مجال
التميز
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تميز دراسي و بحثي
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البحوث المنشورة
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البحث (1):
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عنوان البحث:
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Thieno[2,3-b]pyridine
derivatives are potent anti-platelet drugs, inhibiting platelet activation,
aggregation and showing synergy with aspirin
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رابط إلى البحث:
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Click
Here
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تاريخ النشر:
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07/11/2017
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موجز عن البحث:
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Drugs which inhibit platelet function are
commonly used to prevent blood clot formation in patients with Acute Coronary
Syndromes (ACS) or those at risk of stroke. The thieno[3,2-c]pyridine class
of therapeutic agents, of which clopidogrel is the most commonly used, target
the P2Y12 receptor, and are often used in combination with acetylsalicylic
acid (ASA). Six thieno[2,3-b]pyridine were assessed for in vitro
anti-platelet activity; all derivatives showed effects on both platelet
activation and aggregation, and showed synergy with ASA. Some compounds
demonstrated greater activity when compared to clopidogrel. These compounds,
therefore, represent potential novel P2Y12 inhibitors for improved treatment
for patients.
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المؤتمرات العلمية:
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المؤتمر (1):
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عنوان المؤتمر:
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22nd Congress of the European Hematology Association
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تاريخ الإنعقاد:
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25/06/2017
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مكان
الإنعقاد:
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Madrid. Spain
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طبيعة المشاركة:
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Poster presentation
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عنوان المشاركة:
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NOVEL THIENOPYRIDINES AS POTENT
PLATELET INHIBITORS: FUTURE TREATMENTS FOR PLATELET HYPERACTIVITY DISORDERS?
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ملخص المشاركة:
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Background:
Platelet hyperactivity is associated with a number of disorders including
Acute Coronary Syndromes (ACS) and manifests as increased platelet activation
and often inappropriate thrombus formation. The thienopyridine class of
anti-platelet drugs, of which clopidogrel and prasurgrel are the most well
known, target the P2Y12 receptor on platelets, blocking the effects of the platelet
agonist ADP. However, the effect of these drugs is variable amongst patients,
with some patients responding well and some remaining at risk of thrombosis.
This variability highlights a need for a refinement of this class of P2Y12
inhibitor.
Aims:
The aim of this study was to assess the efficacy of six novel thienopyridine
derivatives synthesized by our group by examining their potential as in-vitro
inhibitors of platelet function.
Methods: Healthy
human platelets were isolated and incubated with novel thienopyridine
compounds (DJ0081, DJ0199, DJ0021, DJ0206, DJ0171, DJ0097) (10μM, 30min)
prior to stimulation with ADP (10μM) and analysis of alpha granule secretion
(CD62P expression), GPIIbIIIa activation (PAC1 expression) and platelet
leukocyte aggregate (PLA) formation using flow cytometry. Furthermore, light
transmission aggregometry (LTA) was used to assess ADP-stimulated aggregation
after these treatments. As clopidogrel is usually prescribed in combination
with the COX-1 inhibitor acetylsalicylic acid (ASA), synergy of the novel
compounds with ASA (30μM) was also analysed by LTA. All results were compared
to ADP-stimulated samples and samples treated with clopidogrel (10μM, 30min)
prior to ADP stimulation.
Results: All six
novel compounds demonstrated a significant reduction in ADP-mediated platelet
aggregation (P<0.001), CD62P expression (p<0.001), PAC1 expression
(p<0.01) and PLA formation (p<0.05). These compounds were also shown to
enhance the inhibitory effects of ASA. DJ0171 and DJ0199 were particularly
potent, displaying greater inhibitory effect than clopidogrel.
Summary/Conclusion: The
study demonstrates the potential for new thienopyridine compounds as
modulators of platelet function and points to the possibility of future use
in patients at risk of platelet hyperactivity and thrombosis.
