JAN. 9, 1960
`
`SURVIVAL OF BONE-MARROW GRAFT
`
`mu~m
`M~mtc~a.
`
`99
`
`antibodies to the recipient’s tissue cells by the marrow
`graft. That this has not been found in the present case
`may be due to the close relationship, and the fact that
`the donor is known to possess all the blood-group
`antigens found in the patient.
`
`Summary
`A patient is described who suffered from acute bone-
`marrow failure due to chemotherapy for Hodgkin’s
`disease. She was treated with a bone-marrow
`transfusion from her sister. Evidence is presented to
`show that the bone-marrow graft survived formore than
`six months, responsible for the production of an
`increasing proportion (now 24%) of the patient’s
`erythrocytes. A skin graft was undertaken between the
`donor of the marrow and the patient, but it was not
`successful.
`
`[ADDENDUM.--We repeated the haematologieal investigation
`on this patient on September 26, 1959. Rh-positive cells
`are still present in her circulation. Titration studies indicate
`that approximately 40% of her circulating ¢rythrocytes are
`Rh-positive. Woodruff and Lennox have recently published
`(Lancet, 1959, 2, 476) further details of the results of the
`skin grafts in blood-group ehimeras.]
`
`. We wish to thank Dr. L. E. Glynn, of the Canadian Red
`Cross Memorial Hospital, Taplow, Bucks, for the report
`on the biopsies; Dr. D. Galton, of the Chester-Beatty
`Institute, for supplies of aminochlorambucil; Dr. J.
`Humble, of the Westminster Hospital, for advice concerning
`the marrow transfusion ; and Dr. A. E. Mourant, of the
`Lister Institute, Chelsea Bridge Road, for reading the
`manuscript and for help given in writing it.
`
`REFERENCES
`Atwood, K. C. (1958). Proe. nat. Acad. Sci. (Wash.), 44, 1054.
`Dacie, J. V., and Mollison, P. L. (1943). Lancet, 1, 550 .
`Ford, C. E., Hamerton, J. L., Barnes, D. W. H., and Loutit, J. F.
`(1956). Nature, 177, 452.
`Humble, J. G., and Newton, K. A. (1958). Lancet, 1, 142.
`Jones, A. Richardson, and Silver, Sheila (1958). Blood, 13, 763.
`Kretchmer (1958). Ibid., 13. 297.
`Math~, G., Jammet, H., Pendi¢, B., Schwarzenberg, L., Duplan,
`J.-F., Maupin, B., Latarjet, R., Larrieu, M.-J., Kali¢, D., and
`Djukic, Z. (1959). Rev. tran¢. £t. ¢lin. biol., 4, 226.
`Porter, K. A., and Murray, J. E. (1958). J. nat. Cancer Inst., 20,
`189.
`Race, R. R., and Sanger, R. (1958). Blood Groups in Man, 3rd
`ed., p. 313. BlackwelL Oxford.
`Thomas, E. Donnall, Ashley, C. A., Lochte, H. L., Jharetzkl, A.,
`Sahler, O. D., and Ferrebee, J. W. (1959a). Blood, 14, 720.
`-- Lochte, H. L., and Ferrebee, J. W. (1959b). Ibid., 14, 1.
`Woodruff, M. F. A. (1957). Quoted by Race and Sanger (1958),
`p. 308.
`
`In his Annual Report for 1958 Dr. I. GORDON, medical
`officer of health of Ilford, comments on the difficulty of
`assessing radiation dangers. Medical officers of health, he
`writes, are worried that they and their staffs are not
`competently trained to evaluate radiation hazards, and
`feel that the Ministry of Health is showing unnecessary
`reluctance in providing this training. He continues: "We
`hope that the Ministry will shortly make it possible for local
`authorities to take an active part in controlling and
`evaluating this potential hazard, but the experience of the
`Essex County Council with regard to their own scheme does
`not give rise to optimism. It is true that if a hazard is
`suspected the medical officer of health can obtain a trained
`expert from the Ministry who will visit, inspect, and advise,
`but how can one even suspect a hazard which is only
`demonstrable with special instruments that one doesn’t
`possess, or how can suspicion be aroused by industrial or
`medical use of radioactive materials when information with
`regard to supply of these materials is withheld ? "
`
`MAINTENANCE TREATMENT OF
`PERNICIOUS ANAEMIA BY MASSIVE
`PARENTERAL DOSES OF VITAMIN
`AT INTERVALS OF TWELVE WEEKS
`BY
`
`J. D. KINLOCH, M.B., Ch.B., F.R.F.P.S.
