JULY 29, 1961
`
`NEW INTRAMUSCULAR HAEMATINIC
`
`BmDICsOHRi_
`
`279
`
`The clinical importance of this
`animal experiments.
`observation, however, has still to be elucidated. Lundin
`(1961), using the same technique as Richmond (1959),
`After iron-
`has confirmed this action of iron-dextran.
`sorbitol, on the contrary, no sarcoma developed.
`
`Summary
`A preparation containing an iron-sorbitol-citric-acid
`complex (" jectofer ") and intended for intramuscular
`injection has been studied from the aspects of tolerance
`Comparisons are
`and therapeutic effect in 39 cases.
`drawn with iron-dextran (" imferon ") (34 cases). The
`clinical tolerance for the iron-sorbitol complex was
`good, and only mild local side-effects were noted. The
`therapeutic result was satisfactory, and in patients with
`an Hb concentration of less than 8 g./100 ml. blood the
`increase in the Hb level was 3.8 g./100 ml. for the iron-
`sorbitol group and 3.9 g./100 ml. for the iron-dextran
`This corresponds approximately to a 60%
`group.
`utilization of the iron in the preparation. About 30%
`of the dose administered is excreted in the urine without
`producing any noticeable effect on the renal function.
`
`REFERENCES
`Agner, Kj. (1947). Kliniska Laborationsmetoder, 5, 573. Astra,
`Sodertalje.
`Andersson, N. S. E., and Nordenson, N. G. (1948). Acta
`haemat. (Basel), 1, 193.
`Andersson, N. S. E. (1950). Acta med. scand., Suppl. 241.
`and Bergstrom, I. (1956). Svenska Lak.-Tidn., 53, 13.
`Baird, I. M., and Podmore, D. A. (1954). Lancet, 2, 942.
`Brown, E. B., and Moore, C. V. (1956). In L. M. Tocantin's
`Progress in Hematology, 1, 22.
`Fletcher, F., and London, E. (1954). Brit. med. J., 1, 984.
`Grimes, A. J., and Hutt, M. S. R. (1957). Ibid., 2. 1074.
`J. nat. Cancer. Inst.,
`Haddow, A., and Homing, E. S. (1960).
`24. 109.
`Karlefors, T., and Norden, A. (1958). Acta med. scand., Suppl.
`342.
`Lindvall, S., and Andersson, N. S. E. (1961). To be published.
`Lundin, P. M. (1961). To be published.
`Nissim, J. A. (1947). Lancet, 2, 49.
`(1949). M.D. thesis, University of London.
`Richmond, H. G. (1959). Brit. med. J., 1, 947.
`(1960). In R. V. Raven's Cancer Progress, p. 24.
`Svard, P. 0. (1961). To be published.
`
`INTRAVENOUS IRON-DEXTRIN IN
`IRON-DEFICIENCY ANAEMIA
`BY
`J. FIELDING, M.R.C.P., D.P.H.
`Consultant Haematologist, Paddington General Hospital,
`London
`
`The use of parenteral iron preparations in the treatment
`of iron-deficiency anaemias has passed through several
`Baird and Podmore (1954) point out that
`phases.
`Claude Bernard used intravenous iron in animals. Many
`preparations have been tried, including iron gluconate
`(Reznikoff and Goebel, 1937), ascorbate (Friend, 1938),
`and triethanolamine (Brownlee et al., 1942), but toxicity
`Cappell (1930),
`and pain precluded their clinical use.
`in an extensive study in mice, demonstrated the reticulo-
`endothelial uptake of saccharated iron oxide after intra-
`and its subsequent redistribution.
`venous injection
`Nissim (1947) established that saccharated iron oxide
`Its
`was an effective therapy by the intravenous route.
`disadvantages were lack of stability in plasma, the risk
`of severe and painful inflammatory reactions when
`injected outside a vein, and a moderate incidence of
`toxic reactions (Nissim, 1954; Ross, 1957).
`
`Cappell et al.
`(1954), Baird and Podmore (1954),
`Jennison and Ellis (1954), and Scott and Govan (1954)
`reported favourably on a high-molecular carbohydrate
`iron complex, iron-dextran ("imferon"), suitable for
`intramuscular use.
`This complex has been the subject
`of many clinical and experimental studies. The ease of
`intramuscular administration and the relative freedom
`from general toxic reactions soon made iron-dextran
`the most frequently chosen preparation when parenteral
`iron was indicated.
`Interest in the intravenous route
`declined.
`Iron-dextran has also been given
`intra-
`venously, but, although no large series has been reported,
`it appears that toxic reactions, including anaphylaxis,
`often occur (Callender and Smith, 1954; Ross, 1955;
`MacKenzie and Lawson, 1959; Brit. med. J., 1960b),
`and no investigator has reported with any enthusiasm
`on its intravenous use.
