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1.
N Engl J Med ; 379(4): 352-362, 2018 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-30044938

RESUMO

BACKGROUND: Hereditary angioedema is a life-threatening illness caused by mutations in the gene encoding C1 inhibitor (also called C1 esterase inhibitor) that lead to overactivation of the kallikrein-bradykinin cascade. BCX7353 is a potent oral small-molecule inhibitor of plasma kallikrein with a pharmacokinetic and pharmacodynamic profile that may help prevent angioedema attacks. METHODS: In this international, three-part, dose-ranging, placebo-controlled trial, we evaluated four doses of BCX7353 (62.5 mg, 125 mg, 250 mg, and 350 mg once daily) for the prevention of angioedema attacks over a 28-day period. Patients with type I or II hereditary angioedema with a history of at least two angioedema attacks per month were randomly assigned to BCX7353 or placebo. The primary efficacy end point was the number of confirmed angioedema attacks. Key secondary end points included angioedema attacks according to anatomical location and quality of life. RESULTS: A total of 77 patients underwent randomization, 75 received BCX7353 or placebo, and 72 completed the trial. The rate of confirmed angioedema attacks was significantly lower among patients who received BCX7353 at daily doses of 125 mg or more than among those who received placebo, with a 73.8% difference at 125 mg (P<0.001). Significant benefits with respect to quality-of-life scores were observed in the 125-mg and 250-mg dose groups (P<0.05). Gastrointestinal adverse events, predominantly of grade 1, were the most commonly reported adverse events, particularly in the two highest BCX7353 dose groups. CONCLUSIONS: Once-daily oral administration of BCX7353 at a dose of 125 mg or more resulted in a significantly lower rate of attacks of hereditary angioedema than placebo. Mild gastrointestinal symptoms were the principal side effect. (Funded by BioCryst Pharmaceuticals; APeX-1 ClinicalTrials.gov number, NCT02870972 .).


Assuntos
Angioedemas Hereditários/prevenção & controle , Inibidores Enzimáticos/administração & dosagem , Calicreína Plasmática/antagonistas & inibidores , Administração Oral , Adulto , Idoso , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/farmacocinética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Qualidade de Vida
2.
Eur J Clin Pharmacol ; 73(8): 949-956, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28523478

RESUMO

INTRODUCTION: Glycoprotein VI (GPVI) is the major platelet receptor for collagen-mediated platelet adhesion and activation. SAR264565 is an anti-GPVI-Fab, binds to GPVI with high affinity, and blocks GPVI function in human platelets in vitro. METHODS: The effect of SAR26456 on platelet responsiveness in the blood of 21 healthy male subjects was investigated using Sakariassen's ex vivo thrombogenesis perfusion chamber model on a collagen-coated surface under conditions mimicking arterial flow. Ex vivo effects of SAR264565 (10 and 100 µg/mL) were investigated before administration of aspirin or clopidogrel to study subjects (baseline), after aspirin (2× 300 mg) administration alone, and after combined aspirin (2× 300 mg)/clopidogrel (600 mg) administration. Additional ex vivo and in vitro platelet tests were also performed. RESULTS: Addition of SAR264565 to the perfusion chamber dose-dependently reduced platelet and fibrin deposition, reaching statistical significance at 100 µg/mL (415 ± 67 compared to 137 ± 36 platelets/cm2, [p < 0.01] and fibrin 0.095 ± 0.014 compared to 0.032 ± 0.008 µg/cm2, [p < 0.001]). Aspirin administration caused an additive and dose-dependent reduction of SAR264565-induced platelet and fibrin deposition. Combined aspirin/clopidogrel administration did not lead to additional SAR264565-induced inhibition of platelet or fibrin deposition. CONCLUSION: GPVI antagonism by the anti-GPVI-Fab fragment SAR264565 dose-dependently inhibits platelet adhesion and fibrin formation on a collagen surface under arterial shear. Additive inhibition is observed after prior aspirin administration with no further amplification on top of a combination of aspirin with clopidogrel. Ex vivo antiplatelet tests confirmed a selective inhibiting effect of SAR264565 on collagen-induced platelet activation.


Assuntos
Plaquetas/efeitos dos fármacos , Fragmentos Fab das Imunoglobulinas/farmacologia , Glicoproteínas da Membrana de Plaquetas/antagonistas & inibidores , Adulto , Plaquetas/fisiologia , Fibrina/metabolismo , Humanos , Masculino , Agregação Plaquetária/efeitos dos fármacos , Glicoproteínas da Membrana de Plaquetas/imunologia , Adulto Jovem
3.
J Transl Med ; 15(1): 2, 2017 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-28049490

