JULY 29, 1961
`
`NEW INTRAMUSCULAR HAEMATINIC
`
`BRMSH
`MEDICAL JOURNAL
`
`275
`
`transferrin.
`About 30% of the dose of iron given is
`excreted with the urine (Fig. 1) (Lindvall and Andersson,
`1961).
`It has no antigenic properties; LD50 for the
`mice is about 35 mg./kg. body weight (Svard, 1961).
`This value may seem low in comparison with other
`parenteral iron preparations, but the margin between the
`clinical dose of about 1.5 mg./kg. and a toxic one is
`nevertheless fully adequate.
`Administration.-The preparations here called iron-
`sorbitol and iron-dextran respectively were injected
`deeply into the gluteal region in a dose corresponding
`to 100 mg. Fe. The injections were made daily, on
`alternate sides.
`Every course of treatment comprised
`10 injections.
`Before the clinical trials started, the
`tolerance for iron-sorbitol was tested by giving
`10
`subjects increasing amounts of this preparation.
`As
`no side-effects were observed in these experiments the
`full therapeutic dose was given without a preceding
`test dose.
`
`Material
`The series comprised 65 patients who satisfied the
`clinical criteria for stabilized iron deficiency.
`In the
`order in which the patients came in for treatment, every
`second case was selected for iron-dextran treatment
`while the others were given iron-sorbitol. Twelve cases
`in the iron-dextran group and 21 in the iron-sorbitol
`group received the treatment in the out-patient depart-
`ment and the others were treated in hospital.
`The sex-and-age distribution in the groups is shown
`in Table I. As may be seen, the groups were equivalent
`in these respects, and women were in the majority.
`Table II presents the distribution of the material with
`respect to the diagnosis. As the material included cases
`
`U.[B.C. and
`n serum
`
`n serum
`
`C
`0-5-
`-1004#
`
`X _0
`1- o.2 0a..-
`
`a 0
`
`Renal
`excretion
`U BC>.
`
`CLINICAL INVESTIGATIONS ON A
`NEW INTRAMUSCULAR HAEMATINIC
`BY
`NILS S. E. ANDERSSON, M.D.
`From the Medical Department, Centrallasarettet, Danderyd,
`Sweden
`
`According to Brown and Moore (1956) there are three
`clear indications for parenteral iron therapy: (1) hypo-
`patients unable to
`tolerate or
`chromic anaemia in
`unwilling to take adequate doses of iron orally; (2)
`hypochromic anaemia in patients unable to absorb
`adequate amounts of orally administered iron; and (3)
`patients who need their
`hypochromic anaemia in
`haemoglobin
`bringing
`rapidly
`to normal but
`for
`whom transfusions are undesirable or unsuitable.
`After the appearance of saccharated oxide of iron
`(Nissim, 1947) and a preparation containing a special
`ferridextrin complex in colloidal form (Agner et al.,
`1948; Andersson, 1950) the intravenous method of
`therapy was that most commonly used; of the two
`preparations,
`the latter can also be injected
`intra-
`muscularly (Andersson and Bergstrom, 1956).
`The intramuscular method of administration has,
`however, been increasingly applied since Fletcher and
`London (1954) produced their iron-dextran complex;
`this preparation, whose clinical properties, after intra-
`muscular injection, were studied by Baird and Podmore
`(1954) and others, has been found to give very good
`therapeutic results.
`Certain side-effects after the use
`of solutions containing this complex have, however, been
`reported (Karlefors and Norddn, 1958;
`and others).
`It has also been found that,
`when given to laboratory animals in high
`total amount for a prolonged period of
`time, the iron-dextran complex produces
`sarcoma at the site of injection (Rich-
`mond, 1959, 1960; Haddow and Horning,
`1960).
`A new iron preparation, " jectofer,"
`intended for intramuscular injection, has
`recently been presented by Lindvall and
`Andersson (1961).
`The present paper
`describes clinical
`studies on its thera-
`peutic effect and on the side-effects it
`produces.
`The previously
`mentioned
`iron-dextran preparation, " imferon," was
`used for purposes of comparison.
