`
`Tolerability of intramuscular injections of testosterone
`ester in oil vehicle
`
`Mary-Anne Mackey, Ann ,].Conway and
`David J.Handelsman‘
`
`Andrology Unit, Royal Prince Alfred Hospital, and Department of
`Medicine and Department of Obstetrics and Gynecology, University
`of Sydney, Sydney NSW 2006 Australia
`
`‘To whom correspondence should be addressed at: Andrology Unit,
`Suite 312C, RPA Medical Centre, I00 Carillon Avenue, Newtown
`NSW 2042, Australia
`
`We undertook a prospective survey of the tolerability of
`deep i.m. injections of testosterone enanthate in a castor oil
`vehicle, the most widely used form of androgen replacement
`therapy. Over a period of 8 months, 26 men received 551
`weekly injections into the gluteal, deltoid or thigh muscle
`and side-effects were recorded immediately and 1 week
`after each injection by the same nurse using a standardized
`questionnaire. Most injections caused no complaints [389/
`551, 70.6% (95% confidence interval 66.6—74.4%)] but
`minor local side-effects, mostly pain and bleeding, were
`common [162/551, 29.4% (25.6—33.4%)]; no serious side-
`effects were observed. Considering all side-effects,
`the
`gluteal site had fewer complaints and was less prone to
`bleeding but was painful more often than deltoid or thigh
`injection sites. The laterality of injection at any site had
`no significant effect on side-effects. The only systemic side-
`effect was episodes of sudden-onset, non-productive cough
`associated with faintness following eight injections [1.5%
`(0.6—2.9%)] which we speculate may have been due to
`pulmonary oil microembolism. We conclude that, when
`administered by an experienced nurse, deep i.m. injection
`of testosterone enanthate in a castor oil vehicle is generally
`safe and well tolerated but causes relatively frequent minor
`side-effects,
`including pain and bleeding. An improved
`depot form of testosterone would be highly desirable
`for androgen replacement therapy and hormonal male
`contraception.
`
`Key words: androgen replacement therapy/intramuscular injec-
`tion/laterality/side-effects/testosterone
`
`Introduction
`
`Testosterone has been used clinically in androgen replacement
`therapy for over 50 years (Nieschlag and Behre, 1990). Over
`the past few decades the most frequent mode of administering
`testosterone has been deep i.m. injections of testosterone esters
`in a vegetable oil vehicle. Despite this long usage, no systematic
`studies of side-effects
`from oil—based i.m.
`injections of
`
`862
`
`testosterone esters could be located after extensive computer-
`based and manual library searching. The opportunity to study
`systematically the tolerability of these injections and the pattern
`of side-effects was provided by an ongoing male contraceptive
`study requiring healthy men to have weekly i.m. injections of
`testosterone enanthate in castor oil vehicle administered by
`the same research nurse for up to 18 months. The aims of this
`study were to estimate prospectively the pattern and incidence
`of side-effects of oil-based, deep i.m. injections in nonnal men
`and to detennine whether anatomical site and/or laterality of
`injection influences the incidence of these side-effects.
`
`Materials and methods
`
`Study design
`
`This was a prospective survey of adverse effects from i.m.
`injections of oil—based testosterone enanthate. The injections
`were given during a World Health Organization (WHO)
`contraceptive efficacy study of a prototype hormonal male
`contraceptive and the design and results of that study have
`been described in detail elsewhere (WHO Task Force on
`Methods for the Regulation of Male Fertility, 1990). Injections
`were given and side-effects recorded by the same right-handed
`research nurse (M.A.M.) both immediately following and 1
`week after
`injection using a standard questionnaire. The
`questionnaire recorded date, site and side of injection as
`well as eliciting specific responses to potential side-effects,
`including pain or stinging, bleeding or bruising, swelling,
`numbness, muscle twitch, erythema, faintness, coughing. For
`reported symptoms,
`the duration,
`severity and degree of
`interference with daily living was recorded. For the analysis,
`the categories of pain and bleeding included both immediate
`and delayed reports. The criterion for recognition of pain was
`the subject’s response to the question ‘Was that
`injection
`painful?’ and was applied and recorded consistently for each
`subject.
