E15b
`
`Rel‘:rm:it Rapart‘:
`
`Resunre
`
`0B.lEC'l'lI-‘: Preciset lea paraunetres do Ia pentmifivlline at the sea
`rrvétnbolitcs suivétnt l'atlrrtinisIraI.ioo or:tle (bid et tid} do doses multiples
`cltcz des patients présentant Imc dysfonctiort ténale.
`v ~
`nevus r.xvsttmm~rr.au. srtmo on L-noon: Etude ouverte. n=.ndotni.~aée. en
`cltnssé-croisd ct aver; groupes pttralleles. lénlisée (fans on centre do
`recherche cliniquc.
`rwt't:Invrs: Les volontaircs out etc regroupés on function de la valeur de
`leur clairance it la créatzinine (Cl,,) cstzimée 9 parts‘: d‘ une collecte
`urinairo do 24 henrcs: groupe I= CI... 2- ED l'nlJt't'tJ'n (n = 9): gmupt‘. [I =
`CI“ 30-80 ml.J1nln{tl = 6); et groupe III = CL, c 30 ntumin {:1 = 10).
`Mttrncnt-3: La pentoxifylllnt‘: a été admittistrtie 3 raison dc #00 mg bid
`on tirl lesjouts 1 it 7 es 400 mg rid on bid les jonrs 14 3 20 avec tine
`période de retrait do T jours. Des prises de sang ont Eté effectuécs aux
`joms 1, 2-‘, at '30. has échanrillrms sanguins out are analyses quant it {cur
`conteuu en pentoxifylline et en metabolites de la pentoxifylline [M-l ,
`M—IV. et M—V} 1Jflt’<:ltn}n‘t.=ttogr'apl1ie liquids on phase ga.-reuse.
`M.‘B5L‘fl.ES on L‘EF'l:‘F.'}': Ies valeurs do Cm, rm, C*‘!,,,.,,. et SSC... on: ere
`déterminées. L‘o.nalysc de variance. le test de L et ul regression linéuire
`not été utilisés avec un valeur do p < 0.05.
`
`RESULTMS: Les tappotts SSE“ (tiI.l}:SSC,,] (bid) pour la pcnt0:tit'ylIinc ct
`SEC“. {bid at lid) pour M-I ne se sont pas avérés significativernent
`différents entre les groupcs (p > 0.5). Des differences significativcs out
`cependnnt été observes.-: en ce: qni cctncemc la Cm do M-TV et M-V, la
`SSCR1, la C"°,,...,, et les rapports SSE?” (M—IVrpeutor.iFyl|.i1rel cotre {es
`grottpes {p < 0.05). Una modification do In posologie cle lid it hit}. .1
`prodtlit des Chnttgentents sigttificatifi an niveau de la C“‘,.,,,, tle M~I\I' cl
`M—V chez les individus ayant une fonction rénalt: nonnale on unc
`dysfunction rénale ntodérée Innis pus chcz lcs intiivitlus ttyant urlc
`dysfunction ténnle grave.
`CONCLLBEONS: La dysfonct-ion rénalc n’ent:tainc pas d’accumui:tt:ion
`sigrtificative dc pentoxifyllinc ou de MJ aprcs !'adminisI:ration bid at titl
`de doses multiples. Cependant. les metabolites M-W et M-V
`s‘accumulcnt de facon sig-nificmive lots d‘insuffisance rénale. Une
`modification de la posologie (400 mg bid si insuffisnrioe rénaie rnuclrirée
`et 200 A 400 mg qd si insuffisancc rénale grave) et un monitt:-mge
`clinique étroit nont recomrrlandés ct r.e,jusqu‘a cc qnc lee interactions
`phnrmacologiqucs complexes entre la pentoxifylline et scs métaboliles
`soicnt miemt tléfinies.
`
`!\.l.-FLEN MARCO'l'|'P.