`Richmond (1957, 1959) reported the induction of
`sarcomas by iron-dextran in rats, and his findings were
`confirmed by Haddow and Homing (1960) in mice.
`There has since been a good deal of speculation on how
`far this
`carcinogenic activity for mice and rats
`is
`applicable to man (Brit. med. J., 1960a; Golberg, 1960;
`Haddow, 1960; Duthie et al., 1960). No definite answer
`can be given to this question at present. One result of
`this unexpected finding has been a renewed interest
`in the intravenous administration of parenteral iron.
`The preparation for intravenous use reported here is
`not a new one, although it has not until recently been
`available in this country.
`Andersson (1950), Lucas and
`Hagedorn (1952), and Hagedorn (1952) report on its
`efficacy in iron-deficiency anaemias and its freedom
`from toxic reactions.
`The Preparation.-The preparation used is a dextrin-
`iron known as " astrafer." The manufacturers describe
`the preparation as a high-molecular-weight iron-carbo-
`hydrate complex.
`It contains 20 mg. of iron per ml. in
`isotonic solution, is stable in saline and plasma, and
`has a pH of 7.3. The iron is trivalent. The complex
`differs from iron-dextran in having a lower-molecular-
`weight carbohydrate, dextrin, as the protective carrier
`for colloidal ferric hydroxide.
`
`Methods and Materials
`Iron-dextrin was used as astrafer, iron-dextran as
`"imferon," and saccharated iron oxide as " ferrivenin."
`Haemoglabin is estimated as oxyhaemoglobin, using
`a Unicam SP 300 photoelectric colorimeter. The instru-
`ment is frequently checked by chemically estimated
`blood samples supplied by the M.R.C. and by a glycerin-
`preserved sample of haemoglobin: 14.6 g. Hb per 100
`ml. is referred to as 100% Hb.
`Serum-iron estimations on patients not receiving iron
`complex were made by the method of Kok and Wild
`(1960), but in the presence of iron-carbohydrate com-
`plex a more vigorous hydrolysis is required to liberate
`all bound iron, and the method of Trinder (1956) was
`used.
`Haemolysis is usually measured by the amount of
`haemoglobin freed from red cells, or by the haemo-
`globin content of residual intact red cells. The dark
`colour and viscosity of iron-complex solutions make
`measurement of their haemolytic power by haemoglobin
`methods rather inaccurate and tedious.
`A red-cell-
`counting technique was used, based on the EEL elec-
`tronic
`blood-cell
`counter.
`The greatly
`improved
`
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`
`

`
`280 JULY 29, 1961
`
`IRON-DEFICIENCY ANAEMIA
`
`BRrrSH
`MEDICAL JOURNAL
`
`Rate of Plasma Clearance
`Single Intravenous Dose.-Fig. 1 shows the rate of
`plasma clearance after intravenous injection of 100 mg.
`of iron as iron-carbohydrate complex in four cases of
`iron-deficiency anaemia given iron-dextrin and in three
`Iron-dextrin is rapidly
`similar cases given iron-dextran.
`The rate of fall is of
`cleared from the circulation.
`exponential form, and half the maximum concentration
`is reached in about one hour, with virtually complete
`This is the general form of
`clearance in 24 hours.
`clearance described for saccharated iron oxide. The rate
`of clearance is unrelated to anaemia or to the degree of
`utilization of iron eventually achieved. In contrast, iron-
`dextran is removed rather slowly from the circulation.
`The maximum concentration achieved is maintained for
`periods up to six hours, and about half remains at 24
`Serum-iron levels do not approach pre-injection
`hours.
`levels for about three days. This characteristic has been
`used to estimate plasma volume (MacKenzie and Tindle,
`1959); the rapid clearance of iron-dextrin makes it
`unsuitable for this purpose.
`Multiple Intravenous Doses.-A common pattern of
`treatment in parenteral iron therapy is a daily intra-
`is of interest to observe the
`venous injection, and it
`Figs.
`serum-iron concentrations under these conditions.
`2 and 3 show the serum-iron levels five minutes and one
`hour after intravenous doses of 100 mg. of iron as iron-
`dextrin and as iron-dextran respectively on 10 and 9
`successive occasions. Repeated injections of iron-dextrin
`produced no accumulation of iron in the circulation.
`There was no significant increase in the maximum
`serum-iron levels after each injection, and the rapid
`rate of clearance on each day was maintained as for a
`In the case of iron-dextran a break of three
`single dose.
`days was made between the fourth and fifth injections.
`There is seen a well-defined trend to increasing maxi-
`mum serum-iron values each day, reflecting the persis-
`After
`tence of the circulating complex at 24 hours.