RESUMO

BACKGROUND: Certain disadvantages of the standard hematopoietic stem and progenitor cell (HSPC) mobilizing agent G-CSF fuel the quest for alternatives. We herein report results of a Phase I dose escalation trial comparing mobilization with a peptidic CXCR4 antagonist POL6326 (balixafortide) vs. G-CSF. METHODS: Healthy male volunteer donors with a documented average mobilization response to G-CSF received, following ≥6 weeks wash-out, a 1-2 h infusion of 500-2500 µg/kg of balixafortide. Safety, tolerability, pharmacokinetics and pharmacodynamics were assessed. RESULTS: Balixafortide was well tolerated and rated favorably over G-CSF by subjects. At all doses tested balixafortide mobilized HSPC. In the dose range between 1500 and 2500 µg/kg mobilization was similar, reaching 38.2 ± 2.8 CD34 + cells/µL (mean ± SEM). Balixafortide caused mixed leukocytosis in the mid-20 K/µL range. B-lymphocytosis was more pronounced, whereas neutrophilia and monocytosis were markedly less accentuated with balixafortide compared to G-CSF. At the 24 h time point, leukocytes had largely normalized. CONCLUSIONS: Balixafortide is safe, well tolerated, and induces efficient mobilization of HSPCs in healthy male volunteers. Based on experience with current apheresis technology, the observed mobilization at doses ≥1500 µg/kg of balixafortide is predicted to yield in a single apheresis a standard dose of 4× 10E6 CD34+ cells/kg from most individuals donating for an approximately weight-matched recipient. Exploration of alternative dosing regimens may provide even higher mobilization responses. Trial Registration European Medicines Agency (EudraCT-Nr. 2011-003316-23) and clinicaltrials.gov (NCT01841476).


Assuntos
Voluntários Saudáveis , Mobilização de Células-Tronco Hematopoéticas , Peptídeos Cíclicos/farmacologia , Peptídeos/farmacologia , Receptores CXCR4/antagonistas & inibidores , Diferenciação Celular/efeitos dos fármacos , Células Dendríticas/citologia , Células Dendríticas/efeitos dos fármacos , Relação Dose-Resposta a Droga , Fator Estimulador de Colônias de Granulócitos/farmacologia , Mobilização de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Masculino , Peptídeos/farmacocinética , Peptídeos Cíclicos/farmacocinética , Receptores CXCR4/metabolismo
5.
Ther Drug Monit ; 38(3): 388-92, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26829599

RESUMO

BACKGROUND: Considerable interest exists in identifying calcineurin inhibitor (CNI)-free and thus, less-toxic immunosuppressive regimens, with mycophenolic acid (MPA)-based treatments being a suitable approach. Because pharmacokinetic analyses of MPA treatments in stable CNI-free renal transplant recipients are lacking, the authors aimed at comparing the steady-state pharmacokinetic characteristics of MPA in patients on stable treatment with mycophenolate mofetil (MMF) or enteric-coated mycophenolate sodium (EC-MPS) plus prednisone (≤5 mg/d). METHODS: In the prospective, nonrandomized, open-label study, patients with stable transplant function since ≥6 months received their routine single dose of either MMF (n = 12) or EC-MPS (n = 11). The MPA plasma concentration was recorded over 12 hours. Parameters assessed were predose MPA concentration (C0), postdose minimum and maximum concentration (Cmin and Cmax), time to maximum concentration (Tmax), and area under the concentration-time curve (AUC) for the 12-hours of exposure (AUC0-12). RESULTS: Baseline characteristics were comparable between both the groups. Consistent with enteric coating, the mean Tmax was significantly longer after the intake of EC-MPS compared with MMF (2.2 versus 0.8 hours; P = 0.0002). The exposure measures Cmin, Cmax, and AUC0-12 were not significantly different despite the higher mean MPA equivalent dose in patients receiving MMF compared with those receiving EC-MPS (85% versus 64% of the recommended single dose, respectively). Exposures as reflected by the median AUC0-12 values were 50.7 and 58.7 mg·h·L with MMF and EC-MPS, respectively (P = 0.340). All patients achieved a target AUC of >30 mg·h·L, and 61% had an AUC of >50 mg·h·L. CONCLUSIONS: The study provides first results on the steady-state pharmacokinetics of the 2 MPA drugs in CNI-free immunosuppressant regimens. Pharmacokinetic parameters measured in this study under real-life conditions were comparable in patients receiving MMF or EC-MPS.


Assuntos
Imunossupressores/administração & dosagem , Transplante de Rim/métodos , Ácido Micofenólico/administração & dosagem , Adulto , Idoso , Área Sob a Curva , Feminino , Humanos , Imunossupressores/farmacocinética , Masculino , Pessoa de Meia-Idade , Ácido Micofenólico/farmacocinética , Estudos Prospectivos , Comprimidos com Revestimento Entérico , Transplantados
6.
Eur J Clin Pharmacol ; 69(9): 1617-33, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23619611

