Download pdf - Relationship between Interferon Beta-1A Administration and ... · ResearchArticle Relationship between Interferon Beta-1A Administration and Intracranial Vascular Tone Regulation

Research ArticleRelationship between Interferon Beta-1A Administrationand Intracranial Vascular Tone Regulation in Patients withRelapsing-Remitting Multiple Sclerosis A Pilot Study

Vincenzo Dattola1 Lilla Bonanno1 Antonino Naro1 Antonino Chillura1

Anna Lisa Logiudice1 Edoardo Sessa1 Fausto Famagrave2 Angelo Quartarone3

Rocco Salvatore Calabrograve1 Silvia Marino1 andMargherita Russo1

1 IRCCS Centro Neurolesi ldquoBonino Pulejordquo Via Ple Palermo SS 113 98124 Messina Italy2Department of Human Pathology University Hospital of Messina Via Consolare Valeria Messina Italy3Department of Clinical and Experimental Medicine University Hospital of Messina Via Consolare Valeria Messina Italy

Correspondence should be addressed to Vincenzo Dattola vincenzodattolagmailcom

Received 30 May 2017 Revised 27 July 2017 Accepted 14 August 2017 Published 13 September 2017

Academic Editor Luca Prosperini

Copyright copy 2017 Vincenzo Dattola et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

Interferon beta (IFN-120573) therapy is one of the most commonly prescribed immunomodulatory therapies in relapsing-remittingmultiple sclerosis (RRMS) A reversible cerebral vasoconstriction syndrome (RCVS) associated with IFN-120573 use has been recentlydescribed For this reason we tested the effect of once a week intramuscular administration of IFN-120573-1A on the function of cerebralvessels in a cohort of RRMS patients Using transcranial Doppler (TCD) ultrasound we measured the mean blood flow velocity(MFV) in intracranial vessels 10 h after IFN-120573 administration Measurements showed a significant increase in MFV compared tothe baseline values in some vessels

1 Background

Multiple sclerosis (MS) is a chronic autoimmune andpredominantly demyelinating disease involving the centralnervous system (CNS) [1] The disease affects mainly youngfemales (femalemale ratio about 2 1) between the sec-ond and fourth decade of life and represents the secondcause of neurological disability after traumatic brain injury[2]

To date due to its complex etiopathogenesis probablyresulting from genetic and environmental factors (only par-tially known) interaction no curative treatment is availablefor MS [1 2]

However over the past 30 years various drugs have beenintroduced into clinical practice namely disease modifyingtherapies (DMTS) able to modify the clinical course of thedisease [3]

The interferon beta (IFN-120573) 1A and 1B represents thefirst widely used DMTS and it is still one of the most

commonly administered drugs for the treatment of therelapsing-remitting MS (RRMS) variant [4]

IFNs are a group of endogenous glycoproteins endowedwith immunomodulatory antiviral and antiproliferativeproperties [5] The mechanism of action lays in their abilityto modulate immune system activity mainly by reducingthe migration of peripheral T-lymphocytes to the CNS [56] Side effects are widely known and there are also manycomplications related to chronic IFN treatment The mostcommon is represented by the flu-like syndrome whosesymptoms (eg headache fever and ubiquitary arthralgia)are prominent at the beginning of the therapy althoughthey decrease progressively in frequency and severity whenthe treatment is prolonged [7] Other side effects of IFN-120573 (include injection site reactions depression liver injuryand hematologic abnormalities) However so far no effecton the vascular tone of the cerebral vessels has beenreported with the exception of a single case of reversiblecerebral vasoconstriction syndrome (RCVS) described by

HindawiBioMed Research InternationalVolume 2017 Article ID 5421416 5 pageshttpsdoiorg10115520175421416

2 BioMed Research International

Strohm et al [8] RCVS is generally associated with unusualheadache episodes with sudden onset and high intensityldquothunderclap headacherdquo due to awidespread segmental vaso-constriction of the intracranial arteries usually regressingwithin a three-month period RCVS is probably triggeredby the acute and transient alteration of the intracranialvascular tone regulation and usually presents a favourabledevelopment Nonetheless serious complications such ascerebral infarction intracranial haemorrhage or cerebraloedema may also occur RCVS may be idiopathic or oftensecondary to the postpartum period or following the use oftoxic agents or vasoactive drugs [9]