`the 72-hour break between the fourth and fifth injections
`the maximum level fell to its original value, but again
`the trend to increasing plasma concentrations is seen
`on subsequent injections.
`
`Therapeutic Results
`Iron-deficiency Anaenia
`Group 1.
`Twenty-five cases of iron-deficiency anaemia are
`recorded here (23 female, two male), selected for intra-
`
`s~5000
`s.oooX
`A
`
`. 4,000-
`
`0 0
`
`'-3.00 0
`
`2.000-
`
`1,000-I
`
`consistency of red-cell counts attainable by electronic
`counting makes it suitable for measuring haemolytic
`activity of both opaque and coloured fluids which are
`The size of the colloidal iron-complex
`particle-free.
`particle is too small to activate the counting mechanism
`and does not interfere with the red-cell count.
`To 4-ml. volumes of serial dilutions of iron complex
`in saline are added 0.02-ml. volumes of a washed
`After three hours at
`suspension of human red cells.
`room temperature the red-cell count is measured. The
`mean of the counts in four 0.2-c.mm. volumes is taken.
`Thus for an original suspension of 5 million per c.mm.
`The difference in counts
`20,000 cells are counted.
`between iron-complex suspensions and a saline control
`suspension is the measure of haemolysis.
`
`Results
`Haemolytic Activity
`Golberg (1958) calls attention to the in vitro haemo-
`lytic activity of iron complexes as a measure of the
`amount of dissociation of free ferric ions. The presence
`of free ions with consequent saturation of the iron-
`binding capacity is believed to be one cause of toxic
`reactions (Klopper, 1951 ; Librach, 1953). Thus haemo-
`lytic activity may be a useful index of toxicity for these
`complexes.
`Table I shows the haemolytic activity of three iron
`counting
`red-cell
`measured
`by the
`complexes
`as
`technique described above. At the highest concentration
`used the amount of red-cell lysis induced by iron-dextrin
`was only just perceptible and could not be detected by
`methods based on haemoglobin measurements.
`Saccharated iron oxide has the highest haemolytic
`activity; under the conditions tested it is eight to sixteen
`as haemolytic
`iron-dextrin.
`Iron-dextran
`times
`as
`occupies an intermediate position.
`TABLE I.-Haemolytic Activity of Three Iron Complexes
`Concentration of Iron Complex
`(Mg. Fe/100 ml.)
`125
`
`1,000
`
`500
`
`250
`
`62-5
`
`Saline
`Controls
`5 41
`5-29
`5-40
`
`4-95
`..
`..
`Iron-dextrin
`032
`Iron-dextran ..
`..
`Saccharated iron oxide -
`
`5-21
`3-8
`-
`
`5.44
`4-43
`0 01
`
`5.34
`5s.
`0-23
`
`5 48
`5-26
`5 25
`
`Red-cell counts in thousands per 0-2 c.mm. after three hours' exposure to
`varying concentrations of iron complexes in saline. Three saline controls
`show the small variability of the cell count by this method.
`
`3.000-
`
`2,500
`
`2,000
`
`1,500-
`
`1,000-
`
`500'
`
`0
`
`IL
`
`U.L
`
`3'
`
`8 ,
`
`E 2i
`
`2
`
`5
`
`6
`
`24 INJECTION 1 2
`3
`DAY
`
`6
`7
`
`7
`8
`
`8
`9
`
`10
`9
`10 1I
`
`INJECTION
`DAY
`
`2
`2
`
`4
`3
`5
`4
`3
`3
`4
`4
`3
`4 5 6
`HOURS
`FIG. 3
`FIG. 2
`FI(. 1
`Fia. 1.-Plasma clearance of iron complex in four cases of iron-deficiency anaemia given 100 mg. iron intravenously as iron-
`FIG. 2.-Serum-iron levels 5 minutes (white columns) and I hour
`dextrin, and in three cases given same dose of iron-dextran.
`FIG. 3.-Serum-iron levels 5 minutes (white columns)
`(black columns) after 10 intravenous iron-dextrin (100 mg. Fe) injections.
`and 1 hour (black columns) after nine intravenous iron-dextran injections.
`
`5
`7
`
`6
`8
`
`7
`9
`
`9
`11
`
`10
`
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`
`Luitpold Pharmaceuticals, Inc., Ex. 2036, P. 2
`
`

`
`JULY 29, 1961
`
`JULY 29, 1961
`
`IRON-DEFICIENCY ANAEMIA
`
`BRITISH
`MMICAL JOURNAL
`
`MKDIc.:iiTj.HuKNAL
`
`281
`
`281
`
`TABLE III.-Iron-dextrin in Pregnancy Anaemias
`Hb%
`Total Fe
`Given
`Mg.