`
`General Medicine
`
`This material ma
`cupyrzgm law mljebe "meted by
`
`PAIN ASSESSMENT OF SUBCUTANEOUS JNJECTIONS
`
`Jan 'l‘Jtargensen, Janna Rornsing, Mette Rasmussen, Jam Muller-Sonnergaa.t'd,
`Lisbeth Vang, and Lise Musaeue
`
`0BJ'EC11'VE:T0 compare injection pain after subcutaneous
`aclministration of four different solution volumes.
`
`DESIGN: Double-blind, rr‘.lJ'lLlO1't1l1tLt‘.(.l. prospective. multiple crossover
`study.
`st-rrrnvo: Steno Diabetes Centre, Cientofto. Denmark.
`
`t-‘Alt'l1(.'li'a\Nni: Eighteen healthy voltmteers, 9 women and 9 men,
`aged 21-30 yettrs.
`METIIODS: The stllzjocts were injected with four different volumes
`(0.2, 0.5, 1.0, 1.5 ml.) ofN:tCl 0.9%. The study was performed on 2
`days with a 1-week washout period between the study days. On
`each study day the stthjccts received four injections in each thigh.
`To evaluate Ibe validity of our pain assessing modtil the subjects
`received eight injections of 0.5 mL on one of the study days. Pain
`
`Jun T Jstrgcnt-ten PM), Research l-‘ell-ow. Depintment of Phnnvtacoutics. The Ruyat
`Danish School of Fharnracy, Copenliagort, Denmark
`Jnnne Itornsltlg PIID, Assistant Professor, l}eyn1ttIIt:nt of Plirumnceoties. The Roy-
`al Danish School of Pharmacy. Copenhagen
`Melt: Rasmussen PhD. Associate Professor. Department nl"PlIn.rmt1oeulics,The
`Royal Danish School of Phttrmney. llniversitetsparlten 1. DK-?.|lII] Copen-
`l'IiIfl|:l|. Denmark. FAX +4535]? 1211'
`Jtlrn Muller-Sonnerguard PhD. Associate Professor. Department afkhnnnaeeutics.
`The Royal Dustitilt School of Pharruocy. Copenhagen!
`Lixhelh Vang RN, Sluno Diabetes Centre. Gents:-flc. Denmark
`Lise Mnsmns RN, Diretzlur of Nursing. Stcuo l)i.:tIJe!.es Centre. Ccnlnftn
`Reprints: Metre Rasmussen PhD
`The study was snpponed by None Nordisk NS. Gentoftc. Denmark.
`
`assessment was done ittmtetiiately after each injection: using both a
`10-cm visual analog scale (VASJ and a six-item verbal rating scale
`(VRS).
`lt.I£Sl.ll..‘1'S: A significant differcixce in pain score on both the VAS [p <
`0.05) and the VRS (p <0.0l) was seen between the four injection
`volumes. The pain was significantly irtcreosed with volumes of L0
`and L5 rnL. No sigrttficant difference in injection pain could be
`detected hetweett 0.2 ant] 0.5 ml. and l'IEt\Tv'6EtI [,0 and L5 tnlu. No
`sigrtific-ant period or carryover effect could be detected in the study.
`A sigrtiftcant correlation between the pain score on the VAS and the
`pain score on the VRS was found (r = (J39. p < 0.0001).
`CUNCLEISIDVS: The pain of a .\‘.tll.)t:ul:tnt-.'(Jt.It; injetzlion is related to
`injection volume in the thigh. The results show that iiicieusing the
`volume from 0.5 to [.0 ml. increases the pain significantly. The
`findings from this study should be considered when injection
`prepartttiotts for subcutnrteous tttlrn.irtist:t':1Iiun are fonnttlntetl. The
`volume should generally be less than 1.0 ml. if injected into the
`thigh.
`
`Arm Pininnacorher l95'6'.3fl:'l'29—32.'