`
`Subjects and injections
`
`Men involved in this study were 26 healthy males aged
`between 21 and 45 years recruited from the general population
`to participate in a multicentre male contraceptive study (WHO
`Task Force on Methods for the Regulation of Male Fertility,
`1990). Entry criteria were that men had to be healthy,
`in a
`stable relationship and requiring contraception. Volunteers
`were required to have their injection administered by the study
`nurse (M.A.M.) on the same day (: 1 day) each week for up
`to 18 months. The vials of testosterone enanthate (250 mg in
`
`© Oxford University Press
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`|nnoPharma Exhibit 10680001
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`
`1 ml castor oil, Testoviron Depot; Schering AG, Berlin,
`Germany) were kept at air-conditioned room temperature and
`injections of 200 mg (0.8 ml) were administered with a 21
`gauge (0.8OX38 mm) needle into one of three muscular sites:
`the anatomical site of the injection (gluteal, deltoid, thigh) was
`chosen by the subjects and injections were routinely alternated
`from side to side. Deep i.m. injections were given according
`to standard methods, including aspirating the syringe to exclude
`vascular puncture before injection and injecting slowly.
`
`Data analysis
`
`Data were cross—tabu1ated and analysed by appropriate methods
`for categorical data using BMDP software (BMDP Statistical
`Software Inc., Los Angeles, CA, USA) implemented on a
`VAX computer network. Power was estimated using Poisson
`confidence intervals (Gardner and Altman, 1989) and PASS
`software (Hintze, 1991).
`
`Results
`
`During 8 months, 602 scheduled injections were given without
`any injections missed and complete information was available
`after 551 (92%) injections. The remainder were accounted for
`by injections administered when men were out of Sydney for
`work or holidays. During this period, only two out of 26 men
`changed their preferred site of injection.
`Most injections caused no complaints [389/551, 70.6% (95%
`confidence interval, 66.6—74.4%)] and any adverse effects were
`recorded after only 162/551 [29.4% (25.6—33.4%)] injections.
`There were no significant differences in rate of complaints of
`side—effects according to laterality of injection for gluteal [left
`19/68 (27.9%) versus right 27/151 (17.9%)], thigh [left 17/51
`(33.3%) versus right 27/85 (3l.8%)] and deltoid [left 49/114
`(43.0%) versus right 29/82 (35.4%)]. The overall pooled
`(Mante1-Haenszel) relative risk was 1.40 [95% (confidence
`interval 0.95-2.06), test for homogeneity of risk across strata
`P = 0.61].
`Considering all adverse effects (Table 1), the total number
`of complaints was significantly higher for deltoid [2.0 (1.5-
`2.8)] and thigh [1.6 (1.1—2.3)] than for gluteal sites of injection.
`Considering specific adverse effects, gluteal injections caused
`more complaints of pain [relative risk 2.4 (1.3—4.3)] and fewer
`of bleeding [O.l6 (0.08—0.32)] compared with the other two
`sites combined (Table 1). Immediate bleeding was minor in all
`cases, requiring only light topical pressure for a few minutes
`or was recorded in retrospect as minor bloodspot staining of
`
`Table I. Side-effects of i.m. injections
`
`Side—effect Deltoid
`
`Thigh
`
`Gluteal
`
`Total
`
`P
`
`Nil
`Bleeding
`Pain
`Muscle
`twitch
`Cough :
`faint
`Other
`Total
`
`119 (61%)
`49 (25%)
`13 (7%)
`10 (5%)
`
`94 (69%)
`27 (20%)
`5 (4%)
`5 (4%)
`
`176 (80%)
`8 (4%)
`23 (11%)
`7 (3%)
`
`389 (70.6%) <0.001
`84 (15.3%) <0.001
`41 (7.4%)
`0.050
`22 (4%)
`0.598
`
`4 (2%)
`
`3 (2%)
`
`2 (1%)
`
`9 (1.6%)
`
`0.552
`
`2(1%)
`1 (1%)
`196 (100%) 36 (100%)
`
`6(1.1%)
`3(1%)
`219 (100%) 551 (100%)
`
`0.621
`
`Testosterone tolerability and intramuscular injections
`
`clothing or slight bruising. Pain was usually not sufficient to
`require analgesia; at worst, discomfort was present for several
`days on sitting or lying on the injection site. There were no
`reports of local erythema or acute inflammatory reactions
`following injections. Apart
`from coughing episodes,
`all
`reported reactions were considered by volunteers and investig-
`ators as minor; none ceased injections due to such side—effects
`during the study.