`Before After ( )Days
`(28i
`65
`77
`720
`(37)
`84
`840
`60
`54
`(42)
`80
`950
`(26)
`65
`840
`80
`(34)
`58
`82
`740
`(63)
`86
`1,040
`54
`(55)
`61
`84
`950
`(17)
`61
`77
`640
`(27)
`58
`77
`440
`(33)
`73
`1,000
`51
`1000
`(92)
`80
`51
`1,140
`(65)
`60
`90
`1,040
`(34)
`58
`75
`(90)
`1,140
`56
`88
`(18)
`58
`71
`640
`(47)
`56
`80
`1,040
`(13)
`65
`77
`740
`(35)
`69
`95*
`1,040
`(28)
`63
`84
`950
`(32)
`1,240
`49
`84
`(28)
`69
`71
`640
`(48)
`58
`1,040
`82
`(46)
`58
`1,040
`80
`(38)
`56
`860
`90*
`(31)
`69
`640
`80
`(22)
`840
`60
`77
`100% Hb= 14-6 g-.100 ml.
`
`No response to oral iron
`folic acid
`
`* Post-partum.
`
`SERUM
`
`17
`
`78
`
`42
`
`66
`
`Fc 0.V./0m
`Fe~~~~~~~~~~.yng .ii .E.
`
`0
`
`2
`
`3
`
`4
`
`6
`
`7
`
`8
`
`9
`
`10
`
`Case
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`26
`
`Age
`
`19
`29
`32
`27
`40
`30
`24
`30
`34
`21
`26
`20
`2 1
`35
`28
`25
`30
`23
`22
`37
`29
`24
`27
`23
`23
`29
`
`venous therapy with a haemoglobin of 66% or less,
`M.C.H.C. 29% or less, and well-marked hypochromia
`in the stained blood film.
`One patient with Hb 68%,
`M.C.H.C. 30%, was included because she had failed to
`respond to oral iron.
`The time of observation was
`sometimes limited by discharge from hospital or failure
`to attend clinics, and the observed responses to treat-
`ment are thus not always maximal.
`The objective chosen was to correct anaemia without
`regard to replacement of iron stores, and the total
`dosage was calculated on the conservative side, so that
`the anticipated haemoglobin response fell short of 100%.
`Intravenous injections of 100 mg. of iron were given
`daily or on alternate days to a total dosage which varied
`from 550 to 1,500 mg.
`Details are shown in Table Il.
`Twenty-four cases showed haematological improve-
`ment. One case of carcinoma of the bronchus failed to
`respond.
`The mean haemoglobin before treatment in these 24
`cases was 51.2% (range 38-68%); after treatment it was
`81.6% (range 65-97%).
`In this group as a whole the utilization of the injected
`iron for haemoglobin synthesis appeared as 1 % increase
`in haemoglobin for every 36 mg. of iron (or 0.4 g. Hb%
`per 100 mg. of iron).
`In the 10 patients observed for
`over 50 days and in whom it could be assumed that the
`maximum response had already occurred, the utilization
`was 1% Hb increase for 33 mg. of iron (or 0.44 g. Hb%
`per 100 mg. of iron).
`The best utilization obtained in an individual case
`was 28 mg. of iron for 1% rise in haemoglobin (0.52 g.
`Hb % per 100 mg. of iron). The response in this case
`is illustrated in Fig. 4.
`
`Group 2. Anaemia of Pregnancy
`Forty-five women with anaemia of pregnancy of less
`than haemoglobin 70% (10.2 g./100 ml.) were treated
`Almost all were out-patients and
`with iron-dextrin.
`included all stages of pregnancy between the twelfth and
`thirty-sixth weeks. Twenty-six are reported here. Those
`TABLE II.-Iron-dextrin in Iron-deficiency Anaemia
`
`Case Sex and
`Age
`
`I
`
`2
`
`F 30
`
`F 72
`
`Total
`
`Fe
`Given
`Mg.
`
`1,200
`
`1,200
`
`'0
`
`58
`
`54
`
`Hb%
`
`M.C.H. C.
`%
`
`Serum
`Ironu.
`100 ml.
`
`p
`
`lo-
`
`93
`
`84
`
`(44)
`
`(54)
`
`27
`
`26
`
`29
`
`28
`
`42
`
`13
`
`26
`
`42
`
`109
`
`61
`
`Remarks
`
`No response to oral iron
`
`Intolerant of oral iron
`Hookworm infestation
`No response to oral iron and
`folic acid
`,.
`
`..
`
`and
`
`70
`
`11
`
`5
`-I
`WEEKS
`Fia. 4.-Woman aged 54 with iron-deficiency anaemia. Haemato-
`logical response to intravenous iron-dextrin given in a divided
`course of 900 mg. and 500 mg. Fe.
