The evaluation of tirofiban hydrochloride in a high shear rate arterial thrombosis model in baboons
Abstract
English: Background: Acute coronary syndrome (ACS) is a major cause of mortality and morbidity
world-wide, and is responsible for roughly 2.5 million hospital admissions world-wide annually.
ACS is commonly associated with platelet thrombus formation on disrupted atherosclerotic
plaques, therefore effective and safe anti-platelet drugs are needed to help treat and prevent
ACS. The current most popular anti-platelet drugs are associated with increased bleeding risk
and reduced efficacy, thus drugs with a wider therapeutic window (more efficacy with less
bleeding) need to be developed. Tirofiban hydrochloride is a small, short half-life molecule that
inhibits platelet aggregation by antagonising the glycoprotein IIb/IIIa receptor on platelets
preventing fibrinogen and von Willebrand factor to cross-link platelets, thereby inhibiting the
final pathway of platelet aggregation. Tirofiban hydrochloride was believed to be a very
promising drug due to its short half-life, as an antidote strategy is not needed to reverse
adverse bleeding events, but it soon fell out of favour when it was found not to be as effective
as for example abciximab in preventing ischaemic events. This was possibly due to the
recommended dose being suboptimal.
Methods and Results: We studied the efficacy of tirofiban hydrochloride to inhibit platelet
thrombus formation on an injured and partially occluded artery by evaluating the effect of
escalating doses on cyclic flow reduction (CFR) formation in a high shear arterial thrombosis
model in baboons, and also evaluated its safety in two different bleeding models. We then
compared our results to results found in the same model using clopidogrel. A significant effect
on the number of CFRs was only observed after injection of three times (30 μg/kg bolus plus
0.45 μg/kg/min infusion) the therapeutic dose tirofiban, but it was a weak inhibitor at this dose.
Only after injection of nine times (90 μg/kg bolus plus 1.35 μg/kg/min infusion) the
recommended therapeutic dose, a strong complete inhibition was observed. A further dose of 27 times (270 μg/kg bolus plus 4.05 μg/kg/min infusion) the recommended therapeutic dose
was given to evaluate the effect of an overdose on the bleeding tendency. A significant
prolongation in bleeding time (3.05 minutes to 11.90 minutes) was observed after injection of
nine times the therapeutic dose, an average 2.7 ± 2.44 fold increase in blood loss was also
observed at this dose. A maximum increase in blood loss of an average of 3.4 ± 1.77 fold was
seen after injection of 27 times the therapeutic dose. The efficacy of tirofiban hydrochloride
was comparable to that of clopidogrel found in earlier studies, but the blood loss was much
less when compared to the average 4.3 ± 2.6 fold increase with clopidogrel at 2.5 mg/kg and
8.0 ± 5.0 fold increase at 5 mg/kg.
Conclusion: Tirofiban hydrochloride is an effective anti-platelet drug, but only offers adequate
protection against arterial thrombosis at a dose between three and nine times the
recommended therapeutic dose. However, it still remains safer in terms of bleeding than the
most common anti-platelet drugs used today. We recommend that further in vivo studies be
done to determine the optimal dose for tirofiban hydrochloride treatment, and that new clinical
trials be done with higher dose tirofiban hydrochloride. Afrikaans: Agtergrond: Akute koronêre sindroom (AKS) is die hoof-oorsaak van mortaliteit en morbiditeit
wêreld-wyd, en is verantwoordelik vir ongeveer 2.5 miljoen hospitaal-toelatings per jaar in die
wêreld. AKS word in die algemeen geassosieer met plaatjie thrombus-vorming op ontwrigte
aterosklerotiese plake, dus is effektiewe en veilige anti-plaatjie-middels noodsaaklik vir die
behandeling en voorkoming van AKS. Huidiglik word die mees populêre anti-plaatjie-middels
geassosieer met ‘n verhoogde risiko vir bloeding en verlaagde effektiwiteit, dus is dit
noodsaaklik om middels met ‘n beter terapeutiese venster (hoër effektiwiteit met minder
bloeding) te ontwikkel. Tirofiban hidrochloried is ‘n klein, kort half-leeftyd molekuul wat plaatjie
aggregasie inhibeer deur die glikoproteïen IIb/IIIa reseptor op plaatjies te antagoniseer. Dit
verhoed dat fibrinogeen en von Willebrand faktor die plaatjies kruisverbind, en inhibeer so die
finale pad van plaatjie-aggregasie. Daar is gedink dat tirofiban hidrochloried ‘n baie belowende
middel is as gevolg van sy korter half-leeftyd, want in so ‘n geval word ‘n omkeer strategie nie
benodig indien ‘n ongewenste bloeding sou voorkom nie. Dit het egter vinnig uit guns geval toe
daar gevind is dat dit nie so effektief soos abciximab was om ischemiese gebeure te voorkom
nie. Dit was moontlik as gevolg van die aanbevole dosis wat suboptimaal was.