RESUMO

BACKGROUND: Novel oral anticoagulants are approved in several indications: rivaroxaban, apixaban, and dabigatran for the prevention of venous thromboembolism after elective hip or knee replacement surgery, and edoxaban for hip or knee replacement surgery and hip fracture surgery (in Japan only); rivaroxaban for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT and PE; and rivaroxaban, apixaban, and dabigatran for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation. These agents overcome some limitations of traditional anticoagulants, are suggested to have no requirement for routine coagulation monitoring, and are administered orally. Rivaroxaban, apixaban, and dabigatran have different pharmacological characteristics, and guidance is needed on optimum doses and dosing intervals and the effects of renal or hepatic impairment, age, food, and other drugs. Dabigatran has stricter prescribing advice than rivaroxaban or apixaban for patients with moderate-to-severe renal impairment. All three drugs have restrictions on use in patients with hepatic impairment. Apixaban requires twice-daily dosing in all indications, whereas rivaroxaban and dabigatran are dosed once- or twice-daily depending on indication. Although head-to-head comparisons are lacking, the novel oral anticoagulants may show favorable cost-benefit relations compared with traditional vitamin K antagonists or no therapy. AIM: This review summarizes the pharmacology of rivaroxaban, apixaban, edoxaban, and dabigatran, and the indications for which they are approved. Issues regarding the optimization of the use of these anticoagulants for the management of thromboembolic disorders will also be discussed.


Assuntos
Anticoagulantes/farmacologia , Administração Oral , Animais , Anticoagulantes/uso terapêutico , Benzimidazóis/farmacologia , Benzimidazóis/uso terapêutico , Dabigatrana , Humanos , Morfolinas/farmacologia , Morfolinas/uso terapêutico , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Piridonas/farmacologia , Piridonas/uso terapêutico , Rivaroxabana , Tiofenos/farmacologia , Tiofenos/uso terapêutico , beta-Alanina/análogos & derivados , beta-Alanina/farmacologia , beta-Alanina/uso terapêutico
7.
Clin Pharmacokinet ; 52(4): 243-54, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23389892

RESUMO

The direct factor Xa (FXa) inhibitors rivaroxaban, apixaban and edoxaban, and the thrombin inhibitor dabigatran etexilate (dabigatran) have gained approval for use in several indications, most notably for the prevention and treatment of venous thromboembolism (VTE) and for the prevention of stroke in patients with atrial fibrillation. Hepatic impairment can affect the disposition of these anticoagulants considerably not only because of the hepatic metabolism of the direct FXa inhibitors but also because moderate to severely impaired hepatic function will affect coagulation. This review describes the key pharmacological properties of novel oral anticoagulants with special attention to patients with impaired hepatic function. In subjects with moderately impaired liver function (i.e. Child-Pugh classification B), the area under the plasma concentration-time curve (AUC) of rivaroxaban (10 mg single dose) is increased by 2.27-fold, which is paralleled by an increase in FXa inhibition. The AUC of apixaban (5 mg single dose) is increased by 1.09-fold, whereas the AUC of edoxaban (15 mg single dose) is decreased by 4.8 % and the AUC of dabigatran (150 mg single dose) is decreased by 5.6 %. Specific labelling restrictions for rivaroxaban, apixaban and dabigatran regarding impaired hepatic function are based on both the Child-Pugh classification and liver-related exclusion criteria applied in pivotal clinical trials. Rivaroxaban is contraindicated in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk, including cirrhotic patients classified as Child-Pugh B and C. Apixaban can be used with caution in patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment or in patients with alanine aminotransferase and aspartate aminotransferase levels >2× upper limit of normal (ULN). Apixaban is not recommended in patients with severe hepatic impairment and is contraindicated in those with hepatic disease associated with coagulopathy and clinically relevant bleeding risk. Dabigatran is not recommended in patients with elevated liver enzymes (>2× ULN). Dabigatran is contraindicated in patients with hepatic impairment or liver disease expected to have any impact on survival. Currently, edoxaban is not available in the US or European markets. However, the Japanese label did not restrict use in hepatic dysfunction but advises care in patients with severe hepatic impairment.


Assuntos
Anticoagulantes/farmacocinética , Anticoagulantes/uso terapêutico , Inibidores do Fator Xa , Hepatopatias/complicações , Trombina/antagonistas & inibidores , Absorção , Anticoagulantes/administração & dosagem , Benzimidazóis/administração & dosagem , Benzimidazóis/farmacocinética , Benzimidazóis/uso terapêutico , Dabigatrana , Relação Dose-Resposta a Droga , Humanos , Hepatopatias/metabolismo , Taxa de Depuração Metabólica , Morfolinas/administração & dosagem , Morfolinas/farmacocinética , Morfolinas/uso terapêutico , Pirazóis/administração & dosagem , Pirazóis/farmacocinética , Pirazóis/uso terapêutico , Piridinas/administração & dosagem , Piridinas/farmacocinética , Piridinas/uso terapêutico , Piridonas/administração & dosagem , Piridonas/farmacocinética , Piridonas/uso terapêutico , Rivaroxabana , Tiazóis/administração & dosagem , Tiazóis/farmacocinética , Tiazóis/uso terapêutico , Tiofenos/administração & dosagem , Tiofenos/farmacocinética , Tiofenos/uso terapêutico , Distribuição Tecidual , Tromboembolia Venosa/sangue , Tromboembolia Venosa/complicações , Tromboembolia Venosa/prevenção & controle
8.
Int J Clin Pharmacol Ther ; 50(12): 873-9, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23006444

