scholarly journals ĐIỀU TRỊ DUY TRÌ BẰNG OLAPARIB Ở BỆNH NHÂN UNG THƯ BUỒNG TRỨNG TIẾN XA MỚI CHẨN ĐOÁN

2022 ◽  
Vol 508 (2) ◽  
Author(s):  
Phạm Trí Hiếu ◽  
Nguyễn Văn Thắng ◽  
Trần Thị Thanh Huyền
Keyword(s):  
Adenosine Diphosphate ◽  
Brca1 Brca2

Đặt vấn đề: Hầu hết phụ nữ ung thư buồng trứng (UTBT) giai đoạn tiến xa mới chẩn đoán, sau khi điều trị chuẩn bằng phẫu thuật và hóa trị liệu có chứa Platinum sẽ tái phát trong 3 năm đầu. Olaparib là thuốc ức chế enzym poly (adenosine diphosphate–ribose) polymerase, có hiệu quả tốt trong điều trị ung thư buồng trứng tái phát, nhưng lợi ích của Olaparib trong điều trị duy trì đối với các trường hợp mới được chẩn đoán chưa được chứng minh. Phương pháp: Thử nghiệm lâm sàng pha 3, đa trung tâm, ngẫu nhiên, mù đôi, nhằm đánh giá hiệu quả của Olaparib như một liệu pháp duy trì ở những bệnh nhân mới được chẩn đoán ung thư buồng trứng giai đoạn III – IV theo FIGO; gồm các thể: ung thư biểu mô thanh dịch hoặc ung thư dạng nội mạc tử cung, độ ác tính cao, ung thư phúc mạc nguyên phát, ung thư vòi tử cung (hoặc các dạng kết hợp), với đột biến ở gen BRCA1, BRCA2 hoặc cả hai; đã có đáp ứng lâm sàng hoàn toàn hoặc một phần sau khi hóa trị liệu bằng hóa trị có chứa Platinum. Các bệnh nhân được chỉ định ngẫu nhiên, theo tỷ lệ 2:1, được uống Olaparib (300mg hai lần mỗi ngày) hoặc giả dược. Tiêu chí chính của nghiên cứu là sống thêm bệnh không tiến triển (PFS). Kết quả: Trong số 391 bệnh nhân, sau chọn ngẫu nhiên có 260 người được chỉ định nhận Olaparib và 131 nhận giả dược. Tổng cộng 388 bệnh nhân có đột biến gen BRCA1/2 dạng di truyền (germline) và 2 bệnh nhân đột biến dạng mắc phải (somatic) được xác nhận bởi phòng xét nghiệm trung tâm. Sau khi theo dõi trung vị 41 tháng, nguy cơ bệnh tiến triển hoặc tử vong ở nhóm dùng Olaparib thấp hơn 70% so với giả dược; tỷ số nguy cơ (HR) bệnh tiến triển hoặc tử vong là 0,30; CI 95% [0,23 – 0,41], p < 0,001). Các biến cố ngoại ý phù hợp với độc tính đã biết của Olaparib. Kết luận: Điều trị duy trì bằng Olaparib giúp cải thiện đáng kể thời gian sống thêm bệnh không tiến triển ở phụ nữ ung thư buồng trứng giai đoạn tiến xa mới chẩn đoán, có đột biến gen BRCA1/2; làm giảm 70% nguy cơ tiến triển bệnh hoặc tử vong so với với giả dược.

Ticlopidine Facilitates the Deaggregation of Human Platelets Aggregated by Thrombin

1994 ◽  
Vol 71 (01) ◽  
pp. 091-094 ◽  
Author(s):  
M Cattaneo ◽  
B Akkawat ◽  
R L Kinlough-Rathbone ◽  
M A Packham ◽  
C Cimminiello ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Platelet Aggregation ◽  
Prostaglandin E1 ◽  
Human Platelet ◽  
Adenosine Diphosphate ◽  
Human Platelets ◽  
Before And After ◽  
Normal Human ◽  
Platelet Aggregates ◽  
Induced Aggregation