Metodes and Resultate: Ons het die effektiwiteit van die middel om plaatjie-trombus vorming
op ‘n beseerde en vernoude arterie te inhibeer bestudeer, deur die effek van verskillende
verhogende dosisse op sikliese vloei reduksie (SVR) vorming in ‘n hoë skuifkrag arteriële
trombose-model in bobbejane te evalueer. Ons het ook die veiligheid in twee verskillende
bloedingsmodelle geëvalueer. Ons het toe ons resultate vergelyk met resultate gevind met
clopidogrel in dieselfde model. ’n Statisties betekenisvolle effek op die hoeveelheid SVRe is
eers na toediening van drie maal (30 μg/kg bolus plus 0.45 μg/kg/min infusie) die aanbevole
terapeutiese dosis tirofiban hidrochloried waargeneem, maar dit is gevind om swak inhibisie te wees. Eers na toediening van nege maal (90 μg/kg bolus plus 1.35 μg/kg/min infusie) die
aanbevole terapeutiese dosis is ‘n sterk, volledige inhibisie waargeneem. Ons het nog ‘n dosis
van 27 maal (270 μg/kg bolus plus 4.05 μg/kg/min infusie) die aanbevole terapeutiese dosis
gegee om die effek van ‘n oordosis op die bloedingsneiging te evalueer. ‘n Statisties
betekenisvolle verlenging in bloeityd (3.05 minute tot 11.90 minute) is waargeneem na
toediening van nege maal die aanbevole terapeutiese dosis, ‘n gemiddelde 2.7 ± 2.44 maal
toename in bloedverlies is ook by dié dosis waargeneem. ‘n Maksimum verhoging in bloeding
van gemiddeld 3.4 ± 1.77 maal is na toediening van 27 maal die aanbevole terapeutiese dosis
waargeneem. Die effektiwiteit van tirofiban hidrochloried was vergelykbaar met dié van
clopidogrel, maar die bloedverlies was baie minder in vergelyking met die gemiddeld 4.3 ± 2.6
maal toename met clopidogrel by 2.5 mg/kg dosis en die 8.0 ± 5.0 maal toename by ‘n 5
mg/kg dosis.
Gevolgtrekking: Tirofiban hidrochloried is ‘n effektiewe anti-plaatjie-middel, maar verskaf
slegs genoegsame beskerming teen arteriële trombose teen ‘n dosis tussen drie en nege maal
die aanbevole terapeutiese dosis. Dit bly egter steeds veiliger in terme van bloeding as die
mees algemene anti-plaatjie-middels in gebruik vandag. Ons stel voor dat verder in vivo
studies gedoen word om te bepaal teen watter dosis tirofiban hidrochloried terapeuties gebruik
kan word, asook dat nuwe kliniese proewe op hoër dosis tirofiban hidrochloried gedoen word.