The contraction strength of the intracranial vessels bothintra- and extraparenchymal ones can usually be evaluatedthrough an angiography or through an angiomagnetic reso-nance imaging (Angio-MRI) however transcranial Doppler(TCD) ultrasounds are more rapid and less invasive [10]In fact other earlier reported studies have demonstratedan inversely proportional relationship between the meanblood flow velocity (MFV) rate measured by TCD andthe vessel diameter measured by means of angiography[10]

In our study we attempted to observe the intracranialhaemodynamic changes in response to the IFN-120573 adminis-tration in patients with RRMS (primary end-point) by usingTCD

In addition we investigated the possible differencesbetween symptomatic and asymptomatic headache patients(secondary end-point) concerning cerebral haemodynamic

2 Materials and Methods

We enrolled 20 MS-RR patients treated with a once weekintramuscular administration of IFN-120573 1A (Avonex) con-secutively examined and followed by the MS centre of theldquoIRCCS Centro Neurolesi-Bonino Pulejordquo of Messina (Italy)from January 2016 to December 2016 The inclusion criteriawere age range between 20 and 40 years no drugs andorother administered substances (including tobacco smoke)that could affect the regulation of the vascular tone absenceof comorbidities that could potentially induce secondaryheadache no history of headache prior initiation of inter-feron conclusive diagnosis of RRMS according to Polman etal criteria [11] stable treatment with IFN-120573 1A started by atleast 6 months earlier

We enrolled MS patients treated with the same formu-lation of IFN-120573 1A in order to standardize the timing ofperformance of the TCD examination

Avonex exerts its biological effects by binding to specificreceptors on the surface of human cells

This interaction gives rise to a complex cascade ofintracellular events that lead to the expression of sev-eral interferon-induced gene products and markers thatis MHC (Major Histocompatibility Complex) Class I Mxprotein 2101584051015840-oligoadenylate synthetase P2 microglobulinand neopterin Some of these products were detected in theserum and in cellular fractions of the blood collected frompatients treated with Avonex [5 6 12]

The pharmacokinetic profile of Avonex was then assessedusing indirectmethod bymeasuring its antiviral activity Fol-lowing intramuscular administration serumantiviral activitylevels reach their peak between 5 and 15 hours (generallyan average of 10 hours) and gradually decrease down to theminimum activity ascertained between 4th and 7th day afterits administration [12]

During the screening visit we collected all data concern-ing other potential side effects related to the administration ofAvonex in particular previous episodes of headache beforethe beginning of treatment with IFN-120573 were inquired

All the enrolled patients underwent a TCD immediatelyafter Avonex administration (T0) and after 10 hours (T1) inaccordance with previous pharmacokinetic studies

The ultrasound protocol performed with Motion-Modemodule and according to standard technique [13] providedthrough the temporal acoustic window the analysis of thefollowing arterial vessels internal carotid artery (ICA) inits distal portion middle cerebral artery (MCA) sectionA1 of the anterior cerebral artery (A1-ACA) and poste-rior cerebral artery (PCA) in order to assess the possibleMFV rate variations in response to the administration ofIFN-120573

At T0 and T1 heart rate (HR) systolic and diastolic bloodpressure (SBP and DBP) of our patients were also recorded

Twenty healthy volunteers (8 males and 12 femalesbetween the ages of 18 and 40 years) after having undergonean anamnestic and a clinical evaluation to exclude headacheand potentially inducing headache illness were enrolled toobtain a normal range of TCD values

21 Statistical Analysis The analysis was conducted withdescriptive statistic of respondentrsquos demographic character-istic Normality test of Shapiro-Wilks and Levenersquos variancehomogeneity test were applied to the data The data werenot normally distributed and there was no homogeneityof variance between the groups Sample clinical parameterswere compared at T0 and T1 by the Wilcoxon signed-rank test in the MS group The MannndashWhitney U testwas used to compare differences between MS and healthyvolunteers (HV) group Correlations between demographic-clinical characteristic (age disease duration and initiation oftherapy) and TCD parameters were computed by Spearmanrsquoscoefficient Subsequently the sample was divided into twogroups headache and no-headache patients The Wilcoxonsigned-rank test was used in order to compare for eachgroup the results between T0 and T1 (intragroups analysis)whereas the comparison between the two groups (intergroupanalysis) at T0 and T1 was performed by mean of theMannndashWhitney U test For intragroup analysis Spearmanrsquoscoefficient was used for the correlation We performed amultiple regression analysis on the TCD parameters (depen-dent variables) At first we focused on the influence ofdemographic and clinical variables by using patientrsquos agedisease duration and initiation of therapy as predictors Weapplied a backward stepwise elimination procedure for thechoice of the best predictive variables according to the Akaikeinformation criterion (AIC) Analyses were performed usingan open source R30 software package A 95 of confidence