`excluded were patients whose course of treatment was
`interrupted by delivery, who received concurrent folic
`acid, or who failed to receive more than 300 mg. of iron.
`Dosage was estimated on the same basis as for group 1,
`although it is realized that the apparent utilization of
`iron for haemoglobin synthesis in pregnancy is lower
`This was consistent
`than in the non-pregnant group.
`with a limited objective of preparing the patient for safe
`delivery, and no attempt was made to achieve the highest
`levels of haemoglobin or to replace diminished iron
`stores or account for foetal needs or loss of blood during
`delivery. No case received more than 1,240 mg. of iron
`as iron-dextrin. An initial dose of 40 mg. of iron in
`2 nil. was given in most cases, followed by daily or
`alternate daily doses of 100 mg. of iron.
`In some cases
`the course of treatment was spread over a longer period,
`depending on the patient's ability to attend. The results
`Of these 26 cases, 25
`are summarized in Table III.
`improvement.
`haematological
`The mean
`showed
`59.3 % (range
`haemoglobin
`before
`treatment
`was
`49-69%); after treatment it was 80.9% (range 71-95%).
`Oral iron had previously failed in 7 of these 26 patients.
`One failed to improve, and the cause of this was not
`It should be noted that the
`subsequently elucidated.
`
`Pulm.tubercu-
`losis
`High gamma-
`
`Menorrhagia
`Haemorrhoids
`Menorrhagia
`haemorrhoids
`
`Varicose ulcers
`Hiatus hernia
`
`Urinaryinfec-
`
`Carcinoma of
`bronchus
`
`Menorrhagia
`
`Carcinoma of
`bladder
`Cholecystitis
`
`3
`4
`5
`6
`
`F 36
`F 55
`F 48
`F 32
`
`7
`F 20
`F 75
`8
`9
`F 61
`10
`F 36
`11 M 73
`
`12
`1 3
`14
`
`F 46
`F 77
`F 73
`
`15
`F 43
`16
`F 67
`17
`F 57
`18
`F 33
`19
`F 34
`20
`F 42
`21
`F 16
`22 M 76
`
`23
`24
`25
`
`F 81
`F 71
`F 54
`
`1,500
`1,000
`1,060
`1,150
`
`1,100
`1,200
`920
`1,200
`800
`
`550
`1,100
`1,100
`
`1,500
`1,100
`1,090
`600
`1,000
`1,200
`1,400
`1,200
`
`1,000
`900
`1,400
`
`42
`58
`51
`54
`
`54
`46
`65
`52
`68
`
`66
`54
`65
`
`43
`54
`43
`50
`52
`52
`42
`41
`
`38
`50
`43
`
`97
`86
`82
`86
`
`78
`70
`82
`82
`86
`
`77
`65
`63
`
`75
`86
`70
`77
`84
`94
`82
`80
`
`80
`71
`92
`
`(112)
`(91)
`(37)
`(21)
`
`23
`25
`24
`24
`
`30
`30
`
`27
`
`34
`
`29
`24
`
`82
`72
`35
`32
`
`(59)
`(21)
`(27)
`(82)
`(74)
`
`(21)
`(24)
`(21)
`(41)
`(46)
`(28)
`(28)
`(42)
`(79)
`(64)
`(31)
`
`(63)
`(31)
`(65)
`
`28
`95
`22
`28
`27
`42 -
`28
`25
`44
`87
`28
`26 - - -
`30
`31
`
`26
`24
`27
`
`23
`24
`23
`27
`27
`23
`21
`21
`
`20
`28
`23
`
`27
`
`6
`
`23
`
`- -
`
`25 - -
`
`29
`30
`
`30
`32
`33
`29
`
`28
`29
`32
`
`15
`
`18
`
`54
`22
`
`10
`
`14
`49
`17
`
`50
`
`-
`
`32
`
`-
`
`92
`34
`
`36
`
`38
`
`70
`
`I-
`
`I 00% Hb=14 6g.'l00 m .
`
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`282 JULY 29, 1961
`
`JULY 29, 1961
`
`282
`
`IRON-DEFICIENCY ANAEMIA
`
`maximum response to treatment was probably not
`cases owing to
`short
`periods
`of
`in
`observed
`all
`observation.
`In this group as a whole, 100 mg. of iron as iron-
`dextrin produced an indrease of 0.35 g. Hb per 100 ml.
`(1 % Hb for 41 mg. of iron).
`Clinical Toxcity
`At Site of Injection.-In a few cases some leakage of
`injected material occurred from the vein which gave rise
`to a minor inflammatory reaction subsiding in 24 to 48
`hours and did not interfere with subsequent injections.
`No thrombophlebitis or pain along the course of the
`vein was observed.