`
`600
`
`500
`
`d
`
`E 0
`
`1
`
`0E
`
`.a
`a 0
`
`0I
`:Li
`
`Properties of Jectofer
`The iron in this preparation is present
`in the form of a sterile solution of an
`iron-sorbitol-citric-acid
`complex
`with
`dextrin as a stabilizer. The solution con-
`tains 50 mg. Fe/ml. and has a pH of 7.5.
`It is stable in serum; it does not cause
`haemolysis
`affect
`and does
`the
`not
`clotting mechanism.
`Absorption after
`intramuscular
`injection
`takes
`place
`rapidly-two-thirds of a dose injected
`into a rabbit is absorbed within three
`hours and 80-85%
`after
`hours.
`12
`Absorption is followed by a rapid rise in
`the iron concentration of serum. A small
`part of the preparation is bound to the
`
`2
`
`3
`
`4
`6
`5
`Hours after injection
`iron-binding
`capacity
`in serum, unsaturated
`FIG. 1.-Iron concentration
`(U.I.B.C.), sum of iron concentration in serum and unsaturated iron-binding
`capacity (five healthy subjects, whose level of total iron-binding capacity-
`T.I.B.C.-is shown), and renal excretion (nine healthy subjects). Mean values
`after intramuscular injections of a dose of 100 mg. Fe.
`
`7
`
`8
`8
`
`9
`9
`
`1
`10
`
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`

`
`276
`
`JULY 29, 1961
`
`NEW INTRAMUSCULAR HAEMATINIC
`
`BRInISH
`MEDICAL JOURNAL
`for both preparations most pronounced in the patients
`showing the lowest initial values for the haemoglobin
`content (Table IV).
`For the group with an initial value of HbS,8 g./100
`ml. blood the Hb increase is given for every case in
`Table V.
`The group treated with iron-sorbitol con-
`sisted of six women and one man; three of the women
`had their menstruation during the observation period.
`The iron-dextran group comprised three women and
`four men; one of the women in this group had her
`menstruation during the observation period. The Hb
`value 7, 14, 21, and 35 days after inception of treatment
`is shown and it is seen that the increase ran parallel in
`both groups; after five weeks it was 3.8 g. /100 ml.
`blood in the iron-sorbitol group and 3.9 g./100 ml. in
`the iron-dextran group.
`The mean serum-iron value
`before treatment was 17 ,ug. /100 ml. blood for the iron-
`sorbitol group and 23 pg./100 ml. for those given iron-
`dextran; after treatment the values were 21 and 37
`jug. /100 ml. blood, respectively.
`Table VI presents the results of treatment of patients
`with a pretreatment Hb level of 8.1-12 g./100 ml. and of
`> 12.1 g./lO0 ml. blood.
`There was no difference in
`TABLE IV.-Maximum Reticulocyte Response per 1,000. Number
`of Cases in Parentheses
`
`Preparation
`
`Iron-sorbitol
`Iron-dextran
`
`..
`..
`
`Hb Value in g./l100 ml. Blood
`8-1-12
`66 (19)
`60 (13)
`
`>_ 12.1
`46 (7)
`37 (6)
`
`< 8
`106 (5)
`91 (7)
`
`TABLE V.-Patients with Hb Value s 8 g./100 ml. Blood Treated
`with Iron-sorbitol or Iron-dextran
`
`Sex
`
`Before
`
`F
`F
`F
`F
`F
`M
`F
`Mean value
`Increase from
`initial value
`
`F
`F
`F
`M
`M
`M
`M
`Mean value
`Increase from
`initial value..