`The only systemic side—effect was coughing fits observed
`immediately after eight
`injections [prevalence 1.5% (0.6-
`2.9%)], associated with faintness and sweating on one occasion.
`On another occasion, faintness and sweating occurred without
`coughing. Two characteristic cases are described. In the first,
`a 25 year old man without known asthma or allergies developed
`an intense, non—productive cough without wheeze immediately
`after having received 21 previous i.m.
`injections into the
`gluteal muscle uneventfully. He also developed an injection
`site reaction after withdrawal of the injection needle which
`required him to remain recumbent until the coughing subsided
`(5 min). After this episode he had six further weekly injections
`without recurrence or complaint before he discontinued from
`the study to initiate a planned pregnancy. In the second, a 35
`year old man without known asthma or allergies and having
`received 24 injections into the deltoid muscle, including one
`previous similar episode, developed an intense non—productive
`cough with associated pallor, nausea and chest tightness but
`no wheeze or injection site reaction which gradually subsided
`after 10 min. He subsequently had another 35 injections into
`the gluteal muscle without experiencing further such episodes.
`The power of this study was >50, >80 and >90% to detect
`(one-sided, ct = 0.05) events with underlying prevalence of
`1.3, 1.7 and 2.0% respectively. Conversely in order to detect
`events with a prevalence of 1.0% with 80% power, a sample
`size of 4000 observations would have been required. For
`adverse effects not observed in this study,
`the upper 95%
`(Poisson) confidence limit was 0.67%.
`
`Discussion
`
`Depot fonnulations are widely used to enhance therapeutic
`compliance and convenience by prolonging the duration of
`drug action. Among the most widely used depot formulations
`are drug esters administered in an oil vehicle. Esterification of
`base drugs with appropriate lipophilic fatty acids fonns a pro-
`drug ester whose hydrophobic side—chains partition preferen-
`tially into the oil vehicle. Prolongation of pro-drug release is
`provided by the rate-limiting retarded diffusion of the pro-
`drug ester into the extracellular fluid where ubiquitous non-
`specific esterases hydrolyse the ester bond to liberate active
`drug.
`In addition to fonning a hydrophobic depot,
`the oil
`vehicle limits local chemical irritation and cytotoxicity caused
`by some drugs (Svendsen and Blom, 1984). This oil—based
`formulation has been widely and successfully used for sex
`steroids including androgens, oestrogens and progestins as
`well as psychotrophic drugs such as fiuphenazine, haloperidol
`and related major tranquilizers (Gilman et al., 1990). Oils
`derived from vegetable sources such as castor or sesame seeds
`863
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`|nnoPharma Exhibit 10680002
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`M.A.Mackey et at.
`
`or peanuts (Arachis) have been widely used whereas mineral
`oils are too irritating (Symmers, 1955).
`Testosterone esters in an oil vehicle have been for decades the
`
`most widely used modality of delivering androgen replacement
`therapy in male hypogonadism (Behre et al., 1990). Despite
`this long usage, or perhaps because of it, there have been few
`systematic studies of tolerability of i.m. administration of
`testosterone esters in oil—based formulations. The general
`pharmacology of i.m.
`injections has been reviewed (Schou,
`1971; Greenblatt and Koch-Weser, 1976; Zuidema et al., 1988)
`but most studies concern aqueous formulations of drugs
`administered to hospitalized patients. For example, the only
`large survey of i.m. injections reported adverse local effects
`in only 0.4% of 12134 hospitalized patients receiving i.m.
`injections of drugs in aqueous formulations (Greenblatt and
`Allen, 1978). No comparable surveys in ambulatory care
`settings or involving oil-based steroid ester formulations are
`available to our knowledge.
`Overall, while nearly 30% of our subjects had some com-
`plaints, they were considered by patients and investigators as
`minor in nature and serious adverse effects were not observed.
`
`lowest for the
`Satisfaction was greatest for the gluteal site,
`deltoid, with the thigh being intermediate. Discrepancies in
`patterns of pain and bleeding accounted for these differences.
`The level of recorded complaints may be conservative as
`determined among highly motivated volunteers agreeing to
`participate in a prolonged study requiring weekly i.m. injection
`for up to 18 months. Administration by less expert staff or by
`se1f—injection may lead more frequently to dissatisfaction.