`Reactions.-Among
`General
`non-pregnant
`the
`anaemias there were two mild general reactions.
`The
`first, in a woman aged 34 who had already received 11
`ml. of iron-dextrin in three days, consisted of a feeling
`of skin heat and flushing, accompanied by slight nausea
`which abated in three minutes. The second, in a woman
`aged 42, began an hour after the first 5-ml. dose.
`She
`complained of a cramping pain over the left loin, accom-
`panied by slight nausea and a taste in the mouth. The
`pain was not severe and lasted about two hours. The
`following day 2.5 ml. produced a little immediate skin-
`flushing, but the next three injections were uneventful.
`The fifth dose gave a similar reaction to the first, and,
`although the symptoms were mild, intravenous therapy
`was discontinued.
`There were no general reactions of any kind among
`the 45 pregnant women treated with iron-dextrin.
`Discu9sion
`The characteristics of iron-dextrin are in several ways
`intermediate to those of the saccharated oxide and iron-
`Its neutral reaction, pH 7.3, may be compared
`dextran.
`with the strongly alkaline saccharated oxide, pH 9, and
`the mildly acid iron-dextran, pH 6.2. The low degree
`of ionic release resulting from the firm union of colloidal
`ferric hydroxide and its carbohydrate carrier
`is a
`property it shares with the dextran. On the other hand,
`it resembles the saccharated oxide in its rapid plasma-
`clearance.
`
`Utilization
`The evaluation of utilization of iron for haemoglobin
`synthesis should be based on measurements of total red-
`cell mass rather than on haemoglobin concentration.
`Individual variation in normal total red-cell mass, and
`the change in the ratio of plasma to red-cell volume in
`iron-deficiency anaemia, make assessment of utilization
`based on haemoglobin concentration only an approxi-
`mate guide.
`In the adult with a blood volume of 5 litres and
`haemoglobin concentration 15 g. /100 ml., the circulating
`red-cell mass contains 2.5 g. of iron. Thus 25 mg. of
`iron is contained in 1% of the total haemoglobin.
`Nissim (1947) and Slack and Wilkinson (1949) obtained
`this order of utilization for saccharated oxide in iron-
`deficiency anaemia. Brown et al. (1950) obtained values
`varying from 0.33 to 0.5 g. Hb % per 100 mg. of iron.
`The mean utilization of iron as iron-dextrin in the non-
`pregnant cases reported here, as measured by the
`increase in haemoglobin concentration, was 0.44 g. Hb
`% per 100 mg. of iron (1% haemoglobin increase for
`33 mg. of iron).
`plasma
`the
`increase
`in
`volume
`pregnancy
`In
`diminishes the apparent utilization of iron for haemo-
`globin synthesis.
`In the pregnant group reported here,
`
`BRaIH
`MEDICAL JOURNAL
`100 mg. of iron as iron-dextrin gave a mean increase of
`0.35 g. Hb per 100 ml. (41 mg. of iron for 1 % haemo-
`globin), which compares with an increase of 0.3 g. Hb
`% reported by Scott and Govan (1951) and 0.44 g. Hb %
`by Klopper and Ventura (1951) for the saccharated
`oxide.
`
`Toxicity
`Comparison of the clinical toxicity of iron complexes
`as described in various trials is often vitiated by the
`varied selection of cases and dose schedules. A useful
`baseline, however, is
`the
`extensive survey of one
`preparation by Ross (1957), who analysed the toxic
`reactions in 779 patients receiving saccharated iron
`oxide (ferrivenin) in 100-mg. doses.
`He found an
`overall incidence of toxic reactions in 7.5% of cases;
`344 pregnancy anaemias provided the lowest incidence
`of 5%. Of all case series published, perhaps the most
`comparable groups are the iron-deficiency pregnancy
`anaemias.
`In the present series, using the same 100-mg.
`dose, no general reactions occurred among the 45 cases
`of pregnancy anaemia treated, and it would appear that
`iron-dextrin compares favourably in this respect with
`saccharated iron oxide.
`The two general reactions
`among the non-pregnant iron-deficiency anaemias were
`mild, and support the conclusion from the pregnancy
`series that iron-dextrin is a complex of low clinical
`toxicity.
`It is unlikely that a single property of iron complexes
`can be made to account for all the toxic manifestations
`of different preparations.
`Instability of the complex in
`plasma with possible in vivo precipitation, the amount
`and rate of ionic iron release in vivo with consequent
`saturation of iron-binding capacity, antigenic power, the
`rate of reticulo-endothelial uptake and release, and the
`variability of molecular size in the preparation are
`probably all factors operative in varying degrees. A
`compound with, for instance, a relatively low release of
`ionic iron into the circulation, could have this advan-
`tageous feature offset by a slow plasma clearance.