`
`5-4
`6-0
`6-2
`6-8
`7.0
`7-6
`7-8
`6-7
`
`-
`
`5-0
`6-0
`7-6
`7-8
`8-0
`8-0
`8-0
`7-2
`
`-
`
`Hb Value in g./100 ml. Blood
`Days from Start of Treatment
`I
`14
`7
`21
`Iron-sorbitol
`6-5
`7-6
`8-1
`8-3
`7-6
`9-2
`9-0
`8-0
`
`8-7
`8-9
`9-6
`10-3
`8-8
`9-8
`10-0
`9-4
`
`8-8
`9-3
`10-5
`11-4
`9.8
`10-0
`10-3
`10-0
`
`1 3
`Iron-dextran
`6-2
`6-0
`9-2
`8-7
`9-2
`9-3
`9-0
`8-2
`
`1-0
`
`2 7
`
`7-8
`7-6
`10-6
`10-0
`9-7
`10-3
`10-3
`9 5
`
`2-3
`
`3- 3
`
`8-5
`9-0
`11-2
`11*2
`10-8
`10-8
`11-4
`10-4
`
`3-2
`
`35
`
`9-2
`9.4
`11-2
`11-4
`10-3
`10-3
`11-4
`10-5
`
`3-8
`
`1
`1
`9-7
`10-8
`11-4
`12-8
`11-8
`11-4
`
`11-1
`
`3-9
`
`TABLE VI.-Increase in Hb Value in the Group with Pretreatment
`Hb Level 8.1-12 g. and > 12.1 g./ 100 ml. Blood
`
`Mean Value of Hb in
`g.'I00 ml. Blood
`
`Seru-n Iron,
`,ug. 100 ml.
`
`Preparation
`
`Hb No. of
`Range Cases Before
`Treat-
`ment
`
`8.1 12423
`Iron-sorbitol
`Iron-dextran f
`16
`. _
`Iron-sorbitol
`>121 f 9
`Iron-dextran 4~ VLl
`
`10-2
`10-2
`12-9
`13-1
`
`increase after Start
`of Treatment
`
`14
`7
`35
`21
`Days Days Days Days
`0-6
`2-3
`1-2
`1-6
`0-6
`1-5
`2-5
`1-1
`1-7
`1-0
`
`Incre5ayse
`Be
`35 Das
`fore
`After
`Treat- Start of
`ment Treat-
`ment
`34
`46
`37
`55
`
`28
`29
`44
`44
`
`showing a wide diversity in the degree of anaemia, it
`was divided into three subgroups (Table III) with a view
`to facilitating assessment of the therapeutic effect.
`In order to obtain a better idea of the degree of
`utilization of the administered iron for the haemoglobin
`synthesis the total dosage given was slightly on the small
`In all cases with anaemia the dosage given-
`side.
`1,000 mg. Fe-was not sufficient to restore the Hb
`TABLE I.-Age-and-sex Distribution of 65 Patients Treated
`
`______________
`
`Preparation
`
`Sex
`
`Age
`
`(Years)
`31-45
`46-60
`
`0-30
`
`Over 60
`
`Iron-sorbitol { Females
`Iron-dextran { Females
`Males
`
`11
`
`5
`2
`
`7
`
`6
`1
`
`8
`
`8
`5
`
`1
`
`3
`1
`
`Total
`
`} 34
`
`} 31
`4
`
`TABLE II.-Clinical Diagnoses
`Iron-
`sorbitol
`
`Iron-
`dextran
`
`Acquired haemolytic anaemia (sequel of
`splenectomy)
`Sideropenia ..
`Menometrorrhagia ..
`Duodenal and gastric ulcer
`Sequel of ventricular resection (B II)
`Ulcerative colitis
`..
`Polyposis of rectum
`.
`Diaphragmatic hernia with melaena
`TABLE III.-Distribution of Cases According to Pre-treatment
`Hb Value
`
`9
`12
`
`7 3
`
`.
`
`Preparation
`
`Iron-sorbitol
`Iron-dextran
`
`.7
`
`Hb Value in g./100 ml. Blood
`8 !81-12
`23
`16
`
`<8
`7
`
`121
`9
`11
`
`concentration to normal and to fill the body's iron
`depots. When the increase in Hb was thought to
`have ceased, eight patients who were still anaemic
`were given a further series of 10 injections of the same
`preparation as they had received before; hence the total
`courses of treatment amounted to 73.
