BACKGROUND: Currently, used oral antiplatelet drugs are both limited and associated with the risk of treatment failure/resistance. Research in this area is hence highly desired. A series of xanthene-3-ones derivatives, we had synthesized, showed us that these derivatives had antiplatelet activity. As far as we know, no research on the effects of xanthen-3-ones in this area has been done. OBJECTIVE: The aim was to study the antiplatelet potential of a series of synthesised 9-phenylxanthene- 3-ones and to find the ideal structural feature(s) for antiplatelet potential and determine the mechanism of action. METHODS: The compounds were synthesized from 1,2,4-triacetoxybenzene and various benzaldehydes. The reaction proceeded smoothly under acidic alcoholic conditions, furnishing the desired products in good yields. The compounds were first screened in whole human blood where platelet aggregation was induced by arachidonic acid. Further analysis was targeted at search of the mechanism of action. RESULTS: Initial screening showed that a majority of the synthesized derivatives had substantial antiplatelet potential. None of the compounds were able to block cyclooxygenase 1 or thromboxane synthase. The mechanism appeared to be based on antagonism of thromboxane effects. The most potent compound 9-(4'-dimethylaminophenyl)-2,6,7-trihydroxy-xanthene-3-one had better potential to block collagen induced platelet aggregation than clinically used acetylsalicylic acid. CONCLUSION: The last mentioned derivative is promising for further in vivo testing.
- Klíčová slova
- Antiplatelet, arachidonic acid, cyclooxygenase, platelet, thromboxane, xanthene-3-one,
- MeSH
- agregace trombocytů účinky léků MeSH
- inhibitory agregace trombocytů chemická syntéza chemie farmakologie MeSH
- lidé MeSH
- molekulární struktura MeSH
- thromboxan A2 antagonisté a inhibitory MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- xantony chemická syntéza chemie farmakologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- 9-(4'-dimethylaminophenyl)-2,6,7-trihydroxyxanthene-3-one MeSH Prohlížeč
- inhibitory agregace trombocytů MeSH
- thromboxan A2 MeSH
- xantony MeSH
AIMS: Platelet function testing is often affected by the existence of different pre-analytical variables that can cause platelet activation. The aim of this study was to assess the effect of such variables that are present when samples are taken (different anticoagulants, incubation temperature, and storage conditions) to select those which enable to reach optimal range of measured plasma concentrations of the two stable thromboxane A₂ metabolites, that is, thromboxane B₂ (TxB₂) and 11-dehydrothromboxane B₂ (11-dTxB₂). MATERIALS AND METHODS: For the purpose of this study, whole blood samples obtained from 20 volunteers were screened for TxB₂ and 11-dTxB₂ concentrations using commercial EIA kits (Cayman Chemicals™; Neogen™) in relation to the effect of different anticoagulants, using different incubation temperatures and storage conditions. RESULTS: Trisodium citrate has been shown not to be affecting the TxB₂ and 11-dTxB₂ concentrations compared with the values measured in the serum. Incubation of the samples for 1 h at 37 °C and freezing at -20 °C or -80 °C give the most suitable concentration range of both thromboxanes in the used EIA measurement. CONCLUSION: This study describes the setup of such pre-analytical phase conditions that enable the screening of platelet function in terms of the plasma concentrations of TxB₂ and 11-dTxB₂ in selected EIA measurement.
- MeSH
- antikoagulancia farmakologie MeSH
- Aspirin terapeutické užití MeSH
- časové faktory MeSH
- citráty farmakologie MeSH
- imunoenzymatické techniky MeSH
- inhibitory agregace trombocytů farmakologie MeSH
- inhibitory cyklooxygenasy farmakologie MeSH
- lidé MeSH
- odběr biologického vzorku * MeSH
- teplota MeSH
- thromboxan A2 krev metabolismus MeSH
- thromboxan B2 analogy a deriváty krev metabolismus MeSH
- trombocyty účinky léků metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- hodnotící studie MeSH
- srovnávací studie MeSH
- Názvy látek
- 11-dehydro-thromboxane B2 MeSH Prohlížeč
- antikoagulancia MeSH
- Aspirin MeSH
- citráty MeSH
- inhibitory agregace trombocytů MeSH
- inhibitory cyklooxygenasy MeSH
- thromboxan A2 MeSH
- thromboxan B2 MeSH
- trisodium citrate MeSH Prohlížeč
Vascular aging is associated with both structural and functional changes that can take place at the level of the endothelium, vascular smooth muscle cells and the extracellular matrix of blood vessels. With regard to the endothelium, reduced vasodilatation in response to agonists occurs in large conduit arteries as well as in resistance arteries with aging. Reviews concerning the different hypotheses that may account for this endothelial dysfunction have pointed out alterations in the equilibrium between endothelium-derived relaxing and constricting factors. Thus, a decreased vasorelaxation due to nitric oxide and, in some arteries, endothelium-derived hyperpolarizing factor as well as an increased vasoconstriction mediated by cyclooxygenase products such as thromboxane A2 are likely to occur in age-induced impairment of endothelial vasodilatation. Furthermore, enhanced oxidative stress plays a critical role in the deleterious effect of aging on the endothelium by means of nitric oxide breakdown due to reactive oxygen species. The relative contribution of the above phenomenon in age-related endothelial dysfunction is highly dependent on the species and type of vascular bed.