`Medical Registrar, Royal Infirmary, Glasgow
`
`Parenteral vitamin B~ is now generally recognized as
`the treatment of choice in pernicious anaemia. Once
`full clinical and haematological remission has been
`obtained, various regimes have been recommended to
`provide adequate maintenance therapy (Mollin and
`Dacie, 1950; Blackburn et al., 1952; Conley et al.,
`1952; Davis and Brown, 1953; Hemsted and Mills,
`1958). The dosage advised has been of the order of
`20 to 100 ttg. every two to four weeks.
`If massive doses of vitamin B12 of the order of
`1,000/~g. or more could be given every three months for
`the maintenance treatment of pernicious anaemia, this
`would be a distinct advantage to the patient if it were
`to prove entirely safe.
`The cost of the larger dose would be slightly more,
`and, as most of the injected vitamin B12 is excreted in
`the urine within a short time of administration (Conley
`et al., 1951; Mollin and Ross, 1953; Reisner and
`Weiner, 1953), there would be greater wastage.
`However, ample compensation would be obtained by the
`reduction in the number of injections required and the
`consequent saving of both the patient’s and the general
`practitioner’s time.
`The effectiveness of large doses of vitamin B~
`parenterally at intervals of over six weeks in the
`maintenance treatment of pernicious anaemia has been
`studied in only a small number of patients (Conley et al.,
`1952; Walker and Hunter, 1952; Reisner and Weiner,
`1953).
`The purpose of this paper is to report the results of
`a trial in which 112 treated cases of pernicious anaemia
`were changed from orthodox maintenance treatment to
`maintenance treatment with 1,000 t~g. of vitamin B12
`parenterally every 12 weeks, most of them being kept on
`this regime for a period of two years.
`
`Material and Method~
`The diagnostic criteria observed for inclusion of
`patients in the trial were a macrocytic anaemia, megalo-
`blastic bone-marrow, histamine-fast achlorhydria, and
`a clinical and haematological response
`to the
`administration of vitamin Bx~ or liver extract.
`Of 155 patients with pernicious anaemia who had
`been fully treated and were attending hospital regularly
`for supervision, 112 were considered suitable for
`inclusion in the trial. Of the remaining 43, 30 were
`regarded as unsuitable because of other complicating
`disease: 9 had. early subacute combined degeneration,
`6 had incapacitating cardiovascular disease, 8 were
`elderly arthritic patients, 2 had cirrhosis of the liver,
`2 had polycythaemia vera, and 3 had other illnesses.
`Eight patients were unable to attend because of their
`employment, and five were partaking in another research
`trial.
`The 112 patients selected consisted of 85 women and
`27 men; their ages ranged from 31 to 85 years, the
`
`Sandoz Inc.
`Exhibit 1029-0001
`
`JOINT 1029-0001
`
`

`
`100
`
`JAN. 9, 1960
`
`PERNICIOUS ANAEMIA
`
`average being 59. Every patient was requested to attend
`for supervision at intervals of four weeks. Injections of
`1,000 ~tg. of vitamin B~ (" cytamen ") were given once
`every 12 weeks. The haemoglobin and red-cell count
`were estimated at least every 12 weeks, and more often
`if the levels were not entirely satisfactory.
`Serum vitamin B~ assays were performed on the
`majority of patients, using the method described by Ross
`(1952) modified by Hutner et al. (1956) using Euglena
`gracilis 3 strain as the test organism. Samples were
`obtained at 18 months at random intervals of one, two,
`or three months after vitamin-B~ administration.
`
`Results
`To determine whether or not there was any
`deterioration in the haematological values during the
`course of the trial the mean of the first three and the
`mean of the last three red-cell counts and haemoglobin
`estimations were compared. The haematological levels
`at which it was considered desirable to maintain patients
`were:--for men: haemoglobin 100%, red-cell count
`5,000,000/c.mm. ; for women: haemoglobin 90%, red-
`cell count 4,500,000/c.mm.
`During the course of the trial three patients died from
`other diseases and nine were withdrawn owing to
`intercurrent illness or inability to attend.
`Of the remaining 100, 87 were maintained in the trial
`throughout a two-year period of study and showed
`no deterioration in their red-cell counts or haemoglobin
`values. Seventeen of these, however, were maintained
`with red-cell counts slightly under the desired levels,
`and two required intermittent oral iron therapy to
`maintain their haemoglobin levels.
`Thirteen patients wer~ withdrawn from the trial at
`intervals varying from 9 to 16 months (mean 14 months)
`on account of unsatisfactory red-cell counts, though
`none were below 4,000,000/c.mm., and in these cases
`the dosage of vitamin Bt~. was increased to 1,000 pg.
`monthly in an effort to determine whether or not an
`improvement might be obtained. Of this group, one
`patient had, after 12 months in the trial, developed
`paraesthesia of the hands and feet, which did not clear
`up until the dosage of vitamin B~. had been increased
`to fortnightly. Three patients were known to have other
`disease: one had mild rheumatoid arthritis, one had
`been under out-patient treatment for a year for
`pulmonary tuberculosis, and one had a probable
`bronchial carcinoma. These four patients had the
`lowest haematological values in the whole survey.