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المؤتمر (2):
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عنوان المؤتمر:
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BRITISH ATHEROSCLEROSIS SOCIETY/ British
Cardiovascular Society
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تاريخ الإنعقاد:
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07/06/2017
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مكان
الإنعقاد:
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Manchester- UK
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طبيعة المشاركة:
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Poster presentation
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عنوان المشاركة:
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NOVEL THIENOPYRIDINES ARE POTENT
ANTI-PLATELET DRUGS, INHIBITING PLATELET ACTIVATION, AGGREGATION AND SHOWING
SYNERGY WITH ASPIRIN
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ملخص المشاركة:
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Background: Management
of Acute Coronary Syndromes (ACS) often involves the use of platelet
inhibitors. The most commonly used drug, clopidogrel, belongs to a class of
thienopyridine molecules which targets the P2Y12 receptor on platelets and it
is commonly used in combination with the COX-1 inhibitor acetylsalicylic acid
(ASA). However, the effect of these treatments is variable amongst patients,
highlighting a need for a refinement of this class of P2Y12 inhibitor. The
aim of this study was to assess the efficacy of six novel thienopyridine
derivatives synthesized by our group by examining their potential as in-vitro
inhibitors of platelet function.
Methods:
Healthy human platelets were isolated and incubated with novel thienopyridine
compounds (DJ0081, DJ0199, DJ0021, DJ0206, DJ0171, DJ0097) (10μM, 30min)
prior to stimulation with ADP (10μM) and analysis of alpha granule secretion
(CD62P expression), GPIIbIIIa activation (PAC1 expression) and platelet
leukocyte aggregate (PLA) formation using flow cytometry. Furthermore, light
transmission aggregometry (LTA) was used to assess ADP-stimulated aggregation
after these treatments. Synergy with ASA (30μM) was also analysed by LTA
following incubation with ASA and thienopyridine. All results were compared
to ADP-stimulated samples and samples treated with clopidogrel (10μM, 30min)
prior to ADP stimulation.
Results: All six
novel compounds demonstrated a significant reduction in ADP-mediated platelet
aggregation (P<0.001), CD62P expression (p<0.001), PAC1 expression
(p<0.01) and PLA formation (p<0.05). These compounds were also shown to
enhance the inhibitory effects of ASA. DJ0171 and DJ0199 were particularly
potent, displaying greater inhibitory effect than clopidogrel.
Conclusion: The
study demonstrates the potential for new thienopyridine compounds as
modulators of platelet function and points to the possibility of future use
in patients at risk of platelet hyperactivity and thrombosis.
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المؤتمر (3):
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عنوان المؤتمر:
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XXXVI World Congress
International Society of Hematology hosted by: British Society for
Haematology
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تاريخ الإنعقاد:
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18-21/04/2016
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مكان
الإنعقاد:
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Glasgow- UK
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طبيعة المشاركة:
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Poster presentation
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عنوان المشاركة:
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Platelet activation and
aggregation is modulated by the Hodgkin Lymphoma ‘secretome’
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ملخص المشاركة:
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Lymphoma
is commonly associated with platelet dysfunction, usually evidenced by the
development of thrombosis in lymphoma patients. However, active bleeding is
also a frequent occurrence and is typically attributed to thrombocytopenia
which occurs due to impaired megakaryocyte production in the bone marrow.
Platelets have been shown to actively sequester growth factors, inflammatory
proteins and even miRNAs from their microenvironment. Therefore, the
lymphoma-secretome containing lymphoma-derived growth factors and cytokines
could be taken up by platelets and contribute to bleeding symptoms in
lymphoma patients via thrombocytopathy in the presence of adequate
megakaryocyte production. The study aimed to determine the effect of the
secretome from L-1236 Hodgkin lymphoma cells and specific cytokines (IL-6 and
TNF-a) present in this secretome, on the activation and function of healthy
platelets.
Conditioned
media (secretome) was collected from L-1236 cells following standard culture
for varying times at varying cell densities. The secretome significantly
inhibited the expression of the activation markers, CD62P and PAC-1 on
platelets obtained from healthy volunteers. This was true at all cell
concentrations and all culture times tested. Platelet aggregation induced by
ADP or collagen was also inhibited following incubation with the secretome.
These results were mirrored when healthy platelets were treated with IL-6 or
TNF-a at various concentrations for various time periods.
The
results provide further evidence of a link between lymphoma and platelet
activity. Further work aims to characterise the specific mechanisms by which
these cytokines interact with and modulate platelet function.
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