`
`tt~r}'EC1'ION PAIN Is A PROt1I,t?.M for tnany patients in relation
`to the daily 3tll2ICl2Ia1l6EI_t.l.S adnLinisn‘ation of different medi-
`cations, such as insulin and growth hormone. The pain in-
`duced by a subcutaneous in;'ection depends on several fac-
`
`The Annals ofPhz2m:aC0ther'apy
`
`I
`
`1996 July/A ngnst Volnnre 30 I
`l
`
`729
`
`
`
`Page 1 of 4
`
`ANTARES Exhibit 1005
`
`Page 1 of 4
`
`ANTARES Exhibit 1005
`
`

`
`tors, such as choice of preservative in the solution,‘ needle
`size (grtuge).’ type of needle insertion,’ and injection site.‘~5
`Other factors, such as the pH and the osmolality of a solu-
`tion, may also contribute to injection pain.
`The volume of the solution may also have an influence
`on injection pain.” Only one previous sntdy’ has focused
`on this subject. In that study. five different volumes of in-
`sulin which ranged from 0.025 to 0.5 ml. were compared.
`No significant differences in pain perception were seen be
`tween these volumes. For comparison of injection pain. a
`21—cm visual analog scale {VAS) was used,’ which is less
`reliable than a 10- or 15-em VAS.“
`The purpose of our study was to compare the injection
`pain of subcutaneous administration of four different vol-
`umes ranging from 0.2 to 1.5 mL. For measurement of the
`injection pain, a 10-cm standard VAS and a 6-item verbal
`rating scale (VRS) were used.
`
`Merhorls
`
`SUBJECTS
`
`Eighteen healthy volunteers (9 women. 9 men). if-30 years Old
`(mean 25.2), weighing between 51.8 and 95.6 kg (mean ’r'3.l) were in-
`cluded in the study. Based on weight and heiglit. the body ntass index
`(BMI) was calculated according to the formula [(body weight in kito~
`grams} + {height in n.".eters)‘}."l'hc ISM} ranged frortt 19.4 £9279 lrgfttd
`(mean 23.5). The subjects were instructed not to trike any analgesics or
`cortsuttte any alcohol during the 43 hours prior to the study. lleforu outi-
`tttion the protocol was approved by the Regional Ethics Cornrnittee, and
`written infomted consent was obtained from each subject.
`
`PROTOCOL
`
`This was 3. double-lztlintl. rartdolrlized. multiple crossover Study. in
`which the injection pain of four different volumes (0.2. 0.5. L0. {.5 ml.)
`ofNaC1 0.9% was compared. The syringes were covered with opaque
`tape The injections were given subcutaneously by two diabetes nurses
`using a coeventiond 2—mL disposable syringe mounted with a 27-gauge
`needle (Neolus Terurno, 27 G x Ti.-'3"). For each subject all injections
`were given by the same nurse. The study was done on '2 days with «it 1-
`wcek washout period between the study days. On ench study (lay the
`subjects received four injections in each thigh (Figtue l). Both the lateral
`and the medial positions were used. For each thigh. two injections were
`
`given proxirnaliy and two distally. According to the rarirlonuzation code.
`each of the four volume-s was given once proximally and once distally.
`On each of the two study days the subjects received either 0.5 ml. in all
`eight injection sites, or four different injection volumes twice — once
`distally and once proxirrtally. The assessment of the injection pain was
`done irrmtcdiutely after each injection using both fl l|J—cnt VAS and a
`si:t—itctn VR3. Tire VRS was categorized as follows: no pain. mild pain.
`moderate pain. severe pain. very severe pain. and worst possible pron.
`'l'he extremes on the VAS were no pain and worst possible pain.
`The VAS and the VRS data were analyzed with the Wileoxon test.
`the Mann-Wh.io1ey test, and the Knrskal—Wallis test. The VAS and VRS
`data were compared by means of the Spearman rank correlation test.