BioMed Research International 3

Table 1 Demographic and clinical characteristics of multiple sclerosis (MS) sample frequencies ()

All subjects Headache No-headache

MS patients 20(9 males 11 females)

8(3 males 5 females)


Age (years) 3135 plusmn 556 3162 plusmn 580 3117 plusmn 564Diseases duration (months) 613 plusmn 6239 5875 plusmn 6361 630 plusmn 6434Therapy duration (months) 565 plusmn 5901 5525 plusmn 6164 5733 plusmn 5996Flu-like syndrome

Yes 6 (30) 3 (375) 3 (25)No 14 (70) 5 (625) 9 (75)

Table 2 Inter-group differences between healthy volunteers (HV) and multiple sclerosis (MS) group at baseline

HV group MS group at Baseline 119901 valueMedian

(first-third quartile)Median

(first-third quartile) (119880MannndashWhitney)

HR 79(755ndash850)

80(775ndash820) 097

SBP 120(1100ndash1250)

1175(1100ndash12125) 042

DBP 775(7375ndash800)

80(7375ndash800) 079

MFV-ICA 50(475ndash5225)

50(480ndash510) 076

MFV- MCA 60(580ndash620)

595(580ndash620) 098

MFV-A1 ACA 45(430ndash4525)

45(420ndash450) 071

MFV-PCA 405(3875ndash420)

40(380ndash4025) 048

HR heart ratio SBP systolic blood pressure DBP diastolic blood pressure MFV-ICA mean blood flow velocity internal carotid artery MFV-MCA meanblood flow velocity middle cerebral artery MFV-A1 ACA mean blood flow velocity section A1 of the anterior cerebral artery MFV-PCA mean blood flowvelocity posterior cerebral artery

level was set with a 5 alpha error Statistical significance wasset at 119901 lt 005

3 Results

31 Descriptive Analysis of Sample Demographic and clinicalfeatures of our MS cohort are shown in Table 1

In the entire MS cohort (headache + no-headachepatients) we found a significant increase in at T1 in MFV-ICA (119901 = 003) MFV-MCA (119901 = 002) MFV-A1 ACA(119901 = 0004) and MFV-PCA (119901 = 0004) No significantcorrelations were found between disease duration ther-apy duration and clinical parameters Intergroup analysisdid not show significant difference between MS and HVgroup

32 Intra-Inter Group Analysis In intragroup analysis wecompared the clinical parameters at baseline (T0) and afterIFN-120573 administration (T1) for each group (headache andno-headache patients) In headache group we observed asignificant increase in MFV-ICA (119901 = 005) MFV-MCA(119901 = 004) MFV-A1 ACA (119901 = 002) and MFV-PCA (119901 =002) In the no-headache group we did not find significant

difference at T1 Intergroups analysis showed a significanttrend between two groups at T0 in MFV-ICA (119901 = 006)(Table 2)

33 Correlation Analysis In the headache group we foundmany significant correlations between age disease and ther-apy duration with hemodynamic parameters (Table 3) Inparticular age was positively correlated with MFV-ICA (119903 =074 119901 = 003) In relation to disease duration we observeda positive correlation with MFV-MCA (119903 = 071 119901 = 005)Concerning initiation of therapywe found a trendwithMFV-MCA (119903 = 067 119901 = 007) In the no-headache groupMFV-MCA was negatively correlated with disease duration(119903 = minus068 119901 = 001) and therapy duration (119903 = minus067119901 = 002)

34 Multiple Regression Analysis We found that the demo-graphic and clinical features of the MS patients do not have asignificant impact onTCDparameters (ie a significant trendwas only found in relation to age influence in MFV-ICA andin disease and therapy duration influence on MFV-A1 ACAand MFV-PCA) as shown in Table 4