RESUMO

OBJECTIVE: Under immunosupression with sirolimus (rapamycin) procoagulant effects and platelet activation have been controversially discussed. METHODS: We evaluated patients of a prospectly designed substudy as part of a randomized trial investigating the effect of a switch from non-mTOR-based immunosuppression to sirolimus in renal transplant recipients. Our substudy consisted of 7 patients who switched therapy from azathioprine to sirolimus (conversion group) and 8 patients who remained on azathioprine (controls) before (V1) and after (V2) 3 months of treatment. In all patients we assessed flowcytometric markers of platelet activation (PAC-1), platelet degranulation (CD62P), formation of platelet leukocyte-aggregates (PLA), monocyte activation (CD11b), endogenous thrombin potential (ETP) and platelet aggregation. RESULTS: Both groups were similar in terms of baseline demographics and had stable transplant function for at least 6 months. CD62P increased significantly in the control group (p < 0.03). PLA were significantly reduced in the sirolimus conversion group at V2 (p < 0.02), whereas no effect was seen in the controls. Expression of PAC-1, CD11b, ETP-peak, ETP-time to peak, ETP-AUC and platelet aggregation showed no significant changes in both groups compared to V2. CONCLUSION: From clinical data, performing in depth platelet function testing, we found no evidence for increased platelet activation parameters in RTR who switched therapy from azathioprine to sirolimus.


Assuntos
Azatioprina/uso terapêutico , Imunossupressores/uso terapêutico , Transplante de Rim , Ativação Plaquetária , Sirolimo/uso terapêutico , Adulto , Idoso , Antígeno CD11b/sangue , Feminino , Citometria de Fluxo , Humanos , Masculino , Pessoa de Meia-Idade , Selectina-P/sangue , Agregação Plaquetária
9.
Pharmacogenet Genomics ; 19(6): 407-14, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19373123

RESUMO

AIM: Addictive behavior is importantly mediated by mesolimbic dopaminergic signaling. Here, we comprehensively analyzed the DRD2 gene locus, and in addition, the ANKK1 rs1800497C>T single nucleotide polymorphism (SNP), formerly known as 'dopamine D2 receptor Taq1A C>T polymorphism', for associations with the risk of opiate addiction and the methadone dosage requirements. METHODS: Allelic frequencies of DRD2/ANKK1 polymorphisms were compared between 85 methadone-substituted Caucasian patients and a random sample of 99 healthy Caucasian controls. Within patients, the average and maximum daily methadone dose during the first year of treatment and the time when that maximum dose was reached were analyzed for an association with DRD2/ANKK1 genetics. RESULTS: Compared with the control group, drug users carried more frequently the minor allele of DRD2 SNP rs1076560G>T SNP (P=0.022, odds ratio 2.343) or the ATCT haplotype of DRD2 rs1799978A>G, rs1076560G>T, rs6277C>T, ANKK1 rs1800497C>T (P=0.048, odds ratio 2.23), with similar tendencies for ANKK1 rs1800497C>T (P=0.056, odds ratio 2.12) and the TCCTCTT haplotype of DRD2 rs12364283T>C, rs1799732C del, rs4648317C>T, rs1076560G>T, rs6275C>T, rs6277C>T, and ANKK1 rs1800497C>T (P=0.059, odds ratio 2.31). The average and maximum daily methadone doses were significantly associated with the DRD2 rs6275C>T SNP (P=0.016 and 0.005 for average and maximum dose, respectively). Carriers of the variant rs6275T allele needed higher methadone doses than noncarriers. In addition, this variant was associated with a longer time to reach the maximum methadone dose (P=0.025). CONCLUSION: On the basis of an analysis spanning the whole gene locus, from the DRD2 promoter to the ANKK1 rs1800497C>T polymorphism, DRD2 genetic polymorphisms modulate both the risk of opiate addiction, leading to the necessity of methadone substitution therapy, and the course of this therapy in terms of dosage requirements.


Assuntos
Variação Genética , Metadona/farmacologia , Entorpecentes/farmacologia , Transtornos Relacionados ao Uso de Opioides/genética , Receptores de Dopamina D2/genética , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Genéticos , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Polimorfismo de Nucleotídeo Único , Proteínas Serina-Treonina Quinases/genética , Fatores de Tempo
10.
J Antimicrob Chemother ; 62(5): 1118-21, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18753189