`Eleven of these 13 cases showed a rise of the red-cell
`count of 100,000-400,000/c.mm. (mean 300,000/c.mm.)
`following the more intensive vitamin-B~ therapy. These
`must be accepted as failures of the regime.
`Serum vitamin-B~ assays performed on the first group
`of 87 patients after 18 months showed satisfactory levels
`in all cases except in one performed three months after
`her last vitamin-B~2 injection, which gave a borderline
`result though her haematological values were normal.
`Facilities were not available for carrying out assays on
`the 13 patients of the second group at the time at which
`they were withdrawn from the trial.
`
`Summary and Conclusions
`One hundred treated cases of pernicious anaemia were
`maintained on a two-year trial to assess the adequacy of
`the maintenance therapy of 1,000 ~tg. of parenteral
`vitamin Bt; every 12 weeks.
`
`Throughout the period of study 87 patients showed
`no deterioration as judged by their haematological
`values (haemoglobin and red-cell count) and serum
`vitamin-B~ assays.
`Thirteen patients showed unsatisfactory red-cell levels
`after 9 to 16 months, and in II of these improvement
`was obtained by increasing the vitamin BI~ dosage to
`1,000/~g. monthly.
`It is concluded that one injection of 1,000 /~g. of
`vitamin B~ every 12 weeks provides adequate
`maintenance therapy for most patients suffering from
`pernicious anaemia. However, as this dosage is
`inadequate in a small number of patients it cannot be
`recommended as a general routine measure.
`I thank Dr. J. F. Adams, Western Infirmary, and Dr. J. C.
`Eaton, Department of Biochemistry, Royal Infirmary,
`Glasgow, for their assistance. I am grateful to Professor
`L. J. Davis and Dr. A. S. Douglas, University Department
`of Medicine, Royal Infirmary, Glasgow, for their advice
`and encouragement.
`
`REFERENCES
`
`Blackburn, E. K., Burke, J., Roseman, C., and Wayne, E. J.
`(1952). Brit. med. J., 2, 245.
`Conley, C. L., Green, T. W., Hartmann, R. C., and Krevans,
`J. R (1952). Amer. J. Med., 13, 284.
`-- Krevans, J. R., Chow, B. F., Barrows, C., and Lang, C. A.
`(1951) J. Lab. clin. Med., 38, 84.
`Davis, L. J., and Brown, A 0953). The Megaloblastic Anaemias.
`Blackwell, Oxford.
`Hemsted, E. II., and Mills, J. (1958). Lancet, 2, 1302.
`Hutner, S. H., Bach, M. K., and Ross, G. I. M. 0956). J.
`Protozool., 3, 101.
`Mollin, D. L., and Dacie, J. V. (1950). Proc. roy. Soc. Med.,
`43, 541.
`. and Ross, G. I. M. 0953). J. din. Path., 6, 54.
`Reisner, E. It., and Weiner, L. 0953). Blood, 8, 81.
`Ross, G. I. M. (1952). J. clin. Path.. $, 250.
`Walker, W., and Hunter, R. B. (1952). Brit. med. J., 2, 593.
`
`/DIETHYLCARBAMAZINE IN TROPICAL
`PULblONARY EOSINOPHILIA
`
`BY
`
`AJAI SHANKER, M.D.
`Lecturer in Medicine
`
`R. K. BHARGAVA, M.D.
`Lecturer in Medicine
`
`AND
`
`B. N. SHRIVASTAVA, M.B., B.S.
`Demonstrator in Medicine
`Gandhi Medical College, Bhopal, India
`
`Tropical pulmonary eosinophilia, which is widespread
`in India, is now recognized as a major cause of
`respiratory illnesses. It is increasingly regarded as an
`eosinophilic disorder in which bone-marrow, blood,
`lungs, liver, and probably other viscera may be involved.
`So far, its aetiology is mainly speculative, though
`allergy, parasitic infection, and viral infection have all
`been incriminated.
`Until recently, arsenic was the sheet anchor in its
`treatment. Antimony and bismuth (D’Abrera, 1946),
`sulphonamides (Joseph, 1946; Chaudhuri et al., 1954),
`chloroquine, and chlorbetamide (" mantomide ")
`(Ganatra and Lewis, 1955) have all given disappointing
`results. Chaudhuri (1950) and Prasada Rao and
`Krishnan (1952) reported encouraging results with
`chlortetracycline, but antibiotics have not proved
`effective in the hands of Misra el al. (1958), Reeder
`and Goodrich 0952), and Diaz Rivera et al. (1950).
`
`Sandoz Inc.
`Exhibit 1029-0002
`
`JOINT 1029-0002