Table 3 Intra- and intergroup differences at T0-T1 in headache and no-headache multiple sclerosis (MS) groups

Headache MS groupMedian

(first-third quartile)

No-headache MS groupMedian


119901 value(U MannndashWhitney)

HR T0 81 (76ndash885) 77 (725ndash825) 026HR T1 83 (775ndash90) 77 (735ndash785) 010119901 value (Wilcoxon) 062 100SBP T0 1225 (115ndash130) 1175 (110ndash125) 037SBP T1 120 (1175ndash125) 115 (110ndash12125) 031119901 value (Wilcoxon) 100 052DBP T0 80 (75ndash8125) 75 (70ndash80) 017DBP T1 80 (7875ndash8125) 725 (70ndash80) 007119901 value (Wilcoxon) 100 042MFV-ICA T0 47 (455ndash4975) 51 (4975ndash535) 006MFV-ICA T1 51 (48ndash53) 525 (48ndash5325) 058119901 value (Wilcoxon) 005lowast 044MFV-MCA T0 58 (58ndash6025) 60 (5875ndash6225) 029MFV-MCA T1 63 (5975ndash68) 60 (59ndash6225) 027119901 value (Wilcoxon) 004lowast 038MFV-A1 ACA T0 45 (445ndash4525) 45 (425ndash4525) 060MFV-A1 ACA T1 47 (455ndash5025) 45 (44ndash46) 015119901 value (Wilcoxon) 002lowast 010MFV-PCA T0 405 (3875ndash4125) 405 (3875ndash42) 078MFV-PCA T1 42 (40ndash4425) 41 (40ndash4225) 038119901 value (Wilcoxon) 002lowast 012HR heart ratio SBP systolic blood pressure DBP diastolic blood pressure MFV-ICA mean blood flow velocity internal carotid artery MFV-MCA meanblood flow velocity middle cerebral artery MFV-A1 ACA mean blood flow velocity section A1 of the anterior cerebral artery MFV-PCA mean blood flowvelocity posterior cerebral artery lowast119901 lt 005

Table 4 Backward linear regression significant predictors on the TCD parameters

Dependent variables Predictors 120573 Std 120573 119901 value Adjusted 1198772

MFV-ICA Age 043 065 006 006

MFV-A1 ACA Disease duration 023 611 008021

Therapy duration minus024 minus627 007

MFV-PCA Disease duration 020 685 007015


120573 regression coefficient Std 120573 standardized regression coefficient MFV-ICA mean blood flow velocity internal carotid artery MFV-A1 ACA mean bloodflow velocity section A1 of the anterior cerebral artery MFV-PCA mean blood flow velocity posterior cerebral artery

4 Discussion

In our sample MS patients showed a statistically significantdifference in MFV rate (probably due to a vascular tonemodification) in cerebral vessels in response to IFN-120573 admin-istration In particular in the headache group we observeda significant increase in MFV-ICA MFV-MCA MFV-A1ACA and MFV-PCA at T1 No significant correlationswere found between disease duration therapy duration andhaemodynamic parameters

RCVS is a rare and often misdiagnosed syndrome whosepathophysiological causes are still unclear [9 10] and so faronly a single case associated with IFN-120573 1A has been reported[8] In this report a twenty-year-old woman with recent MS

diagnosis following a two-month treatment with IFN-120573 1Adeveloped a RCVS which regressed immediately after theimmunomodulating drug was discontinued

IFN-120573 1A is a polypeptide normally produced by fibrob-lasts that ultimately induces antiproliferative and antivi-ral effects [5 6] Recognized side effects include flu-likesymptoms injection site reactions severe cutaneous reac-tion depression liver injury hematologic abnormalitiesand headache [7] Other reported side effects involvingvascular system include Raynaud Phenomenon (RP) livedoreticularis (LR) and pulmonary artery hypertension [14 15]