`Furthennore, the tolerance of discomfort among hypogonadal
`men requiring life—long androgen replacement therapy or fertile
`men considering hormonal male contraception among other
`family planning methods may be lower. Although the sites of
`injection were not
`randomized but were selected by the
`subjects, it is unlikely that this significantly biased the out-
`comes, unless men predisposed to complain of side-effects
`were systematically more likely to choose a particular injection
`site, which seems unlikely. Although this survey included
`nearly 550 injections,
`it could provide reliable estimates for
`only relatively common (>2%) side-effects. The frequency of
`rare side-effects, especially those not observed during the
`survey period, could not be reliably estimated. For example,
`the power of this survey was adequate (>80%) for events
`with a true underlying rate of occurrence of 21.7%, but would
`need to include more than seven times as many injections to
`detect events with a 1.0% prevalence.
`The lower risk of minor bleeding at the gluteal injection
`site may be attributed to its lower blood flow (Evans et al.,
`1975) as well as the fact that most gluteal i.m. injections are
`actually intralipomatous (Cockshott et al., 1982) and adipose
`tissue blood flow is even lower than muscle. Conversely, the
`reason for the higher rate of discomfort following gluteal
`injections is unclear and conflicts with experimental observa-
`tions that intralipomatous injection causes less local toxicity
`than i.m.
`injection of irritant psychoactive drugs in rabbits
`(Svendsen et al., 1985). The precise cause of injection pain
`remains unclear (Travell, 1955), although presumably local
`cytotoxicity due to insertion of the injection needle as well as
`
`864
`
`its vehicle and their local
`the chemical nature of the drug,
`metabolites are relevant factors. Possibly the functional signi-
`ficance of various anatomical sites may also influence injection
`pain. For example, extrinsic pressure on the injection site may
`be more common after gluteal injections (e.g. during sleeping
`or sitting) than for other sites.
`including
`More serious local
`injection site side—effects,
`sciatic nerve damage, muscular fibrosis, gas gangrene, and
`distal
`ischaemia following intra-arterial
`injection were not
`observed in this survey, consistent with their rarity among
`adults. We also observed no evidence of either acute or chronic
`
`inflammatory reactions which have been reported rarely to
`cause lipogranulomas and/or pseudotumour foreign body reac-
`tions (Symmers, 1955; Balogh, 1986; Hamann et al., 1990;
`Khankhanian and Hammers, 1992) causing diagnostic confu-
`sion and serious clinical consequences. As inflammatory reac-
`tions have been reported following subdermal
`injections of
`vegetable oils alone (Brown et al., 1944) or containing non-
`steroidal drug esters (Hamann et al., 1990) while aqueous
`suspensions of testosterone esters are non—irritating (Behre and
`Nieschlag, 1992), the side-effects observed in this study are
`most likely to be attributable to the oil vehicle rather than the
`testosterone ester. As the present survey had sufficient power
`to exclude non-observed events with an underlying frequency
`of at
`least 2%,
`this figure provides an upper limit for the
`likelihood of such reactions which were not observed during
`our study.
`The only systemic side-effect observed was coughing reac-
`tions consisting of sudden-onset, non—productive coughing
`with or without faintness which was observed on eight occa-
`sions giving a prevalence of 1.5% [95% (confidence interval
`0.6-2.9%)]. Although disturbing to subjects, the coughing was
`transient, lasting for 10 min at most and subsided spontaneously
`without known sequelae. Acute drug—related respiratory distress
`not due to bronchospasm or laryngopulmonary oedema is rare
`but has been described after i.m. administration of an oil-
`
`based solution of pitressin tannate (Hoigne et al., 1990). The
`sudden onset of coughing without wheeze or injection site
`reaction together with a history of uneventful injections before
`and after the episodes suggests an idiosyncratic, mechanical
`phenomenon related to a particular injection. Neither allergy
`to testosterone enanthate or the castor oil vehicle have been
`
`reported and would seem clinically unlikely given the isolated
`occurrence of the events and speed of onset. We speculate that
`these respiratory reactions may be due to pulmonary oil
`microembolization following lymphogenic (Svendsen et al.,
`1980) or venous absorption of oil
`(Svendsen and Aaes-
`Jorgensen, 1979), leading to transient acute pulmonary hyper-
`tension possibly related to mechanical vascular occlusion and/
`or intravascular liberation of free fatty acids from hydrolysis
`of the oil (Hofmann et al., 1976; Szabo et al., 1977). Clinically
`significant pulmonary manifestations of oil embolism have
`been reported following injection of 2.5 ml oil reaching the
`bloodstream (Bron et al., 1963; Gough and Thomas, 1964).