`Two characteristics with inplications for toxicity have
`been investigated here: the in vitro haemolytic action
`and the plasma clearance rate. The negligible haemo-
`lytic power of iron-dextrin, indicating little ionic release,
`combined with its rapid plasma clearance which is main-
`tained on repeated injections, are possible explanations
`of the low incidence of clinical toxicity.
`
`Indications
`of simple iron-deficiency anaemias
`The majority
`respond as well to oral iron as to parenteral treatment.
`The mucosal block theory (Granick, 1949) led to the
`belief that, once anaemia has been corrected, replace-
`stores by oral
`administration was
`iron
`ment of
`inadequate.
`This theory is now in doubt.
`It has been
`shown, for instance (Pirzio-Biroli and Finch, 1960), that
`in normal subjects whose iron stores have been depleted
`by repeated phlebotomy, but whose haemoglobin, serum
`iron, and ir6n-binding capacity have remained in the
`normal range, absorption of labelled iron from the
`intestinal tract, measured at intervals over a period of
`two years, was of the same order, 19%, as in established
`iron-deficiency
`anaemias.
`This compared with an
`absorption of only 3 % in normal subjects given a
`Clearly neither anaemia nor
`parenteral iron load.
`intestinal
`directly
`controls
`serum-iron
`concentration
`absorption and there is no need to doubt that iron stores
`are replaceable by oral iron, given over a sufficient
`period of time.
`
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`

`
`JULY 29, 1961
`
`IRON-DEFICIENCY ANAEMIA
`
`BPSH
`MEDICAL JOURNAL
`
`283
`
`is an
`indicated
`iron
`When properly
`parenteral
`irreplaceable remedy, but it should be reserved for cases
`Such
`of iron deficiency in which oral iron has failed.
`failure may be the result of poor intestinal tolerance,
`to malabsorption, or to the patient's inability to sustain
`There are also
`oral treatment for an adequate time.
`situations, such as late pregnancy, in which the efficiency
`of intestinal absorption is in doubt and time does not
`permit an adequate trial of oral therapy, when parenteral
`iron may be justified.
`
`Intravenous or Intramuscular?
`The intramuscular route for parenteral iron has
`obvious practical advantages in ease of administration,
`and while general toxic reactions to intramuscular iron-
`dextran are known, they appear to be uncommon.
`Of greater importance are two observations which are
`Firstly, the relatively high propor-
`perhaps connected.
`tion of iron remaining at the site of injection, and there-
`fore not available for haemoglobin synthesis, variously
`estimated at from 10 to 20% of the injected dose.
`Secondly, the carcinogenic action demonstrated in mice
`and rats presents at the moment an unknown hazard for
`man. In experiments still in progress I have so far found
`one sarcoma at the site of injection after six months of
`weekly iron-dextrin by subcutaneous injection in mice.
`It is likely, therefore, that iron-dextrin will prove to be
`of the same order of carcinogenicity as iron-dextran in
`experimental animals, and thus does not commend itself
`to intramuscular use.
`The intravenous route has the merit of encouraging
`careful attention to the indications for parenteral iron.
`In the presence of iron deficiency, the high utilization
`for haemoglobin synthesis ensures that no undue excess
`of iron is deposited at any site. The main disadvantages
`have been the risk of severe local inflammation and
`reactions which seem to have been
`general
`toxic
`minimized with iron-dextrin at the 100-mg. dose level.
`Summary
`The response to treatment with intravenous iron-
`dextrin in 51 cases of iron-deficiency anaemias, includ-
`ing 26 in pregnancy, is described. A satisfactory
`haematological response was obtained in 49 of these
`cases, with a mean utilization of iron for haemoglobin
`synthesis in the non-pregnant group of 0.44 g. Hb %
`per 100 mg. of iron (1 % Hb increase for 33 mg. of iron).
`In the pregnant group, apparent utilization was 0.33 g.
`Hb % per 100 mg. of iron (I % Hb increase for 41 mg.
`of iron).
`With doses of 100 mg. of iron clinical toxicity was
`infrequent and mild in degree. There was no instance
`of thrombophlebitis or pain along the vein used for
`injection. No general reactions occurred among the
`pregnancy anaemias.
`Indications for, and the administration of, parenteral
`iron are discussed.
`My thanks are due to my colleagues at Paddington
`General Hospital for their co-operation.
`The iron-dextrin
`(astrafer) was kindly supplied by Astra-Hewlett Ltd.
`REFERENCES
`Andersson, N. S. E. (1950). Acta med. scand., Suppl. 241.
`Baird, 1. M., and Podmore, D. A. (1954). Lancet, 2, 942.
`Brit. med. J., 1960a, 1, 788.
`1960b, 2, 406.