SummaryNormal human platelets aggregated by thrombin undergo the release reaction and are not readily deaggregated by the combination of inhibitors hirudin, prostaglandin E1 (PGE1) and chymotrypsin. Released adenosine diphosphate (ADP) plays an important role in the stabilization of thrombin-induced human platelet aggregates. Since ticlopidine inhibits the platelet responses to ADP, we studied thrombin-induced aggregation and deaggregation of 14C-serotonin-labeled platelets from 12 patients with cardiovascular disease before and 7 days after the oral administration of ticlopidine, 250 mg b.i.d. Before and after ticlopidine, platelets stimulated with 1 U/ml thrombin aggregated, released about 80–90% 14C-serotinin and did not deaggregate spontaneously within 5 min from stimulation. Before ticlopidine, hirudin (5× the activity of thrombin) and PGE1 (10 μmol/1) plus chymotrypsin (10 U/ml) or plasmin (0.06 U/ml), added at the peak of platelet aggregation, caused slight or no platelet deaggregation. After ticlopidine, the extent of platelet deaggregation caused by the same inhibitors was significantly greater than before ticlopidine. The addition of ADP (10 μmol/1) to platelet suspensions 5 s after thrombin did not prevent the deaggregation of ticlopidine-treated platelets. Thus, ticlopidine facilitates the deaggregation of thrombin-induced human platelet aggregates, most probably because it inhibits the effects of ADP on platelets.

Adenosine Diphosphate-Induced Aggregation of Human Platelets in Flow Through Tubes: III. Shear and Extrinsic Fibrinogen-Dependent Effects

1994 ◽  
Vol 71 (01) ◽  
pp. 078-090 ◽  
Author(s):  
H L Goldsmith ◽  
M M Frojmovic ◽  
Susan Braovac ◽  
Fiona McIntosh ◽  
T Wong
Keyword(s):  
Shear Rate ◽  
Single Cells ◽  
Adenosine Diphosphate ◽  
Human Platelets ◽  
Size Analysis ◽  
Fibrinogen Concentration ◽  
Human Fibrinogen ◽  
Shear Rates ◽  
Rate Dependent ◽  
Induced Aggregation

SummaryThe effect of shear rate and fibrinogen concentration on adenosine diphosphate-induced aggregation of suspensions of washed human platelets in Poiseuille flow at 23°C was studied using a previously described double infusion technique and resistive particle counter size analysis (1). Using suspensions of multiple-centrifuged and -washed cells in Tyrodes-albumin [3 × 105 μl−1; (17)] with [fibrinogen] from 0 to 1.2μM, the, rate and extent of aggregation with 0.7 μM ADP in Tyrodes-albumin were measured over a range of mean transit times from 0.2 to 43 s, and at mean tube shear rates, Ḡ, = 41.9, 335 and 1,335 s−1. As measured by the decrease in singlet concentration, aggregation at 1.2 μM fibrinogen increased with increasing Ḡ up to 1,335 s1, in contrast to that previously reported in citratcd plasma, in which aggregation reached a maximum at Ḡ = 335 s−1. Without added fibrinogen, there was no aggregation at Ḡ = 41.9 s1; at Ḡ = 335 s1, there was significant aggregation but with an initial lag time, aggregation increasing further at Ḡ = 1,335 s−1. Without added fibrinogen, aggregation was abolished at all Ḡ upon incubation with the hexapeptide GRGDSP, but was almost unaffected by addition of an F(ab’)2 fragment of an antibody to human fibrinogen. Aggregation in the absence of added fibrinogen was also observed at 37°C. The activation of the multiple-washed platelets was tested using flow cytometry with the fluorescently labelled monoclonal antibodies FITC-PAC1 and FITC-9F9. It was shown that 57% of single cells in unactivated PRT expressed maximal GPIIb-IIIa fibrinogen receptors (MoAb PAC1) and 54% expressed pre-bound fibrinogen (MoAb 9F9), with further increases on ADP activation. However, incubation with GRGDSP and the F(ab’)2 fragment did not inhibit the prebound fibrinogen. Moreover, relatively unactivated cells (8% expressing receptor, 14% prebound fibrinogen), prepared from acidified cPRP by single centrifugation with 50 nM of the stable prostacyclin derivative, ZK 36 374, and resuspension in Tyrodes-albumin at 5 × 104 μl−1, aggregated with 2 and 5 μM ADP at Ḡ = 335 and 1,335 s−1 in the absence of added fibrinogen. We therefore postulate that a protein such as von Willebrand factor, secreted during platelet isolation or in flow at sufficiently high shear rates, may yield the observed shear-rate dependent aggregation without fibrinogen.