`
`Clinical Methods
`The Hb and erythrocyte values were determined
`twice a week during treatment and subsequently once
`a week for at least four weeks.
`In the first 57 patients
`a daily reticulocyte count was made for 10 to 14 days.
`All these analyses were carried out by the same
`The serum-iron level was determined by
`assistant.*
`Agner's (1947) method before and 35 days after the start
`of treatment.
`The sedimentation rate, urinary sediment, and non-
`protein nitrogen were investigated in all patients, and the
`liver status was followed by bilirubin determinations,
`thymol turbidity tests, Takata-Ara tests, and determina-
`tions of the alkaline phosphatase.
`In some of the cases
`function was studied by means of an
`renal
`the
`endogenous creatinine-clearance test.
`
`Results
`Therapeutic Effect
`The therapeutic effect was assessed from the reticulo-
`cyte response and the increase obtained in the Hb and
`serum-iron values. The rise in the reticulocyte count,
`which for both preparations reached its maximum six
`to eight days after the start of therapy with a less-
`marked peak in
`the reticulocyte response than is
`observed in the treatment of pernicious anaemia, was
`*The analyses were made by Mrs. Kerstin Brumark, to whom
`I am greatly indebted.
`
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`

`
`JULY 29, 1961
`
`NEW INTRAMUSCULAR HAEMATINIC
`
`INTRAMUSCULAR HAEMATINIC
`
`277
`
`BRriTsH
`MEDICAL JOURNAL
`described as being similar to the reaction following an
`In no
`intramuscular vitamin or penicillin injection.
`case was the discomfort severe enough to warrant dis-
`In two of the patients
`continuation of the treatment.
`TABLE VII.-Renal Excretion of Iront in a Female Patient with
`Impaired Renal Function. Endogenous Creatinine-clearance
`Intramuscular
`N.P.N. 60 mg./100 ml. Blood.
`17 ml./min.
`in a Dose Corresponding to
`Iron-sorbitol
`Injection
`of
`50 mg. Fe
`
`Renal Excretion (%)
`Hours After Injection
`6-9
`3-6
`
`4-2
`
`1.9
`
`9-24
`2-1
`
`Total
`
`11-3
`
`0-2
`3 1
`
`the tenderness persisted for about a week after conclu-
`sion of the treatment. With the injection technique used
`no discoloration of the skin was observed.
`In one patient treated with iron-dextran a temperature
`rise to 38.2° C. was noted after the tenth injection.
`the
`Another patient, not included in
`evaluation,
`therapeutic
`refused
`to
`undergo further treatment on account
`of severe pain at the injection site in
`with a general
`feeling
`of
`association
`illness and a temperature rise to around
`Besides these two patients, a
`38° C.
`six who received iron-dextran
`further
`complained of pain around the site of
`injection; two of them took to their beds
`for a couple of days with highly inflamed,
`tender buttocks and thighs. No local
`discoloration of the skin was, however,
`the iron-dextran injec-
`observed after
`tions.
`
`therapeutic effect between the two preparations, as the
`increase in haemoglobin was the same for both. The
`in the serum-iron concentration recorded after
`rise
`treatment was also similar for both preparations. Some
`illustrative cases from the treatment are seen in Figs.
`2-5.
`
`Side-effects
`No general reactions in the form of temperature
`elevation, headache, nausea, vomiting, or chills were
`observed after the injection of iron-sorbitol in doses
`Some of the patients
`100 mg. Fe.
`equivalent
`to
`reported, however, that at a meal about one hour after
`the injection their normal sense of taste was affected;
`this reaction had disappeared completely after about 12
`hours.
`In five cases treated with iron-sorbitol a mild local
`reaction at the injection site, in the form of a feeling of
`distension with moderate tenderness to palpation, arose
`The sensation was
`immediately after the injection.
`
`RBC
`milL
`
`Hb
`gms
`
`Retic.
`
`5,0-
`
`15,0
`
`10,0-
`
`4,01 12,01 8,0-
`
`R.E
`
`3,01 9,01 6,0-
`
`2,0] 6,0] 4,0-
`
`/Retic.