RESUMO

INTRODUCTION: Thromboembolic complications under antiretroviral therapy (ART) have been described in the past. In particular, the influence of protease inhibitors (PIs) on platelet activation and coagulation is currently under discussion. METHODS: HIV-1-infected, PI-naive adults (n = 18) were investigated before and 4 weeks after the start of the ART, consisting either of boosted PI regimens (n = 13) plus reverse transcriptase inhibitors (RTIs) or a double PI regimen (n = 5) without RTI co-medication. Administered PIs were saquinavir (n = 15), lopinavir (n = 4), fosamprenavir (n = 2) and atazanavir (n = 2). Platelet CD62P, CD40L (%+ cells) and PAC-1 binding [mean fluorescence intensity (MFI)] as well as monocyte CD11b (MFI) and monocyte-associated CD41 (%+ cells and MFI) expression were assessed by flow cytometry with or without platelet stimulation. To investigate the influence of platelets on coagulation, the endogenous thrombin potential (ETP) [render fluorescence units (RFI)] was determined. RESULTS: CD62P, PAC-1 binding and CD11b expression remained unchanged. In contrast, the mean+/-SD MFI of CD40L (from 18.2+/-9.0 to 25.5+/-10.4, P = 0.038) and CD41 (from 446.1+/-213.8 to 605.0+/-183.8, P = 0.010) as markers for increased platelet-leucocyte interaction increased significantly. The collagen-induced ETP time-to-peak was altered significantly from 23.8+/-11.4 to 17.0+/-4.2 min (P = 0.028), although the ETP RFI peak showed no evidence for increased procoagulatory capacity (47.1+/-18.6 to 57.3+/-19.9, P = 0.085). CONCLUSIONS: Effects of the evaluated PI HIV therapy on platelet function assessed under field conditions seem to be minor, not affecting all investigated parameters. We found no evidence for increased platelet activation under PI-containing ART. However, CD41 as a marker for increased platelet-leucocyte interaction and CD40L, which can contribute to atherosclerosis, increased significantly.


Assuntos
Plaquetas/efeitos dos fármacos , Moléculas de Adesão Celular/biossíntese , Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/efeitos adversos , Inibidores da Protease de HIV/uso terapêutico , Leucócitos/efeitos dos fármacos , Adulto , Plaquetas/química , Antígeno CD11b/análise , Ligante de CD40/análise , Feminino , Citometria de Fluxo , Humanos , Leucócitos/química , Masculino , Pessoa de Meia-Idade , Selectina-P/análise , Glicoproteína IIb da Membrana de Plaquetas/análise
11.
J Antimicrob Chemother ; 61(2): 394-9, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18156609

RESUMO

OBJECTIVES: In the past, bleeding events have been described for patients with haemophilia taking HIV-1 protease inhibitors. Recently, the FDA published a warning concerning intracranial haemorrhage in patients taking the HIV-1 protease inhibitor tipranavir co-administered with ritonavir. METHODS: We investigated (i) platelet aggregation in vivo in HIV-1-infected adult patients (n = 5) immediately before and 2 and 4 h after dosing of tipranavir/ritonavir 500/200 mg. To further characterize the effects, we then evaluated (ii) platelet aggregation and (iii) thromboxane B2 (TxB2) formation (ELISA) with increasing tipranavir concentrations (TPV(conc)) in vitro of up to 100,000 ng/mL. Platelet aggregation was stimulated either with 2 microM ADP (ADP) or 10 mg/L collagen (COL). TPV(conc) were measured with validated EPI-LC-MS/MS. Intraindividual comparisons of values at time points and TPV(conc), respectively, were carried out with repeated samples ANOVA. RESULTS: Platelet aggregation (mean, maximal light transmission A(max)) was significantly decreased in patients 4 h post-dose in collagen- (from 79.8% to 57.1%; P < 0.001) and in ADP-stimulated (from 58.5% to 54.0%; not significant) samples at a median (range) TPV(conc) of 62 500 ng/mL (22,990-67,500). These results could be reproduced in vitro at TPV(conc) 50,000 ng/mL (A(max)ADP/A(max)COL = 20.7/36.9%; P = 0.003/<0.001) and 100 000 ng/mL (A(max)ADP/A(max)COL = 14.5/17.1%; P < 0.001/<0.001). Median (range) TxB2 concentrations were reduced (P = 0.07) from 327 ng/mL (187-500) at baseline to 265 ng/mL (152-428) at 5000 ng/mL and were significantly reduced (P < 0.001) to 187 ng/mL (81-362) at a TPV(conc) of 50,000 ng/mL, respectively. CONCLUSIONS: Five HIV-1-infected patients on tipranavir-containing highly active antiretroviral therapy presented marked decreases in platelet aggregation. In vitro these effects were reproduced and decreased TxB2 formation was also demonstrated. Inhibition of platelet aggregation while receiving tipranavir treatment might contribute to increased risk of bleeding.