`
`I-iestnlrs
`
`The pain scores resulting from the VAS and the VRS for -
`all volunteers following injection of the four different vol-
`umes are shown in Figures 2 and 3, respectively. A sign.i.t'1—
`cant difference in pain score on both the VAS (p < 0.05)
`and VRS (p 4. 0.0!) was seen among the Four volumes.
`When examining the individual injection volumes in cle~
`tail, significant differences were found between 0.5 and [.0
`ml. and between 0.5 and 1.5 rn[.. No sigrtificant difference
`was seen betweeri 0.2 and 0.5 ml. or between 1.0 and [.5
`mL.
`
`The validity of our pain assessing model was tested us-
`ing a volume oflJ.5 ml. in all eight injection sites. The in-
`dividual pain scores from this volume did not show any
`significant trend toward decrease or increase in pain score
`with the eight injections. Furtherrnore, the comparison be-
`tween pain scores on the first and the second injection day
`showed no Significant difference. No significant period or
`carryover efiect could be detected.
`
`PainscoreVAS
`
`I-'igure 1. The [out injection sites on the thigh.
`
`O . 2
`
`0 . 5
`
`1 . G
`
`1 . 5
`
`Injection volume [I11].-l
`Figure 3. Multiple btlx-arid-whisker plot Ixtstttl on vimtnl unsittg settle (VHS) paint
`scores from the 13 volunteers following injection oflhe four volumes. For each vol-
`ume. the hnx encloses the middle 505%: oflhe \r".«\S dam, and the whiskers indicate.
`minimum and mastimnm mines. A cross indicates the mean and ahcrizontal line the
`median. lKnI$lt:lI-Wallis test. p 4 0.05).
`
`730
`
`I The Amtals o_,H’t’rrttvtracorhempy
`
`I
`
`1996 .Inly/Atrgtrst. l/0.lttme'30
`
`Page 2 of 4
`
`Page 2 of 4
`
`

`
`Reserrrc.-’I Reports
`
`To assess the validity of our pain—assessing mode}. 0.5
`mL was administered to the volunteers at all eight injection
`sites on one of the two study days. Using these data we
`showed that there was no significant period or carryover
`effect. The 0.5 ml. volume was chosen because it was re-
`garded as being a clinically relevant injection volume. The
`BMI from the individual subjects can also be regarded as
`being 1'ep1'esenIat'ive for the normal population. Our model
`proved to be reliable for healthy subjects and valid for the
`purpose of this study. The correlation between the pain
`scores of the VAS and the VRS was high, indicating that
`the subjects had understood and used the pain scales co.'t—
`rectly.
`Since compliance is a problem in many types of utedical
`therapy, issues relating to compliance should be considered
`during drug development.“ One way to improve compli-
`ance could be through an improvement in patient conve-
`nience. From this point of view, the volume of a subcuta-
`neous injection should be less than 1.0 m[.. We therefore
`recommend that the results from this study be considered
`when injection preparations for subcutaneous adn1in.istra-
`tion are formulated.
`
`Summary
`
`The pain of 11 subcutaneous injection is related to the in-
`jection volume hi the thigh. The results show that increas-
`ing the volume from 0.5 to 1.0 ml. increases the pain sig-
`nificantly. In order to optirnize patient convenience in rela-
`tion to subcutaneous atlm.iru'stration, the results from this
`study should be considered in relation to the formulation
`of injection fluids. The volume should generally be less
`than i.0 ml. if injected into the thigh. -_~—
`
`We tlmik pharmacy assistant Ruth Hansen. pluumncy student Ulla S kruen. and phar-
`macy student Mullo Monk-?cIcrscn for technical assistance and novice. and medical
`writer Nuillu Holteu Pind for linguistic ndvice. We also Iliznkchicfphysiciaui Hans-
`Henrik Panning. Slcnn Iliabetes Celltte, for his suppurt.
`
`References
`
`I. Bridges A. Stirling H. McDowell I. Jensen 3, lorgensen J'l'. Kelnar C.