The Inhibition of Platelet Aggregation by an Aorta Intima Extract

1974 ◽  
Vol 32 (02/03) ◽  
pp. 417-431 ◽  
Author(s):  
A. du P Heyns ◽  
D. J van den Berg ◽  
G. M Potgieter ◽  
F. P Retief
Keyword(s):  
Platelet Aggregation ◽  
Degradation Products ◽  
Adenosine Diphosphate ◽  
Inhibitory Effect ◽  
Protective Role ◽  
Vascular Trauma ◽  
Wear And Tear ◽  
Sequential Addition ◽  
Aggregation Activity

SummaryThe platelet aggregating activity of extracts of different layers of the arterial wall was compared to that of Achilles tendon. Arterial media and tendon extracts, adjusted to equivalent protein content as an index of concentration, aggregated platelets to the same extent but an arterial intima extract did not aggregate platelets. Platelet aggregation induced by collagen could be inhibited by mixing with intima extract, but only to a maximum of about 80%. Pre-mixing adenosine diphosphate (ADP) with intima extracts diminished the platelet aggregation activity of the ADP. Depending on the relationship between ADP and intima extract concentrations aggregating activity could either be completely inhibited or inhibition abolished. Incubation of ADP with intima extract and subsequent separation of degradation products by paper chromatography, demonstrated a time-dependent breakdown of ADP with AMP, adenosine, inosine and hypoxanthine as metabolic products; ADP removal was complete. Collagen, thrombin and adrenaline aggregate platelets mainly by endogenous ADP of the release reaction. Results of experiments comparing inhibition of aggregation caused by premixing aggregating agent with intima extract, before exposure to platelets, and the sequential addition of first the intima extract and then aggregating agent to platelets, suggest that the inhibitory effect of intima extract results from ADP breakdown. It is suggested that this ADP degradation by intima extract may play a protective role in vivo by limiting the size of platelet aggregates forming at the site of minimal “wear and tear” vascular trauma.

The Effect of Mitomycin C on Platelet Aggregation and Adenosine 3′, 5′-Monophosphate Metabolism

1978 ◽  
Vol 39 (01) ◽  
pp. 177-185 ◽  
Author(s):  
Shuichi Hashimoto ◽  
Sachiko Shibata ◽  
Bonro Kobayashi
Keyword(s):  
Platelet Aggregation ◽  
Cyclic Amp ◽  
Mitomycin C ◽  
Blood Platelets ◽  
Adenosine Diphosphate ◽  
Cellular Membrane ◽  
Adenyl Cyclase ◽  
Cyclic Amp Phosphodiesterase ◽  
Membrane Structure And Function ◽  
And Function

SummaryThe effect of Mitomycin C on aggregation, adenosine 3′, 5′-monophosphate (cyclic AMP) metabolism and reactions induced by thrombin was studied in rabbit platelets. Mitomycin C inhibited the platelet aggregation induced by adenosine diphosphate or thrombin. The level of radioactive cyclic AMP derived from 8-14C adenine or 8-14C adenosine increased after incubating intact platelets with Mitomycin G. Formation of radioactive adenosine triphosphate also increased though mitochondrial oxidation was not stimulated. Similar effect was observed also in rabbit liver. Mitomycin C failed to stimulate platelet adenyl cyclase but inhibited cyclic AMP phosphodiesterase in the absence of theophylline. In the platelets preincubated with Mitomycin C, thrombin-induced inhibition of adenyl cyclase, stimulation of membrane-bound cyclic AMP phosphodiesterase, and release of 250,000 dalton protein from platelet membranes were prevented. These results suggest that Mitomycin C will affect cellular membrane structure and function, and this extranuclear effect of Mitomycin C will lead to inhibition of aggregation in blood platelets.

