between active drugs and placebo: •0• >e>0.05 (bor-
`derline); tP<0.05; tP<0.01.
`
`Technetium
`index
`
`TABLE II-CHANGES IN LABORATORY MEASUREMENTS AFTER 6 MONTHS'
`TREATMENT WITH LEVAMISOLE, TE-PENICILLAMINE, OR PLACEBO
`
`Latex
`titre
`(dilutions)
`
`-
`
`E.S.R.
`(mm/hr)
`
`IgA
`IgM
`IgG
`(mg/di) Complement
`(mg/dl)
`(mg/di)
`-18.8
`-25.7
`-23.3
`-301.7•
`-1.3t
`-28.71
`Levamisole
`-74.7
`-29.4
`-68.9
`-505.01
`-1.01.
`-39.5t
`Penicillamine
`-17.0
`-25.5
`+17.0
`+1520
`+0.1
`0
`Placebo
`Significance of differences between active drugs and placebo: •P<0 05; tP<0.01.
`
`Ex. 1086 - Page 4
`
`(cid:9)
`(cid:9)
`(cid:9)
`

`

`394
`
`THE LANCET, FEBRUARY 21,1976
`
`..k2 (cid:9)
`
`180
`160
`Cj••• 140
`120
`1,)
`C11 Le) 100
`80
`•c t., 60
`jh 40
`20
`0
`14
`12
`141
`10
`ik (cid:9)
`20 8
`(tn) 5
`4
`2
`0
`
`Lk (cid:9)
`
`2 4 6 8 10 12 14 16 18 20 22 24 26
`Week of treatment
`
`Fig. 1—Mean weekly pain-relief scores and duration of morning stiffness.
`These figures are based on assessments made by patients at home
`and show the delayed effect of levamisole.
`
`significant reduction in technetium index and in patients
`receiving levamisole (t=2.71, r<0.05) and a similar
`reduction in those on penicillamine (t=2.06,
`0-1>p>0•05).
`Mean weekly pain-relief scores and duration of morn-
`ing stiffness (fig. 1) are based on the patients' assess-
`ments at home and do not correspond exactly to the as-
`sessments made at the clinic (table 1). The effects of
`levamisole developed slowly, reaching a peak between 4
`and 6 months after treatment.
`There was no significant difference between the initial
`values of any measurements in the penicillamine and
`
`+40
`
`+30
`
`k +20
`O
`
``') +10
`
`•
`•
`
`•
`
`
`
`• •
`
`•
`
`t.) (cid:9)
`
`0
`
`•
`• • • •
`
`—10
`
`•
`
`•
`
`•
`
`•
`•
`
`• S
`
`• •
`
`•
`
`Levamisole Placebo
`
`Fig. 2—Changes in degree of induration with intradermal P.P.D. after 3
`months' treatment with either levamisole or placebo.
`
`-0\73
`/•-• 90
`
`D Levamisole
`— MI Control
`
`Giant-cell count
`
`80
`
`41 70
`
`60
`
`k, 50
`O
`
`40
`
`44 30
`
`w 20
`
`4 10
`
`0
`
`•
`
`Control
`
`A
`7 (cid:9)
`10
`3
`Duration of implantation (days)
`
`0 (cid:9)
`
`Fig. 3—Changes in cell migration and giant-cell formation, using subcu-
`taneous coverslips in mice treated with levamisole and in control mice.
`
`levamisole groups. However, the mean initial values of
`pain and morning stiffness were lower in the placebo
`group than in the other two groups.
`There was a tendency for patients on levamisole to
`show increased responsiveness to tuberculin (fig. 2), and
`a statistically significant correlation was found between
`changes in skin tests and pain relief (r=0.44, P<0.05).
`There was also a tendency for patients on levamisole to
`show enhancement of leucocyte migration inhibition to
`P.P.D. As expected, there was a correlation between skin
`response to P.P.D. and leucocyte migration inhibition
`with tuberculin (r=0.59, p<0.01).