`Doul,tle—bluId study to compare. the local tolerance of three tlifferent sol-
`vents used to reconstitute growth hormone (abstract). Presented at the
`British Pharmacological Society Meeting. London University College,
`London. England. December 17-19. 199].
`2. Coley RM, Butler CI), Beck Bl, Mullanc IF. Effect of needle size on
`pain and hernatoma fonnation with subcutaneous injection of heparin
`Sodium. Clin Phnrm l987:6:':’25-'1.
`3. Inrgcnscn IT. Impn:-vcmcut of patient convenience in treatment with
`gnovnh hormone. J Pcdiatr Entlocrinol 19‘)-l-'.'l': [15-30.
`4. Lee DM. 1-low painful is illtclasivc insulin injection therapy‘? 2'. Gcsanitc
`Inn Med l992:47:2I5fi-E}.
`5. Christiaosen IS. Sorensen IP. Hansen 1!, (Iltristensen T. A double blind.
`Innujorruzed study on the ricgrec of pail: on penetration by Tnsujt:-:'.t ilnti
`Novopcn needle either proxituaily ordistally of the Iliigii (abstract). Pre-
`sented at 8th Workshop of the .»\IDS§'l'l.‘Study Group. igls. fitusu-ia. Ian-
`uary 29---31, 1939.
`6. Jorgcnsen IT. lvtomensen H13. Jorgenscn IOL. Patient acceptance of
`Nordijcct: at new drug delivery system for growth horrnom-.. DICP‘ Ann
`Pharrnacollicr I991 :25-535-8.
`7. Chantcleu E. Lee DM. Hcmmann UM. Zipfel U. Ecliterilort’ 3. What
`makes insulin injection painful? BM] ll.l9l.:303:'2fi-T.
`3. Seymour RA. Simpson }l.’vl. Charlton IE. Phillips MIE. An evaluation of
`length and cr!d—pl1rase of visual analog scilies in dental pain. Pain I985;
`2l:l'il'T-35.
`9. (Jlcfsky MI. Obesity. In: Braunwaltl E. lssclbe.cheI‘I K. Peters-Llurf KG,
`Wiiscn'JD, Martin J13. Fauei P-S, crls. Harrison's plinciplcs of inlcmai
`
`731
`1996 July./August. Voltune 30 I
`I
`The Arrnals oj"Phonmtcorherupy
`---.-_-;...j;;. um -or.-...-.u-....,.w_—-_-_7_-—_---s .-_-_.-. --.--J...“
`_..._.,... . ..- ..........-___._.__.._ .._ _..-...
`
`.
`
`Page 3 of 4
`
`The pain scores from the two scales were compared. A
`statistically significant conelation between the pain scores
`on the VAS and the pain scores on the YRS was found (r =
`0.79, p < 0.0001).
`
`Discussion
`
`To our Knowledge this study is the first to demonstrate
`that the pain of a subcutaneous injection is related to the
`solution volume. Only one study’ has previously dealt with
`this subject, but failed to show any correlation. The main
`reasons for this may be that the largest volume injected
`was 0.5 ml. and that a nonstandarclized VAS was used.
`The results from our study show that pain is significantly
`increased at an injection volume greater than or equal to
`1.0 ml...
`
`The study was carefully designed to rule out any contri-
`bution to injection pain from known factors such as needle
`sire, preservative, and injection mode.“-" All injections of
`the NaCl 0.9% were performed by trajrted diabetes nurses
`using syringes mounted with a 27—gauge needle. The vol-
`umes in the range from 0.2 to 1.5 ml. were chosen because
`this interval was regarded as being clinically relevant for
`subcutaneous injections. It is also known that injection
`pain varies with the injection site.‘-5 A previous study in in-
`sulin-dependent diabetic patients show {I that pain was
`significantly greater distally on the thig compared with
`the proximal position.‘ To avoid any systematic errors in
`the study design. the randomization was performed in such
`a way that each of the four different volumes was injected
`once proximaliy and once distally.