- MeSH
- acetylcholin farmakologie MeSH
- biologické faktory fyziologie MeSH
- cévní endotel fyziologie MeSH
- cyklooxygenasy metabolismus MeSH
- lidé MeSH
- oxid dusnatý metabolismus MeSH
- relaxace svalu účinky léků MeSH
- stárnutí * MeSH
- svaly hladké cévní fyziologie MeSH
- thromboxan A2 metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- Názvy látek
- acetylcholin MeSH
- biologické faktory MeSH
- cyklooxygenasy MeSH
- endothelium-dependent hyperpolarization factor MeSH Prohlížeč
- oxid dusnatý MeSH
- thromboxan A2 MeSH
Fourteen patients with chronic proliferative glomerulonephritis were given for the period of one year 400 mg acetylsalicylic acid and 225 mg dipyridamole per day. During this treatment the thrombocyte aggregation became normal, however, the mean reduction of antiheparin plasma activity was not statistically significant. Normal synthesis of renal prostacyclin declined significantly as a result of treatment, while the renal thromboxane A2 synthesis remained normal even during treatment. Treatment did not influence proteinuria. The mean annual decline of glomerular filtration was greater during the investigation period than the mean annual decline in previous years, the difference was, however, only at the borderline of statistical significance. The authors did not prove a favourable effect of this treatment in patients with chronic proliferative glomerulonephritis.
- MeSH
- agregace trombocytů účinky léků MeSH
- Aspirin aplikace a dávkování terapeutické užití MeSH
- chronická nemoc MeSH
- dipyridamol aplikace a dávkování terapeutické užití MeSH
- dospělí MeSH
- epoprostenol biosyntéza MeSH
- kombinovaná farmakoterapie MeSH
- lidé MeSH
- membranoproliferativní glomerulonefritida krev farmakoterapie metabolismus MeSH
- thromboxan A2 biosyntéza MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- anglický abstrakt MeSH
- časopisecké články MeSH
- Názvy látek
- Aspirin MeSH
- dipyridamol MeSH
- epoprostenol MeSH
- thromboxan A2 MeSH
In 14 patients with chronic proliferative glomerulonephritis, corrected arterial hypertension and normal or marginal glomerular filtration the authors assessed plasmatic and urinary metabolites of PGI2 and TXA2. They found that the production of both PGI2 and TXA2 was raised in the organism and they assume that in the stimulated synthesis hypertension and its treatment participated. The production of both prostaglandins in the kidneys was, however, normal.
- MeSH
- 6-ketoprostaglandin F1 alfa metabolismus MeSH
- chronická nemoc MeSH
- epoprostenol metabolismus MeSH
- lidé MeSH
- membranoproliferativní glomerulonefritida metabolismus MeSH
- prostaglandiny metabolismus MeSH
- thromboxan A2 metabolismus MeSH
- thromboxan B2 metabolismus MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- anglický abstrakt MeSH
- časopisecké články MeSH
- Názvy látek
- 6-ketoprostaglandin F1 alfa MeSH
- epoprostenol MeSH
- prostaglandiny MeSH
- thromboxan A2 MeSH
- thromboxan B2 MeSH
- MeSH
- lidé MeSH
- prostaglandiny metabolismus účinky záření MeSH
- rentgenové záření MeSH
- thromboxan A2 metabolismus účinky záření MeSH
- záření gama MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- anglický abstrakt MeSH
- časopisecké články MeSH
- přehledy MeSH
- Názvy látek
- prostaglandiny MeSH
- thromboxan A2 MeSH