Particularly Hanaoka et al demonstrated that IFN-alpha (IFN-120573 pharmacologically related compound with anexpected similar side effect profile) induces pulmonary artery


hypertension linked to a thromboxane cascade with conse-quent elevated concentrations of thromboxane-B2 in plasma[16] Currently there are no experimental data related to theinfluence of IFN-120573 on activation of thromboxane cascade butbiochemical similarity may suggest a similar mechanism ofaction Both the IFNs in fact induce expression of variouscytokines [17] and increased plasma levels of IL-1 IL-2 IL-6 TNF alpha and interferon gamma were also observedin MS patients after IFN-120573 injection [17 18] Thereforewe hypothesize that some of these cytokines could inducecerebral vasoconstriction directly or through the activationof the thromboxane cascade

41 Study Limitations The relatively small sample size of thestudy groups and the lack of a control group for the effect oftime (ie a group of MS patients that undergoes two testingsessions but does not take the drug) are the main limitationsof the study

5 Conclusion

Our data together with literature findings suggest that IFN-120573 could have vasoactive effects manifesting in multiple organsystems probably mediated by a similar mechanism of IFN-alpha Thus we believe that clinicians should be aware of thevascular side effects of IFN-120573 and perform TDC in those MSpatients developing headache during the immunomodulanttreatment

However this work can be considered a pilot study andfurther efforts combining laboratory (cytokines dosage) andinstrumental methods (TCD and Angio-MRI) are requiredto confirm these results

Conflicts of Interest

The authors declare that they have no conflicts of interest

Acknowledgments

The authors would like to thankMs AntoninaDonato for theediting of the text

References

[1] H Lassmann and M Bradl ldquoMultiple sclerosis experimentalmodels and realityrdquo Acta Neuropathologica vol 133 no 2 pp223ndash244 2017

[2] J Howard S Trevick and D S Younger ldquoEpidemiology ofMultiple Sclerosisrdquo Neurologic Clinics vol 34 no 4 pp 919ndash939 2016

[3] G Comi M Radaelli and P Soelberg Soslashrensen ldquoEvolvingconcepts in the treatment of relapsing multiple sclerosisrdquo TheLancet vol 389 no 10076 pp 1347ndash1356 2017

[4] T R Einarson B G Bereza and M Machado ldquoComparativeeffectiveness of interferons in relapsingndashremitting multiplesclerosis ameta-analysis of real-world studiesrdquoCurrentMedicalResearch and Opinion vol 33 no 3 pp 579ndash593 2016

[5] Y Tao X Zhang R Zivadinov et al ldquoImmunologic and MRImarkers of the therapeutic effect of IFN-120573-1a in relapsing-remitting MSrdquo Neurology vol 2 no 6 article no e176 2015

[6] C E Markowitz ldquoInterferon-beta mechanism of action anddosing issuesrdquo Neurology vol 68 4 no 24 pp S8ndash11 2007

[7] J T Phillips E Fox W Grainger D Tuccillo S Liu and ADeykin ldquoAn open-label multicenter study to evaluate the safeand effective use of the single-use autoinjector with an Avonexprefilled syringe inmultiple sclerosis subjectsrdquo BMCNeurologyvol 11 article no 126 2011

[8] T Strohm B Chaudhry M AWillis and S Shook ldquoReversiblecerebral vasoconstriction syndrome associated with interferonbeta-1a use for multiple sclerosisrdquoMultiple Sclerosis vol 22 no12 pp 1626ndash1628 2016

[9] L H Calabrese D W Dodick T J Schwedt and A BSinghal ldquoNarrative review Reversible cerebral vasoconstrictionsyndromesrdquo Annals of Internal Medicine vol 146 no 1 pp 34ndash44 2007

[10] T R Miller R Shivashankar M Mossa-Basha and D GandhildquoReversible cerebral vasoconstriction syndrome part 2 Diag-nostic work-up imaging evaluation and differential diagnosisrdquoAmerican Journal of Neuroradiology vol 36 no 9 pp 1580ndash1588 2015

[11] C H Polman S C Reingold B Banwell et al ldquoDiagnosticcriteria for multiple sclerosis 2010 revisions to the McDonaldcriteriardquo Annals of Neurology vol 69 no 2 pp 292ndash302 2011

[12] A M Vallittu A A Salmi and J P Eralinna ldquoMxA proteininduction in MS patients treated with intramuscular IFN120573-1ardquoNeurological Sciences vol 26 no 6 pp 438ndash443 2006