Assuntos
Agregação Plaquetária/efeitos dos fármacos , Piridinas/farmacologia , Pironas/farmacologia , Tromboxano B2/sangue , Adulto , Infecções por HIV/sangue , Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/farmacologia , Inibidores da Protease de HIV/uso terapêutico , HIV-1 , Humanos , Masculino , Pessoa de Meia-Idade , Agregação Plaquetária/fisiologia , Piridinas/uso terapêutico , Pironas/uso terapêutico
12.
J Clin Pharmacol ; 47(11): 1398-407, 2007 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17873238

RESUMO

Rivaroxaban (BAY 59-7939) is an oral, direct factor Xa inhibitor in advanced development. This study was undertaken to investigate its effects on thrombin generation. In this placebo-controlled, randomized, crossover study, 12 healthy subjects received rivaroxaban (single 5- or 30-mg dose) or placebo. Thrombin generation was investigated by measuring the endogenous thrombin potential and prothrombinase-induced clotting time. Maximal effect of rivaroxaban was observed 2 hours after drug administration: prothrombinase-induced clotting time was prolonged 1.8 and 2.3 times baseline after rivaroxaban 5 and 30 mg, respectively. Collagen-induced endogenous thrombin potential was reduced by approximately 80% and approximately 90% compared with baseline after rivaroxaban 5 and 30 mg, respectively, and tissue factor-induced endogenous thrombin potential was reduced by approximately 40% (5 mg) and approximately 65% (30 mg), respectively. Thrombin generation remained inhibited for 24 hours. There was a close correlation between plasma concentration of rivaroxaban and prolongation of prothrombinase-induced clotting time and reduction in endogenous thrombin potential. Rivaroxaban strongly inhibits platelet-induced thrombin generation, after activation of either platelets or the coagulation pathway, even in the presence of minimal factor Xa inhibition in plasma.


Assuntos
Anticoagulantes/farmacocinética , Inibidores do Fator Xa , Morfolinas/farmacocinética , Tiofenos/farmacocinética , Administração Oral , Adulto , Coagulação Sanguínea/efeitos dos fármacos , Plaquetas/citologia , Plaquetas/enzimologia , Estudos Cross-Over , Relação Dose-Resposta a Droga , Fator Xa/análise , Humanos , Masculino , Rivaroxabana , Trombina/análise , Tempo de Trombina , Tromboplastina/análise , Fatores de Tempo
13.
Clin Ther ; 29(3): 438-47, 2007 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17577465

RESUMO

BACKGROUND: Based on a PubMed search of the literature using the terms parecoxib, platelets, thromboxane, bleeding, and platelet aggregation, the effects of parecoxib on platelet function have not fully been established under clinical conditions. OBJECTIVE: The aim of this study was to determine platelet aggregation, thromboxane B(2) (TxB(2)) formation, and plasma concentrations with the use of parecoxib in postoperative pain management. METHODS: This double-blind, randomized, parallel-group trial was conducted at the University Hospital for Orthopedic Surgery, Friedrichsheim, Frankfurt, Germany. Male and female patients aged 18 to 55 years and scheduled to undergo routine partial meniscectomy (or a similar arthroscopic procedure) were eligible. All patients received dose-adjusted enoxaparin before surgery and parecoxib 40 mg BID or dipyrone 1000 mg QID. Blood samples were drawn before first injection (predose) and at 0.5, 2, and 6 hours after injection. Platelet aggregation (expressed as percentage of the maximal light transmittance [A(max)]) was induced with arachidonic acid (A(max)AA) and collagen (A(max)CO). TxB(2) formation was determined using enzyme-linked immunosorbent assay. RESULTS: This study included 26 patients. In both treatment groups, 8 males and 5 females, all white, were enrolled. In the dipyrone group, the mean age was 48 years (range, 32-61 years) and the mean weight was 85 kg (range, 63-122 kg); in the parecoxib group, the mean age was 47 years (range, 31-61 years) and the mean weight was 81 kg (range, 57-100 kg). Median (interquartile range [IQR]) predose values for A(max)AA were 76% (65%-83%) in the parecoxib group and 87% (80%-89%) in the dipyrone group. At 0.5 hour after injection, A(max)AA was 52% (5%-77%) with parecoxib and 8% (0%-11%) with dipyrone (P=0.004). At 2 hours after injection, A(max)AA was 78% (72%-80%) in the parecoxib group versus 7% (5%-11%) in the dipyrone group (P<0.001). At 6 hours after study drug administration, no treatment differences were found. For A(max)CO, no statistically significant differences were found. Consistent with the stronger inhibition of aggregation, patients who received dipyrone had lower TxB(2) formation values. Six hours after parecoxib administration, mean TxB(2) formation was significantly enhanced compared with predose values (132 ng/mL [IQR, 62-228 ng/mL] vs 185 ng/mL [IQR, 135-239 ng/mL]; P=0.05). CONCLUSIONS: Platelet aggregation and TxB(2) formation were significantly lower for 6 hours in dipyronetreated patients compared with parecoxib-treated patients. In contrast, TxB(2) formation was increased with parecoxib 6 hours after administration compared with pretreatment values. In this small study, parecoxib did not affect platelet aggregation in a population of patients undergoing routine partial meniscectomy (or a similar arthroscopic procedure) under clinical conditions.


Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Inibidores de Ciclo-Oxigenase/efeitos adversos , Dipirona/efeitos adversos , Isoxazóis/efeitos adversos , Agregação Plaquetária/efeitos dos fármacos , Tromboxano B2/metabolismo , Adulto , Idoso , Anti-Inflamatórios não Esteroides/uso terapêutico , Artroscopia , Criança , Inibidores de Ciclo-Oxigenase/uso terapêutico , Dipirona/uso terapêutico , Método Duplo-Cego , Quimioterapia Combinada , Enoxaparina/uso terapêutico , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Isoxazóis/uso terapêutico , Masculino , Pessoa de Meia-Idade , Dor Pós-Operatória/tratamento farmacológico
14.
Clin Pharmacol Ther ; 78(5): 468-76, 2005 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-16321613

RESUMO

BACKGROUND: Increased platelet activation has been described during treatment with various immunosuppressive agents and may contribute to the high cardiovascular mortality rate in renal transplant patients. Platelets are thought to propagate the inflammatory process of atherosclerosis by interaction with leukocytes. METHODS: We tested an experimental therapy with clopidogrel in renal transplant patients treated with either tacrolimus (n = 20) or cyclosporine (INN, ciclosporin) (n = 19). All patients took low-dose steroids and had stable transplant function. Untreated healthy volunteers (n = 11) were included as the reference group. Degranulation (CD62P), glycoprotein IIb/IIIa receptor activation (PAC1), formation of platelet-leukocyte aggregates (monocyte-platelet-leukocyte aggregate, CD11b, mean fluorescence intensity), and platelet CD40 ligand (CD40L) expression (percent positive) were assessed by flow cytometry before therapy (visit 1) and after 4 weeks of clopidogrel (75 mg/d) intake (visit 2). To assess systemic anti-inflammatory effects, we measured levels of high-sensitivity C-reactive protein, soluble CD40L (sCD40L), monocyte chemoattractant protein 1, and matrix metalloproteinase 9 (MMP-9) by enzyme-linked immunosorbent assay. RESULTS: At visit 1, cyclosporine-treated patients had significantly enhanced CD62P and PAC1 expression and platelet-leukocyte aggregate formation, as well as elevated sCD40L concentrations, compared with tacrolimus-treated patients (all P < .03). Clopidogrel intake led to a significant decrease in platelet-leukocyte aggregate formation in tacrolimus-treated patients (median, 237 [interquartile range, 177-510] to 194 [interquartile range, 159-275] mean fluorescence intensity; P < .035) and cyclosporine-treated patients (median, 450 [interquartile range, 362-782] to 254 [interquartile range, 211-458] mean fluorescence intensity; P < .035). CD40L expression was reduced in tacrolimus-treated patients (median, 34 [interquartile range, 28-41] to 21 [interquartile range, 12-26] mean fluorescence intensity; P < .002) and cyclosporine-treated patients (median, 33 [interquartile range, 30-37] to 26 [interquartile range, 19-26] mean fluorescence intensity; P < .02). In addition, CD62P, PAC1, and CD11b were significantly reduced in both groups at visit 2 (P < .02). MMP-9 decreased from 88 ng/mL (range, 49-135 ng/mL) to 57 ng/mL (range, 38-73 ng/mL) (P < .05) in tacrolimus-treated patients and from 79 ng/mL (range, 54-148 ng/mL) to 66 ng/mL (range, 41-97 ng/mL) (P < .01) in cyclosporine-treated patients. The sCD40L concentration decreased significantly only in cyclosporine-treated patients (P < .004). In contrast, high-sensitivity C-reactive protein and monocyte chemoattractant protein 1 were not affected. CONCLUSION: The P2Y(12) receptor antagonist clopidogrel inhibits the expression of platelet activation markers and the interaction of platelets and leukocytes. Because the synthesis of vascular disease markers and inflammatory products such as sCD40L and MMP-9 has been inhibited, anti-inflammatory properties of clopidogrel are likely to be a result of decreasing platelet activation.


Assuntos
Anti-Inflamatórios , Plaquetas/efeitos dos fármacos , Antígenos CD40/biossíntese , Inflamação/metabolismo , Transplante de Rim/fisiologia , Leucócitos/efeitos dos fármacos , Inibidores da Agregação de Plaquetas/uso terapêutico , Ticlopidina/análogos & derivados , Adulto , Idoso , Biomarcadores , Proteína C-Reativa/metabolismo , Antígeno CD11b/sangue , Antígenos CD40/sangue , Quimiocina CCL2/metabolismo , Clopidogrel , Feminino , Citometria de Fluxo , Humanos , Imunossupressores/sangue , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Pessoa de Meia-Idade , Monócitos/efeitos dos fármacos , Ativação Plaquetária/efeitos dos fármacos , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação de Plaquetas/efeitos adversos , Ticlopidina/efeitos adversos , Ticlopidina/uso terapêutico
15.
Semin Thromb Hemost ; 31(4): 458-63, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-16149024