`
`PainscoreVRS
`
`._L_..,.....
`
`l
`
`- ._._l
`
`J.
`..i
`
`.1
`
`B . 2
`
`B . 5
`
`1 . B
`
`1. . 5
`
`injection volume (m[.}
`Figure 3. Multiple. box—and—whisicer plot based on verb-1! rating scale NR-Si pain
`scores rmm me Is volunteers following injection of the four volumes. I-‘or cnch vol-
`ume, the box encloses till‘: mirl-llc Sim of the '1 R5 dale. and the whiskers indicate
`I'rtinimurI| and maximum values. A cross indicalcs lha mean and :1 horizontal line lhc
`median. (Kru.-.-kn! -Wallis Icsl. p < 0.01).
`
`
`
`Page 3 of 4
`
`

`
`I Ilh ed. New York: McGra\v—Hi|I Book Company. 1937.‘
`
`Rfisumé
`
`medicilua.
`I57 l-5.
`
`BXTIEACIU
`
`OIIJECTII-‘: Compancr la douleur résultant dc riujection sous-cutanée dc
`quatre volumes diff:‘.IcJ1Ls the liquids.
`
`mans F.xPERm1ZEN'rn!.: Etude prospective, croisée pour lcs quutm
`volumes, randomiséa, ct 9. douh1e—aveugJc.
`Lmu on L'1§1'I.|IJE.' Sumo Diabetes Centre, Genzoflc, Danemark.
`mnncxmms: Dix—huit volomaires sains. 9 ‘hornrnas e: 9 fcrnmcs. ligés
`[la 21 21 30 ans.
`
`Mt-‘.TIronoLo(:n:: On a injoclé uux participants quatre volumes différcms
`dc solution saline. isatoniquc (0.2. 0.5. 1.0. at 1.5 mL). L'él1:dc :1 61¢ fajte
`su; Zjours séparés d'11n irmcwalic d‘une ssrnnine ct Lous lees sujem ant
`regu, A chaquejour. quatre injections sur chacunc dcs dcux cuisscs. Afin
`de vérificr Ia validité du models choisi pour I’évaluau‘on dc Ia douieur.
`chaquc participant at requ huit injections (J: 0.5 ml. an cours de l' um: des
`dcuxjoumées d’c'.tudc. L‘évaluation dc Ea duulcur ¢‘.:ait faitc
`immédiatement aprts cheque injection en utiiisant um: échclle visuelle
`analogue (EVA) do ll) cm at une échelle vctbalc (EV) componam six
`tcmics.
`
`RE.'iUl.«'l'A1‘S: Une £liFFércrLcr.: sigrmificauvu: a 616 détectée cntre Iae. volumes
`§ Pétude salon its deux mudalilés d'év£Llual:iOn utjlisées (EVA. p < 0.05;
`as EV, p < 0.01). La doulcur était significativement plus lmportamc aw-,.;
`lea volumes dc 1.0 et 1.5 mL. Les aulacurs n'onl pas déteclé de différcncc
`significalive enue {es Volumes dc 0.2 ct 0.5 mi. dc méme qu'cnU.'c coup:
`de 10 ct L5
`H n'y a pas eu non plus dz rllfféreuce auribuablc an
`facteur temps. Les auteurs out Lrouvé une honnc: conélation cnlxe les
`dcux échclles ulilisécs lomqn 'ils en out oamparé lcs résultal.-i (r = 0.79.
`p < 0.000 I}.
`l20N(‘.‘I.LlS[0rlS: La douleur resascmic apres une injeclion sans-::uin.mEe
`dans la cuissc serait reliée an volume injecté. Les résultats ici lnontrem.