[13] A DrsquoAndrea M Conte M Cavallaro et al ldquoTranscranialDoppler ultrasonography Frommethodology to major clinicalapplicationsrdquo World Journal of Cardiology vol 8 no 7 p 3832016

[14] U Rot and A H Ledinek ldquoInterferons beta have vasocon-strictive and procoagulant effects A woman who developedlivedo reticularis and Raynaud phenomenon in associationwith interferon beta treatment for multiple sclerosisrdquo ClinicalNeurology and Neurosurgery vol 115 no 1 pp S79ndashS81 2013

[15] E M Govern E P Judge E Kavanagh S Gaine and T LynchldquoInterferon beta related pulmonary arterial hypertension anemerging worrying entityrdquo Multiple Sclerosis and Related Dis-orders vol 4 no 3 pp 284ndash286 2015

[16] MHanaoka K Kubo THayano T Koizumi and T KobayashildquoInterferon-120572 elevates pulmonary blood pressure in sheep -Therole of thromboxane cascaderdquo European Journal of Pharmacol-ogy vol 370 no 2 pp 145ndash151 1999

[17] T Kumpfel F T Bergh T Pollmacher F Holsboer and CTrenkwalder ldquoAcute effects of interferon beta-1a on plasmacytokine levels in patients with MSrdquo Neurology vol 55 no 8pp 1231ndash1233 2000

[18] F Nicoletti R DiMarco F Patti et al ldquoShort-term treatment ofrelapsing remitting multiple sclerosis patients with interferon(IFN)-1205731b transiently increases the blood levels of interleukin(IL)-6 IL-10 and IFN-120574 without significantly modifying thoseof IL-1120573 IL-2 IL-4 and tumour necrosis factor-120572rdquoCytokine vol12 no 6 pp 682ndash687 2000

Submit your manuscripts athttpswwwhindawicom

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The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

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Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


Strohm et al [8] RCVS is generally associated with unusualheadache episodes with sudden onset and high intensityldquothunderclap headacherdquo due to awidespread segmental vaso-constriction of the intracranial arteries usually regressingwithin a three-month period RCVS is probably triggeredby the acute and transient alteration of the intracranialvascular tone regulation and usually presents a favourabledevelopment Nonetheless serious complications such ascerebral infarction intracranial haemorrhage or cerebraloedema may also occur RCVS may be idiopathic or oftensecondary to the postpartum period or following the use oftoxic agents or vasoactive drugs [9]

The contraction strength of the intracranial vessels bothintra- and extraparenchymal ones can usually be evaluatedthrough an angiography or through an angiomagnetic reso-nance imaging (Angio-MRI) however transcranial Doppler(TCD) ultrasounds are more rapid and less invasive [10]In fact other earlier reported studies have demonstratedan inversely proportional relationship between the meanblood flow velocity (MFV) rate measured by TCD andthe vessel diameter measured by means of angiography[10]

In our study we attempted to observe the intracranialhaemodynamic changes in response to the IFN-120573 adminis-tration in patients with RRMS (primary end-point) by usingTCD

In addition we investigated the possible differencesbetween symptomatic and asymptomatic headache patients(secondary end-point) concerning cerebral haemodynamic

2 Materials and Methods

We enrolled 20 MS-RR patients treated with a once weekintramuscular administration of IFN-120573 1A (Avonex) con-secutively examined and followed by the MS centre of theldquoIRCCS Centro Neurolesi-Bonino Pulejordquo of Messina (Italy)from January 2016 to December 2016 The inclusion criteriawere age range between 20 and 40 years no drugs andorother administered substances (including tobacco smoke)that could affect the regulation of the vascular tone absenceof comorbidities that could potentially induce secondaryheadache no history of headache prior initiation of inter-feron conclusive diagnosis of RRMS according to Polman etal criteria [11] stable treatment with IFN-120573 1A started by atleast 6 months earlier

We enrolled MS patients treated with the same formu-lation of IFN-120573 1A in order to standardize the timing ofperformance of the TCD examination

Avonex exerts its biological effects by binding to specificreceptors on the surface of human cells

This interaction gives rise to a complex cascade ofintracellular events that lead to the expression of sev-eral interferon-induced gene products and markers thatis MHC (Major Histocompatibility Complex) Class I Mxprotein 2101584051015840-oligoadenylate synthetase P2 microglobulinand neopterin Some of these products were detected in theserum and in cellular fractions of the blood collected frompatients treated with Avonex [5 6 12]