`Brown E. B., Moore, C. V., Reynafarje, C., and Smith, D. E.
`J. Amer. med. Ass., 144, 1084.
`(1905).
`Brownlee, G., Bainbridge, H. W., and Thorp, R. H. (1942).
`Quart. J. Pharm., 15, 148.
`
`D
`
`Callender, S. T., and Smith, M. D. (1954). Brit. med. J.. 2, 1487.
`Cappell, D. F. (1930). J. Bact. Path., 33, 175.
`-Hutchison, H. E., Hendry, E. B., and Conway, H. (1954).
`Brit. med. J., 2, 1255.
`Duthie, J. J. R., Girdwood, R. H., Hubble, D., Macgregor, A. G.,
`Wayne, E. J., Wilson, A., and Wilson, G. M. (1960). Lancet,
`2, 155.
`Friend, D. G. (1938). New Engl. J. Med., 219, 910.
`Golberg, L. (1958). In Iron in Clinical Medicine, p. 77, edited by
`R. 0. Wallerstein and S. R. Mettier. Univ. California Press,
`Berkeley.
`(1960). Brit. med. J., 1, 958.
`BIll. N.Y. Acad. Med., 25, 403.
`Granick, S. (1949).
`Brit. med. J., 1, 1734.
`il.'idow, A. (1960).
`and Horning, E. S. (1960). J. nat. Cancer itnst., 24, 109.
`Hagedorn, A. B. (1952). Proc. Mayo Clin., 27, 277.
`Jennison, R. F., and Ellis, H. R. (1954). Lancet, 2, 1245.
`Ibid., 1, 531.
`Klopper, A. (1951).
`and Ventura, S. (1951). Brit. med. J., 2, 1251.
`Kok, D'A., and Wild, F. (1960). J. clin. Path., 13, 241.
`Librach, I. M. (1953). Brit. med. J., 1, 21.
`Lucas, J. h., and Hagedorn, A. B. (1952). Blood, 7, 358.
`MacKenzie, A., and Lawson, I. R. (1959). Lancet, 2, 462.
`Ibid., 1, 333.
`- and Tindle, J. (1959).
`Ibid., 2, 49.
`Nissim, J. A. (1947,.
`(1954). Brit. med. J., 1, 352.
`J. Lab. clin. Med.,
`Pirzio-Biroli, G., and Finch, C, A. (1960).
`55, 216.
`J. clin. Invest., 16,
`Reznikoff, P., and Goebel, W. F. (1937).
`547.
`Scot. med. J., 2, 169.
`Richmond, H. G. (1957).
`Brit. med. J., 1, 947.
`(1959).
`Ross, 1. P. (1955). Luaicet, 1, 51.
`- (1957). Ibid., 2, 77.
`Scott, J. M., and Govan, A. D. T. (1951). Ibid., 1, 367.
`Brit. med. J., 2, 1257.
`- - (1954).
`Slack, H. G. B., and W'ilkinson, J. F. (1949). Lancet, 1, 11.
`Tnnder, P. (1956). J. clin. Path., 9, 170.
`
`CYCLOPHOSPHAMtDE IN ADVANCED
`BREAST CANCER
`A CLINICAL AND HAEMATOLOGICAL
`APPRAISAL
`BY
`BASIL A. STOLL, F.F.R., M.R.C.S.
`AND
`JAMES H. MATAR, M.B., B.S.
`Peter MacCallumt Clinic, Melbourne, Australia
`Nitrogen mustard was introduced into the treatment
`of cancer in 1946, and its derivatives and al'ied com-
`pounds, the alkylating agents, still maintain a leading
`Their effect on the cell
`place in cancer chemotherapy.
`is both cytotoxic and nucleotoxic, vital enzymes in the
`The cytostatic
`synthesis of protein being blocked.
`activity of these compounds is probably due to the
`reactivity of the chloroethyl group attached to the
`nitrogen atom, and most of them are associated with
`high toxicity in the body.
`In the development of these compounds, attempts
`have been made to widen the toxic-therapeutic ratio,
`basic compound have
`the
`of
`modifications
`and
`decreased the toxicity. Thus in nitrogen mustard oxide
`(" nitromin ") and mannomustine (" degranol ") there is
`a delayed activity of the functional group, and therefore
`a lower toxicity. The concomitant therapeutic results
`are, however, not outstanding. The ethylenimine com-
`pounds-for example, tretamine (triethylene melamine),
`the
`thiophosphoramide)
`and
`(triethylene
`thiotepa
`ethylene-iminoquinone (E.39)-are very active cytotoxic
`all
`agents but are at the same time very toxic to
`Watson and Turner
`elements of haemopoietic tissue.
`(1959) suggested a possible modification of thiotepa
`toxicity by concomitant administration of androgens.
`
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