`que passer d'un volume injacté dc 0.5 31 L0 :11]. augme-ante
`significativcmcnt la doulcur. Les aulzurs suggérent qul: ceue émde suit
`prise en c0ns1'dératioI1 pm’ l'industrie phnnrlaocutiquc au moment Lin:
`formuler has liquidrs
`H l'injucu'on soI.IS—cUi.m1ée. Au niveau de la
`cuissc. 1:: volume devrailgénémleancntétreinfén-ie1.1rh 1.0 ml...
`MIC!-ISLE-: PI .nN'rE
`
`nasznvo: Compara: cl dolor asocindo a la inyeocifin subcutziuea dc:
`ctlnuo voldmenes distiulcm dc solucifin isolénica dc czlorurc} de audio.
`
`msgaiu: Esmdin an doblc ciego, aleatorio. prospective. dc dosis
`mlilliplcs, yr cnlzado.
`Escummo: Cemro Dinbélico Slnno, Gcntofte, Denrnark.
`
`Mtmuos: Se inyoctumn 4 vblfinlents dislintos (0.2, 0.5, 1.0, y 1.5 ml.)
`dc solucidn isolénica dc clorurc dc sodio{ismor1it sodium chloride. 9
`mg;'n1L. DAIC) :1 I3 voiuntm-ios szmos. E! csmdio se zeaiizé en 2 slfas
`separados um dc oiro per una semana librc de la arJmi.n.istrI1ci6n de las
`soluciones dc cstudio. En cada uno de los dim: do c.-studio, [os
`volunrarios mcibier-an -1 inyecciones en cada muslo. Para detenninar Ia
`validez del modelo de evaillacltin dc dolor utilizndx) I05 volunlarios
`recibiemn. bicn and un volumcn L1: 0.5 mL an cada music 0 4
`volfimenes distiutus de inyeocién par dnplicado. La evaluacifin de dolor
`so rculizé inmedintamente. después dz: cada inyeocién usancb una escala
`analégica visual (EAV) de 10 cm dc lungitud y una ascala dc
`clasificacitin \'e1lJal (ECV) de 6 elcntentos.
`R_E5UL'l‘AD-BS: Se obscnré uml tliferencia significativa enlxc I06 4
`volflmenz-.-: dc iuyeccién can 1-espuclo al dolor repc-nado usartdn la EAV
`(p -< 0.05) yr la EVC (p -: 0.01]. El doior st: lrncrenwnlo con el vohlmcn
`ck: inyaccién (Ir. [.0 mL 3; 1.5 1‘nL. No se detectamn diftzrmcias
`significativzu; an dolor entre los voltimenes dc 0.3 y 0.5 ml. 3! I105
`volfimcm.-.5 LI: [.0 y 1.5 mL. Tampoco dc detcctfi influcncia dc}
`tratamiamo prccsdense. I-[ubo una corralacién significaliva en cuamo a
`dolorentrc: la EAV y la EVC .(r = 0.19. p < 0.0001).
`o(JNL1.I.$ioi'I!-)8: Se concluyc quc el dolor asociadu a la inyelzcifin
`saubcutéllea do una solucilflrl cstal relacionudo al volumen dc myeccién cn
`cl mus-la. Los resultados dennucstran que el incmementar cl vc-lumen dc
`inycccién dc 0.5 ml. :1 1.0 ml. irlcremcnta el dolor significutivasnenle.
`L04; hallurgos (le est: csmdio deherran set to-mados an cortsiderucidn
`cuando se. formulen prcparaciones paxemcrales dc adnru'r|.istracién
`subcutéma. Sc we-sanzienda rpm cl volumen dc iuywcisfin sea mennr dc
`1.0 mL cuando sc inyecta en :1 rnuslo.
`
`ENCARNACICN C SU.v1RE:«‘.
`
`732
`
`I The Anrtals 0fPk(£miacor!zerapy
`
`I
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`1996 July/Attgeist, Volume 30
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`Page 4 of 4
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`Page 4 of 4