`The relatively mild clinical manifestations observed with our
`smaller injection volume (0.8 ml) are consistent with this
`mechanism. An alternative, albeit unlikely, explanation that
`cannot be fully excluded is that
`intralipomatous injection
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`|nnoPharma Exhibit 10680003
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`may rarely provoke embolism of cellular fragments such as
`adipocyte lipids. The low frequency and mild clinical features
`observed do not require any major change in current standard
`clinical practice but suggest caution when injecting larger
`volumes of oil i.m. Apart from the recent addition of warnings
`concerning the occurrence of ‘coughing fits, urge to cough and
`respiratory distress’ to the product information for testosterone
`enanthate, such side—effects do not appear to have been reported
`previously.
`We conclude that deep i.m. injections of testosterone enan—
`thate in castor oil vehicle are generally safe and reasonably
`tolerated when administered by a single experienced research
`nurse. Minor side—effects, mainly pain and bleeding, are
`relatively common but serious side—effects are rare. The
`anatomical site, but not
`laterality, of injections influences
`tolerance, as the gluteal site has fewer overall side—effects and
`is less prone to bleeding but more liable to pain than the
`deltoid or thigh sites. Coughing reactions, not previously
`reported but observed after 1.5% of injections, we speculate
`may be due to pulmonary oil microembolization. As our
`observations reflect the properties of an oil vehicle, similar
`findings would be expected with other similarly formulated
`drugs. These findings highlight
`the need for better depot
`testosterone formulations for patients requiring life—long andro-
`gen replacement therapy, as well as for future regimens for
`hormonal male contraception.
`
`Acknowledgements
`The authors are grateful to the Task Force for Methods of Regulation
`of Male Fertility of the World Health Organization’s Human Reproduc-
`tion Programme for supporting this study and to Schering AG (Berlin)
`for generous supply of testosterone enanthate.
`
`References
`
`(1986) The histologic appearance of corticosteroid
`Balogh, K.
`injection sites. Arch. Pathol. Lab. Med., 110, 1168-1172.
`Behre, H.M. and Nieschlag, E. (1992) Testosterone buciclate (20
`Aet—l)
`in
`hypogonadal
`men:
`phannacokinetics
`and
`pharmacodynamics of the new long-acting androgen ester. J. Clin.
`Endocrinol. Metab., 75, 1204-1210.
`Behre, H.M., Oberpenning, F. and Nieschlag, E. (1990) Comparative
`pharmacokinetics of androgen preparations: application of computer
`analysis and simulation. In Nieschlag, E. and Behre, H.M. (eds),
`Testosterone: Action Deficiency Substitution. Springer-Verlag,
`Berlin, pp. 115-135.
`Bron, K.N., Baum, S. and Abrams, H.L. (1963) Oil embolism in
`lymphography.
`Incidence, manifestations,
`and mechanisms.
`Radiology, 80, 194-202.
`Brown, W., Wilder, V. and Schwartz, P. (1944) A study of oils used
`for intramuscular injections. 1. lab. Clin. Med., 29, 259-264.
`Cockshott, W.P., Thompson, G.T., Howlett, LJ. and Seeley, E.T.
`(I982) Intramuscular or intralipomatous injections? N. Engl. J.
`Med., 307, 356-358.
`and
`J.
`J.D., Fratkin, M..l., Velandia,
`Evans, E.F., Proctor,
`Wassennan, A.J. (1975) Blood flow in muscle groups and drug
`absorption. Clin. Pharm. Then. 17, 44-47.
`(1989) Statistics with
`Gardner, M.J. and Altman, D.G.
`(eds)
`Confidence: Confidence Intervals and Statistical Guidelines. British
`Medical Journal, London.
`
`Gilman, A.G., Rall, T.W., Nies, A.S. and Taylor, P. (eds) (1990)
`
`Testosterone tolerability and intramuscular injections
`
`of
`
`The Pharmacological Basis
`and Gilman’s
`Goodman
`Therapeutics. Pergamon Press, New York.
`Gough, J.H. and Thomas, M.L.