`
`1,o0
`
`3,0]
`
`2,0
`
`Effect on Renal Function
`As already mentioned, about 30% of
`the iron is excreted with the urine after
`There was
`an injection of iron-sorbitol.
`no disturbance of the urinary sediment
`or increase in the non-protein nitrogen
`The urinary
`in any of the patients.
`sediment was normal also at the time
`when the iron excretion was at its maxi-
`mum and when the urine was somewhat
`function
`darkened.
`renal
`was
`The
`in an
`observed in about 10 patients
`creatinine-clearance
`endogenous
`test
`before
`and
`after
`the
`treatment; no
`+ +changes were demonstrated.
`Two patients with greatly impaired
`renal function were also studied. They
`were given gradually increasing doses,
`terminating in the one case with a dose
`of iron nine times and in the other case
`six times the 100-mg. dose.
`The first
`patient had a non-protein nitrogen level
`of 57 mg./00 ml. blood and a filtration
`of 10 ml./ min. before the treatment. The
`values were the same after the treatment.
`In the other patient the filtration value
`was 17 ml./min. both before and after
`nitrogen
`The non-protein
`treatment.
`was 60 mg./100 ml. blood before and
`after treatment;
`47 mg./100 ml.
`the
`sediment showed no changes. The urine
`patient was collected
`from the latter
`to
`d
`e24 hor su
`e
`s
`during the 24 hours subsequent to the
`
`6o
`Days
`-Woman aged 46 with abnormally profuse menstruation but in other
`respects normal.
`!etic.
`RBC Hb Ri
`%
`mill gms
`0,0-
`
`,Jectofer
`00100mg.x 0o
`o,oJ o,oI
`6
`
`12
`
`t8
`
`24
`
`30
`
`36
`
`42
`
`48
`
`54
`
`Fio. 2.-
`
`5,0o ]s,o 1
`
`8,0
`
`,Rs.c
`
`o-
`_-+
`
`/ +
`
`3.0-
`
`2,01
`
`1,0O
`
`6,0-
`
`40-
`
`2,0
`
`Hb+
`
`/
`
`\
`
`Retic,
`
`n-ju,u
`
`u,v
`
`Imferon
`0,0 1l00mg.x10 I
`12
`6
`
`18
`
`24
`
`30
`
`36
`
`42
`
`48
`
`54
`
`60
`Days
`-Man aged 68 with anaemia after a gastric haemorrhage (duodenal
`FIG. 3.-
`No other features of interest obtained from the clinical examination
`ulcer).
`or laboratory tests.
`
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`
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`
`JULY 29, 1961
`
`NEW INTRAMUSCULAR HAEMATINIC
`
`BR1TISH
`MEDICAL JOURNAL
`
`injection of a dose corresponding to 50 mg. of iron.
`The result is shown in Table VII. As may be seen, the
`patient excreted only 11.3% of the amount given, while
`healthy subjects excrete about 30% of this dose as well.
`
`mg. Fe, while only 100 mg. Fe was given in the present
`series.
`Systemic side-effects were also reported by these
`authors, but the incidence of such cannot be ascertained
`from their case reports.
`In the material with iron-
`dextran described in the present paper, 4 out of 32
`patients had severe side-effects and a further four
`complained of considerable discomfort after the treat-
`ment; hence the total incidence of side-effects amounted
`to about 25%.
`When iron-sorbitol was used, I noted neither systemic
`side-effects nor local discoloration.
`Local reactions
`in
`the form of
`feeling
`distension
`of
`occurred
`a
`in 5 of the 34 cases treated, or approximately 15%. A
`few patients also reported a transient effect on the taste.
`This ran approximately parallel to the absorption of the
`preparation as reflected in the increase of the iron
`concentration in serum.
`Recently there has been much discussion regarding
`the possible risk of a carcinogenic action of iron-dextran,
`since a high incidence of sarcoma was demonstrated in
`
`RmBC Hb Retic.