`One patient receiving D-penicillamine was withdrawn
`after 2 months because of rash, loss of taste, and neutro-
`penia. She was replaced and was not included in the
`clinical assessments. No patients were withdrawn from
`the levamisole or placebo groups. Minor and transient
`side-effects occurred in all three groups. The most
`common side-effects in the penicillamine group were
`nausea, vomiting, rash, and loss of taste. Side-effects in
`the levamisole group included nausea, rash, mouth
`ulcers, minor disturbance of taste, and tremor. Nausea
`occurred within the first few weeks of treatment and
`lasted for 6 to 10 weeks. The typical rash was itchy and
`erythematous with an urticarial component. In three pa-
`tients with rashes, it was necessary to change to an in-
`termittent regimen (150 mg daily on 2 days of each
`week) after 3 to 5 months of continuous treatment.
`There was a significant increase in hxmoglobin con-
`centrations and a significant fall in white-blood-cell
`count in both the D-penicillamine and levamisole groups.
`No patients receiving levamisole became neutropenic.
`There were no significant changes in serum-creatinine
`or liver function tests in patients receiving levamisole.
`Levamisole had no effect in carrageenan pleurisy nor
`on the primary lesions of adjuvant arthritis. Secondary
`lesions of adjuvant arthritis appeared from the 12th day
`and were more severe in animals receiving levamisole.
`
`f n
`Paw volume was greater in the uninfected feet i
`levamisole-treated animals than in controls, the d1-
`i
`ference being statistically significant at 21 days after n-
`
`Ex. 1086 - Page 5
`
`(cid:9)
`

`

`it
`
`THE LANCET, FEBRUARY 21, 1976
`
`395
`
`jection. The subcutaneous coverslip technique showed
`an increase in cell migration in levamisole-treated ani-
`mals, which was most pronounced on the 7th day and
`an increase in giant-cell formation, most marked on the
`10th day (fig. 3).
`
`DISCUSSION
`These results show that levamisole has a specific
`action in rheumatoid arthritis, of the type shown by
`D-penicillamine. Drugs of this type act slowly, taking
`months to achieve their maximum effect and produce
`changes in E.S.R., rheumatoid factor, and other extra-ar-
`ticular features of the disease.8 Reduction in technetium
`index has also been shown to be a marker of drugs of
`this type.9 By contrast, anti-inflammatory drugs act
`quickly and relieve symptoms without effects on E.S.R. or
`rheumatoid factor. In the present study levamisole pro-
`duced relief of pain, reduction in the duration of morn-
`ing stiffness, proximal interphalangeal joint circum-
`ference, and articular index, accompanied by changes in
`E.s.R., rheumatoid factor titre, and technetium index.
`The absence of anti-inflammatory activity was con-
`firmed in conventional animal models; levamisole had
`no effect on carrageenan pleurisy or the primary lesions
`of adjuvant arthritis. Enhancement of the secondary
`lesions of adjuvant arthritis and of macrophage mi-
`gration using subcutaneous coverslips indicates stimula-
`tion of cells involved in the immunological response.
`The secondary lesions of adjuvant arthritis are usually
`regarded as a manifestation of delayed hypersensitivity.
`There was also evidence of enhanced cell-mediated
`immune responses in patients with rheumatoid arthritis.
`That this enhancement showed a correlation with im-
`provement in the disease suggests that stimulation of
`cell-mediated immune responsiveness may be an impor-
`tant part of the treatment.
`A model of delayed hypersensitivity has been devel-
`oped using pertussis vaccine as an antigen.'° " In this
`model, both levamisole and D-penicillamine enhanced
`the response, supporting the view that both compounds
`are immunostimulant. D-penicillamine, like levamisole,
`has been shown to increase skin responses to P.P.D.I2 and
`to enhance the secondary lesions of adjuvant arthritis."
`It is therefore of great interest that both compounds
`have a specific action in rheumatoid arthritis. If rheu-
`matoid arthritis is a chronic inflammatory response
`maintained by the persistence of a foreign antigen, it is
`as logical to stimulate the immune system to remove the
`antigen as it is to suppress it in the hope of blocking the
`inflammatory reaction which follows.
`Levamisole, though not free of side-effects, may prove
`to be a useful alternative to D-penicillamine.