Involvement of 5-Hydroxytryptamine in Platelet Aggregation In Vivo in Rats and Guinea Pigs

1989 ◽  
Vol 61 (03) ◽  
pp. 463-467 ◽  
Author(s):  
G M Smith
Keyword(s):  
Platelet Count ◽  
Guinea Pigs ◽  
Platelet Adhesion ◽  
Adenosine Diphosphate ◽  
Rate Of Return ◽  
Low Doses ◽  
Dose Dependent ◽  
Higher Doses ◽  
Rat Platelets

SummaryIn this study, 5-hydroxytryptamine (5-HT) caused a dose- dependent fall in the circulating platelet count suggesting that 5-HT receptors are activated in rat platelets to cause platelet adhesion and aggregation. When low doses of adenosine diphosphate (ADP) were simultaneously injected with 5-HT, there was a significant potentiation of the responses to ADR Ketanserin significantly reduced the potentiated responses. When higher doses of ADP were infused with bolus injections of 5-HT there was no potentiation and ketanserin did not reduce these responses. Ketanserin did not inhibit the collagen-induced fall in circulating platelet count, but did significantly increase the rate of return to the basal platelet count compared with control. 5-HT did not cause a fall in platelet count in guinea-pigs

A Monoclonal Antibody to the Human Platelet Glycoprotein II b/III a Complex Induces Platelet Activation

1988 ◽  
Vol 60 (01) ◽  
pp. 068-074 ◽  
Author(s):  
Piet W Modderman ◽  
Han G Huisman ◽  
Jan A van Mourik ◽  
Albert E G Kr von dem Borne
Keyword(s):  
Human Platelet ◽  
Adenosine Diphosphate ◽  
Dense Granule ◽  
Platelet Glycoprotein ◽  
Activated Platelets ◽  
Complex Functions ◽  
Slow Aggregation ◽  
Irreversible Aggregation ◽  
Platelet Release ◽  
Aggregation Of Platelets

SummaryThe platelet glycoprotein (GP) IIb/IIIa complex functions as the receptor for fibrinogen on activated platelets. The effects of two anti-GPIIb/IIIa monoclonal antibodies on platelet function were studied. These antibodies, 6C9 and C17, recognized different epitopes, which were exclusively present on the undissociated GPIIb/IIIa complex. Whereas C17 inhibited the binding of fibrinogen to platelets and platelet aggregation induced by adenosine diphosphate (ADP) or collagen, 6C9 caused irreversible aggregation of platelets, both in the presence and absence of extracellular fibrinogen. When incubated with unstirred (nonaggregating) platelets, 6C9 induced release of alpha and dense granule-constituents as well as binding of 125I-fibrinogen to platelets. The latter was evidently mediated in part by platelet-derived ADP, since it was inhibited to a large extent by apyrase, the ADP-hydrolyzing enzyme. F(ab’)2 fragments of 6C9 did not induce platelet-release reactions but caused (slow) aggregation of platelets in the presence of extracellular fibrinogen.These results indicate that binding of an antibody to a specific site on the platelet GPIIb/IIIa complex may cause fibrinogen-mediated aggregation. The Fc part of the platelet-bound antibody appears to be involved in the induction of platelet release.