`%
`15,0- 10,0-
`
`5,0
`
`4,0-
`
`3,0
`
`2,0
`
`1,0
`
`5,0- 15,0- 10,0-
`
`3,0-
`
`2,0
`
`6,)-
`
`1,0
`
`3,0-
`
`0.0'I
`
`Imferon
`|100 mg.x 10
`6
`
`12
`
`.I
`18
`
`24
`
`I
`
`30
`
`36
`
`42
`
`48
`
`54
`
`60
`Oays
`FIG. 5.-Man aged 73 with polyposis of the rectum. No other pathological
`features noted in laboratory tests or on clinical examination.
`
`Discussion
`Treatment or iron-deficiency anaemia by intravenous
`therapy gave, according to Nissim (1949) and Andersson
`(1950), a rise in the Hb level of 0.64 g./100 ml. blood per
`100 mg. Fe; this corresponds to 100% utilization.
`Baird and Podmore (1954) stated
`that an intra-
`muscular injection of iron-dextran in a dose correspond-
`ing to 100 mg. Fe produced a rise in the Hb level of
`0.24 to 0.48 g./100 ml. blood (mean value 0.34). The
`results achieved with iron-dextran in this investigation
`fall within the values mentioned by Baird and Podmore,
`and in the group with the most advanced anaemia the
`increase was on an average 0.39 g. Hb per 100 ml.
`blood.
`With iron-sorbitol an increase of 0.38 g. /100
`ml. blood was obtained.
`Using the same
`basis for calculation as that applied by
`Nissim and by Andersson, the values
`obtained are equivalent to approximately
`60% utilization.
`In the groups with a pretreatment Hb
`level of 8.1-12 g./100 ml. blood the
`utilization of the two preparations was
`the same, or, applying the aforemen-
`tioned calculation basis, 36% for the iron-
`sorbitol and 39% for the iron-dextran
`group; in the patients with an initial Hb
`level of over 12 g. /100 ml. blood the
`corresponding figures were 27% and 16%
`for iron-sorbitol and iron-dextran, respec-
`tively. The lower utilization percentage
`in the last-named group is due to the fact
`that in a large number of these cases the
`Hb value had been normalized, and it
`must therefore
`be assumed that
`the
`excess was present as depot iron. Hence
`the clinical investigation has shown that
`in
`the
`iron-deficiency
`of
`treatment
`anaemia iron-sorbitol
`gives
`the same
`good therapeutic results as iron-dextran,
`despite the fact that 30% of the injected
`iron is excreted with the urine.
`As approximately 60% of the iron given
`in the form of iron-sorbitol had been
`Hb-synthesis
`utilized
`the
`for
`in
`the
`patients
`highest
`with
`degree
`the
`of
`anaemia, about 90%of the dose admini-
`stered could thus be accounted for. For
`iron-dextran
`about
`60%
`could
`be
`accounted for; this may be explained by
`the fact that a large amount may remain
`in the muscle.
`Grimes and Hutt (1957),
`for instance, when using preparations
`marked with 59Fe, found that 17-45%
`remained at the site of injection, and
`Karlefors and Norden (1958) reached a
`similar conclusion.
`The latter authors
`noted discoloration of the skin in 25%
`of their patients
`after treatment with
`iron-dextran;
`complications
`such
`no
`were observed in the present material.
`The explanation of this may be that
`Karlefors and Norddn gave doses of 250
`
`O. of
`V,
`
`O. 0J,
`.V,
`
`.
`
`Jectofer
`lOOmg.x 10
`O_LI
`6
`12
`
`18
`
`--
`
`24
`
`.
`
`30
`
`..I
`36
`42
`
`48
`
`54
`
`60
`Days
`FIG. 4.-Woman aged 68 with hyperten sion of several years' standing. Severe
`attacks of haemorrhage from the nose in 1958. Now she had anaemia after
`a gastric haemorrhage (duodenal ulcer). No other observations of interest.
`RBC H b Retic.
`mill.gms %
`
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`
`Luitpold Pharmaceuticals, Inc., Ex. 2044, P. 4
`
`

`
`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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