`(1964) Pulmonary complications
`following lymphography. Br J. Radial., 37, 416-421.
`Greenblatt, D.J. and Allen, M.D. (1978) Intramuscular injection-site
`complications. J. Am. Med. Assoc., 240, 542-544.
`Greenblatt, D.J. and Koch-Weser, J. (1976) Intramuscular injection
`of drugs. N. Engl. J. Med., 295, 542-546.
`Hamann, G.L., Egan, T.M., Wells, B.G. and Grimmig, J.E. (1990)
`Injection site reactions after
`intramuscular administration of
`haloperidol decanoate 100 mg/ml. J. Clin. Psychiatry, 51, 502-504.
`Hintze, J.L. (1991) NCSS: Power Analysis and Sample Size version
`1.0. Published by J. L. Hintze, Kaysville, USA, pp. 143-149.
`Hofmann, K., Brunner, P. and Tulusan, A.H. (1976) Abbau oliger
`substanzen in der kaninchenlunge. Wrchows Arch., Abt. A, Path.,
`Anat. Histol., 369, 347-358.
`Hoigne, R., Jaeger, M.D., Hess, T., Wymann, R., Muller, U.,
`Galeazzi, R., Maibach, R. and Kunzi, U.P. (1990) Acute severe
`dyspnea as a side effect of drugs. Report
`from the CHDM
`(Comprehensive Hospital Drug Monitoring). Schweiz. Med.
`Wochenschr, 120, 1211-1216.
`Khankhanian, N.K. and Hammers, Y.A. (1992) Exuberant local tissue
`reaction to intramuscular injection of nandrolone decanoate (Deca-
`Durabolin) - a steroid compound in sesame seed oil base -
`mimicking soft tissue malignant tumors: a case report and review
`of the literature. Mil. Med., 157, 670-674.
`Nieschlag, E. and Behre, H.M. (eds) (1990) Testosterone: Action
`Deficiency Substitution. Springer-Verlag, Berlin.
`Schou, J. (1971) Subcutaneous and intramuscular injection of drugs.
`In Brodie, B.B., Gillette, J.R. and Ackennan, H.S. (eds), Concepts
`in Biochemical Pharmacology. Springer-Verlag, Berlin, pp. 47-66.
`Svendsen, O. and Aaes-Jorgensen, T. (1979) Studies on the fate of
`vegetable oil after
`intramuscular
`injection into experimental
`animals. Acta Pharmacol. Toxicol., 45, 352-378.
`Svendsen, O. and Blom, L. (1984) Intramuscular injection and muscle
`damage: effects of concentration, volume,
`injection speed and
`vehicle. Arch. Toxicol., Suppl. 7, 472-475.
`Svendsen, 0., Dencker, S.J., Fog, R., Gravem, A.O. and Kristansen, P.
`(1980) Microscopic evidence of lymphogenic absorption of oil in
`humans
`receiving neuroleptic oily depot preparations
`intra-
`muscularly. Acta Pharmacol. Toxicol., 47, 157.
`Svendsen, 0., Blom, L., Aaes-Jorgensen, T. and Larsen, JJ. (1985)
`Local
`toxicity
`of different
`drugs
`after
`intramuscular
`or
`intralipomatous injection in pigs: serum concentrations after three
`different
`formulations of cis(Z)-clopenthixol. Acta Pharmacol.
`Toxicol., 57, 78-87.
`Symmers, W.
`(1955) Simulation of cancer by oil granuloma of
`therapeutic origin. Br. Med. J., 2, 1536-1539.
`Szabo, G., Magyar, Z. and Reffy, A. (1977) The role of free fatty
`acids in pulmonary fat embolism. Inj., Br: J. Accident Surg., 8,
`278-283.
`
`Travel], 1. (1955) Factors affecting pain of injection. J. Am. Med.
`Assoc., 158, 368-371.
`WHO Task Force on Methods for the Regulation of Male Fertility
`(1990) Contraceptive efficacy of testosterone-induced azoospermia
`in normal men. Lancet, 336, 955-959.
`(1988)
`Zuidema, J., Pieters, F.A..l.M. and Duchateau, G.S.M.J.E.
`Release and absorption rate aspects of intramuscularly injected
`pharmaceuticals. Int. J. Pharmaceutics, 47, 1-12.
`
`Received on August II, 1994; accepted on January 25, I995
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