Haemostatic Platelet Plug Formation in the Isolated Rabbit Mesenteric Preparation - An Analysis of Red Blood Cell Participation

1980 ◽  
Vol 44 (01) ◽  
pp. 006-008 ◽  
Author(s):  
D Bergqvist ◽  
K-E Arfors
Keyword(s):  
Whole Blood ◽  
Platelet Rich Plasma ◽  
Adenosine Diphosphate ◽  
In Vitro Test ◽  
Pharmacological Agents ◽  
Vitro Test ◽  
Releasing Effect ◽  
Plug Formation

SummaryIn a model using an isolated rabbit mesenteric preparation microvessels were transected and the time until haemostatic plugs formed was registered. Perfusion of platelet rich plasma gave no haemostasis whereas whole blood did. Addition of chlorpromazine or adenosine to the whole blood significantly prolonged the time for haemostasis, and addition of ADP to the platelet rich plasma significantly shortened it. It is concluded that red cells are necessary for a normal haemostasis in this model, probably by a combination of a haemodynamic and ADP releasing effect.The fundamental role of platelets in haemostatic plug formation is unquestionable but there are still problems concerning the stimulus for this process to start. Three platelet aggregating substances have been discussed – thrombin, adenosine diphosphate (ADP) and collagen. Evidence speaking in favour of thrombin is, however, very minimal, and the discussion has to be focused on collagen and ADP. In an in vitro system using polyethylene tubings we have shown that "haemostasis" can be obtained without the presence of collagen but against these results can be argued that it is only another in vitro test for platelet aggregation (1).To be able to induce haemostasis in this model, however, the presence of red blood cells is necessary. To further study this problem we have developed a model where haemostatic plug formation can be studied in the isolated rabbit mesentery and we have briefly reported on this (2).Thus, it is possible to perfuse the vessels with whole blood as well as with platelet rich plasma (PRP) and different pharmacological agents of importance.

Platelet Incorporation of Labelled Adenosine and Adenosine Diphosphate

1969 ◽  
Vol 22 (02) ◽  
pp. 304-315 ◽  
Author(s):  
E. W Salzman ◽  
T. P Ashford ◽  
D. A Chambers ◽  
Lena L. Neri
Keyword(s):  
Platelet Rich Plasma ◽  
Adenosine Diphosphate ◽  
Platelet Inhibition ◽  
Electron Microscopic ◽  
Platelet Binding ◽  
Minor Degree ◽  
A Minor ◽  
Plasma Marker ◽  
Electron Microscopic Radioautography ◽  
Simultaneous Assessment

SummaryAfter incubation of platelet-rich plasma with labelled adenosine or ADP, platelet incorporation of radioactivity was assessed. Platelets were rapidly separated for counting by filtration through cellulose acetate Millipore. Inulin-H3 served as a plasma marker, and triple isotope techniques permitted simultaneous assessment of the behavior of the adenine and phosphate moieties of ADP without washing of platelets. In other experiments, electron microscopic radioautography was employed to trace the label after platelet incorporation.The results were consistent with previous reports that ADP is dephosphorylated in plasma and is incorporated by platelets only as a dephosphorylated residue, probably adenosine. The label crossed the platelet membrane and entered the platelet, where it was distributed in platelet granules and the agranular cell sap. Concentration within granules occurred to a minor degree.The results support the hypothesis that platelet aggregation by ADP occurs without a persistent bond of ADP to the platelet. Inhibition of aggregation by adenosine probably depends on a metabolic or transport process rather than on competition between adenosine and ADP for platelet binding sites.

Adenosine Diphosphate (ADP) Breakdown in Human Plasma with Reference to Platelet Aggregation and Uraemia

1968 ◽  
Vol 19 (03/04) ◽  
pp. 438-450
Author(s):  
I. E. T Gan ◽  
B. G Firkin
Keyword(s):  
Platelet Aggregation ◽  
Human Plasma ◽  
Platelet Function ◽  
Adenosine Diphosphate ◽  
Plasma Enzyme ◽  
Aggregation Of Platelets ◽  
Plasma Activity

Summary1. A correlation between platelet aggregation and the plasma enzyme(s) ability to degrade Adenosine Diphosphate (ADP) has been confirmed.2. This plasma activity has been shown to be reduced in 6 patients with uraemia in whom platelet aggregation was demonstrably impaired but not in two whose platelet function was normal. The incorporation of 14C labelled ADP-8-14C was also only reduced in uraemic patients with abnormal platelet aggregation.3. These findings are discussed with particular reference to possible implication in mechanism involved in ADP aggregation of platelets.

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