The evaluation of tirofiban hydrochloride in a high shear rate arterial thrombosis model in baboons
| dc.contributor.advisor | Meiring, S. M. | |
| dc.contributor.advisor | Roodt, J. P. | |
| dc.contributor.author | Janse van Rensburg, Walter James | |
| dc.date.accessioned | 2017-02-02T07:17:41Z | |
| dc.date.available | 2017-02-02T07:17:41Z | |
| dc.date.issued | 2009-11 | |
| dc.description.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. | en_ZA |
| dc.description.abstract | 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. | af |
| dc.identifier.uri | http://hdl.handle.net/11660/5474 | |
| dc.language.iso | en | en_ZA |
| dc.publisher | University of the Free State | en_ZA |
| dc.rights.holder | University of the Free State | en_ZA |
| dc.subject | Dissertation (M.Med.Sc. (Haematology and Cell Biology))--University of the Free State, 2009 | en_ZA |
| dc.subject | Acute coronary syndrome | en_ZA |
| dc.subject | Anti-platelet drugs | en_ZA |
| dc.subject | Arterial thrombosis | en_ZA |
| dc.subject | Atherosclerosis | en_ZA |
| dc.subject | GP IIb/IIIa inhibitor | en_ZA |
| dc.subject | Non-human primates | en_ZA |
| dc.subject | Tirofiban hydrochloride | en_ZA |
| dc.subject | Thrombosis -- Drug therapy | en_ZA |
| dc.subject | Atherosclerosis -- Prevention | en_ZA |
| dc.subject | Anticoagulants (Medicine) | en_ZA |
| dc.subject | Drugs -- Dosage | en_ZA |
| dc.subject | Baboons as laboratory animals | en_ZA |
| dc.title | The evaluation of tirofiban hydrochloride in a high shear rate arterial thrombosis model in baboons | en_ZA |
| dc.type | Dissertation | en_ZA |