`
`We thank the Joint Research Board of St. Bartholomew's Hospital,
`the Arthritis and Rheumatism Council, the Wellcome Trust, and the
`European Biological Research Association for financial support.
`Requests for reprints should be addressed to E.C.H.
`
`Hypothesis
`
`REFINED CARBOHYDRATE,
`SMOOTH-MUSCLE SPASM AND DISEASE OF
`THE COLON
`
`DAVID S. GRIMES
`Department of Medicine, Withington Hospital,
`Manchester 20 8LR
`
`Summary (cid:9)
`
`A diet high in refined carbohydrate is
`implicated in the xtiology of some dis-
`eases of the colon—i.e., diverticular disease, irritable
`bowel syndrome, ulcerative colitis, non-occlusive ischx-
`mic colitis, and pseudomembranous colitis. It is sug-
`gested that spasm of the smooth muscle is the common
`pathogenetic mechanism in these colonic diseases. The
`strength of the spasm producing increased pressure in
`the colonic lumen or wall and the length of time for
`which the colon has been affected are believed to deter-
`mine the type of disease resulting. A diet high in refined
`carbohydrate allows the intense muscle spasm to occur
`because the physical buffering effect of fxcal bulk is con-
`siderably reduced.
`
`INTRODUCTION
`THE possible pathogenic role of refined carbohydrate
`may unify the aetiology of several gastrointestinal dis-
`eases, but this approach is not usually matched by a
`unifying concept of the mechanisms involved.
`
`EVIDENCE
`
`Diverticular Disease
`Painter and Burkitt's hypothesis that diverticular dis-
`ease of the colon results from a diet high in refined
`carbohydrate' is based on epidemiological studies
`together with observations that patients with diverticu-
`lar disease tend to generate a high pressure within the
`lumen of the colon2 and lose their symptoms when
`treated with a low-sugar high-fibre diet.' They view the
`high intraluminal pressure as being due to excessive con-
`traction of the colon and propose that the large faecal
`bulk of a high-fibre diet would act as a physical buffer
`against this contraction.
`Diverticular disease is not unique in being associated
`with excessive contraction of the wall of the colon and
`a high pressure within its lumen.
`
`Irritable Bowel Syndrome
`Perhaps the most common clinical manifestation of
`colonic muscle spasm is the irritable bowel syndrome. It
`has been considered to be a result of a diet high in
`refined carbohydrate,* and it is associated with a high
`
`REFERENCES
`
`1. Lancet, 1975, i, 151.
`2. Schuermans, Y. Lancet, 1975, i, 111.
`3. Ritchie, D. M., Boyle, J. A., McInnes, J. M., Jasani, M. K., Dalakos, T. G., ,
`Grieveson, P., Buchanan, W. W. Q. j1 Med. 1968, 37, 393.
`4. Berry, H., Huskisson, E. C. Am. rheum. Dis. 1974, 33, 523.
`5. Rosenberg, S. A., David, J. R. J. Immun. 1970, 105, 1447.
`6. Di Rosa, M., Giroud, J. P., Willoughby, D. A. y. Path. 1970, 104, 15.
`7. Ryan, G. B., Spector, W. G. Proc. R. Soc. Med. 1970, 175, 269.
`
`References continued at foot of next column
`
`8. Huskisson, E. C. Reports on Rheumatic Diseases, no. 54. Arthritis and
`Rheumatism Council, 1974.
`9. Huskisson, E. C., Scott, P. J., Balme, H. W. Ann. rheum. Dis. (in the press).
`10. Arrigoni-Martelli, E., Bramm, E., Huskisson, E. C., Willoughby, D. A.,
`Dieppe, P. A. Ag. Actions, (in the press).
`11. Dieppe, P. A., Willoughby, D. A., Huskisson, E. C., Arrigoni-Martelli, E.
`Ag. Actions, (in the press).
`12. Berry, H., Huskisson, E. C. Ag. Actions, (in the press).
`13. Arrigoni-Martelli, E., Bramm, E. Ag. Actions, 1975,5, 264.
`
`Ex. 1086 - Page 6
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`