The pharmacokinetic profile of Avonex was then assessedusing indirectmethod bymeasuring its antiviral activity Fol-lowing intramuscular administration serumantiviral activitylevels reach their peak between 5 and 15 hours (generallyan average of 10 hours) and gradually decrease down to theminimum activity ascertained between 4th and 7th day afterits administration [12]

During the screening visit we collected all data concern-ing other potential side effects related to the administration ofAvonex in particular previous episodes of headache beforethe beginning of treatment with IFN-120573 were inquired

All the enrolled patients underwent a TCD immediatelyafter Avonex administration (T0) and after 10 hours (T1) inaccordance with previous pharmacokinetic studies

The ultrasound protocol performed with Motion-Modemodule and according to standard technique [13] providedthrough the temporal acoustic window the analysis of thefollowing arterial vessels internal carotid artery (ICA) inits distal portion middle cerebral artery (MCA) sectionA1 of the anterior cerebral artery (A1-ACA) and poste-rior cerebral artery (PCA) in order to assess the possibleMFV rate variations in response to the administration ofIFN-120573

At T0 and T1 heart rate (HR) systolic and diastolic bloodpressure (SBP and DBP) of our patients were also recorded

Twenty healthy volunteers (8 males and 12 femalesbetween the ages of 18 and 40 years) after having undergonean anamnestic and a clinical evaluation to exclude headacheand potentially inducing headache illness were enrolled toobtain a normal range of TCD values

21 Statistical Analysis The analysis was conducted withdescriptive statistic of respondentrsquos demographic character-istic Normality test of Shapiro-Wilks and Levenersquos variancehomogeneity test were applied to the data The data werenot normally distributed and there was no homogeneityof variance between the groups Sample clinical parameterswere compared at T0 and T1 by the Wilcoxon signed-rank test in the MS group The MannndashWhitney U testwas used to compare differences between MS and healthyvolunteers (HV) group Correlations between demographic-clinical characteristic (age disease duration and initiation oftherapy) and TCD parameters were computed by Spearmanrsquoscoefficient Subsequently the sample was divided into twogroups headache and no-headache patients The Wilcoxonsigned-rank test was used in order to compare for eachgroup the results between T0 and T1 (intragroups analysis)whereas the comparison between the two groups (intergroupanalysis) at T0 and T1 was performed by mean of theMannndashWhitney U test For intragroup analysis Spearmanrsquoscoefficient was used for the correlation We performed amultiple regression analysis on the TCD parameters (depen-dent variables) At first we focused on the influence ofdemographic and clinical variables by using patientrsquos agedisease duration and initiation of therapy as predictors Weapplied a backward stepwise elimination procedure for thechoice of the best predictive variables according to the Akaikeinformation criterion (AIC) Analyses were performed usingan open source R30 software package A 95 of confidence








Yes 6 (30) 3 (375) 3 (25)No 14 (70) 5 (625) 9 (75)





HR 79(755ndash850)

80(775ndash820) 097

SBP 120(1100ndash1250)

1175(1100ndash12125) 042

DBP 775(7375ndash800)

80(7375ndash800) 079


50(480ndash510) 076


595(580ndash620) 098


45(420ndash450) 071


40(380ndash4025) 048



3 Results

















MFV-ICA Age 043 065 006 006






4 Discussion









5 Conclusion





Acknowledgments


References
























of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of























Yes 6 (30) 3 (375) 3 (25)No 14 (70) 5 (625) 9 (75)





HR 79(755ndash850)

80(775ndash820) 097

SBP 120(1100ndash1250)

1175(1100ndash12125) 042

DBP 775(7375ndash800)

80(7375ndash800) 079


50(480ndash510) 076


595(580ndash620) 098


45(420ndash450) 071


40(380ndash4025) 048



3 Results

















MFV-ICA Age 043 065 006 006






4 Discussion









5 Conclusion





Acknowledgments


References
























of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


























MFV-ICA Age 043 065 006 006






4 Discussion









5 Conclusion





Acknowledgments


References
























of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



















5 Conclusion





Acknowledgments


References
























of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of