RESUMO

Decreased retention in the retention test Homburg (RTH) indicates a loss of platelet function; increase is associated with an increased activation of platelets, for example, in patients with vascular diseases. Compared with other materials (e.g., collagen, glass pearls, etc.) the filter surface in the retention tubes is nonthrombogenic. Therefore, the RTH seems to be well suited for measuring an in vivo over-reactivity of platelets. In a pilot study using the RTH we evaluated the postoperative over-reactivity of platelets in 14 patients and observed a significant heterogeneity of the platelet population concerning size and stickiness. Reliable platelet function tests are also necessary for "drug monitoring," since they deliver important clinical laboratory parameters for efficient control of a therapy with antiplatelet drugs. Therefore, we evaluated in vitro how, after administration of platelet aggregation-inhibiting medications (such as acetylsalicylic acid, Prostaglandin and ReoPro in various concentrations, the adenosine diphosphate (ADP), collagen, ristocetin, or suprarenin increased retention can be reduced. The reaction of the platelets in platelet-rich plasma of different patients or donors to the addition of ADP is variable. The platelet function inhibitor effect is dose dependent. In a clinical pilot study, a significant platelet-inhibiting effect of clopidogrel using the RTH has been shown.


Assuntos
Plaquetas/citologia , Monitoramento de Medicamentos/métodos , Inibidores da Agregação de Plaquetas/farmacologia , Testes de Função Plaquetária/métodos , Abciximab , Difosfato de Adenosina/metabolismo , Anticorpos Monoclonais/farmacologia , Aspirina/farmacologia , Forma Celular , Clopidogrel , Colágeno/sangue , Humanos , Fragmentos Fab das Imunoglobulinas/farmacologia , Selectina-P/sangue , Projetos Piloto , Plasma/metabolismo , Agregação Plaquetária , Contagem de Plaquetas , Prostaglandinas/farmacologia , Ristocetina/sangue , Ticlopidina/análogos & derivados , Ticlopidina/farmacologia
16.
Semin Thromb Hemost ; 31(4): 482-5, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-16149028

RESUMO

Treatment with glycoprotein (GP) IIb/IIIa inhibitors in combination with aspirin and clopidogrel have become essential therapeutic strategies during invasive procedures and coronary events. However, the ideal monitoring test for the effects of these treatments is still missing. Therefore, we investigated the new Platelet Adhesion Assay (PADA) for its sensitivity in characterizing antiplatelet therapy. Five healthy volunteers were studied before and after a single dose of aspirin (500 mg). Samples were spiked in vitro with increasing doses of abciximab (0, 0.25, 1, 3 microg/mL), eptifibatide (0, 0.25, 1, 2 microg/mL), and AR-C 69931 MX (1 microg/mL) in citrated and hirudinized whole blood. The adhesion index (AI), as the characteristic parameter of the PADA test, decreased in a dose-dependent fashion for abciximab and eptifibatide. Variable effects between the different anticoagulants were shown for eptifibatide. Aspirin showed no additional effect, while inhibition by AR-C 69931 MX was demonstrated in hirudinized blood only. We concluded that different levels of GPIIb/IIIa inhibitors and adenosine diphosphate-receptor inhibition could be assessed with the PADA test, although different anticoagulants led to different results. The suitability of this test for daily use will have to be elucidated in further patient studies.


Assuntos
Aspirina/farmacologia , Monitoramento de Medicamentos/métodos , Inibidores da Agregação de Plaquetas/farmacologia , Testes de Função Plaquetária/instrumentação , Testes de Função Plaquetária/métodos , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/antagonistas & inibidores , Ticlopidina/análogos & derivados , Abciximab , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/farmacologia , Anticorpos Monoclonais/farmacologia , Anticoagulantes/farmacologia , Clopidogrel , Relação Dose-Resposta a Droga , Eptifibatida , Hirudinas/farmacologia , Humanos , Fragmentos Fab das Imunoglobulinas/farmacologia , Peptídeos/farmacologia , Adesividade Plaquetária , Sensibilidade e Especificidade , Ticlopidina/farmacologia
17.
Br J Pharmacol ; 146(4): 514-24, 2005 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16086030

RESUMO

We have recently shown that in polymorphonuclear leukocytes, 11-keto boswellic acids (KBAs) induce Ca2+ mobilisation and activation of mitogen-activated protein kinases (MAPK). Here we addressed the effects of BAs on central signalling pathways in human platelets and on various platelet functions. We found that beta-BA (10 microM), the 11-methylene analogue of KBA, caused a pronounced mobilisation of Ca2+ from internal stores and induced the phosphorylation of p38 MAPK, extracellular signal-regulated kinase (ERK)2, and Akt. These effects of beta-BA were concentration dependent, and the magnitude of the responses was comparable to those obtained after platelet stimulation with thrombin or collagen. Based on inhibitor studies, beta-BA triggers Ca2+ mobilisation via the phospholipase (PL)C/inositol-1,4,5-trisphosphate pathway, and involves Src family kinase signalling. Investigation of platelet functions revealed that beta-BA (> or =10 microM) strongly stimulates the platelet-induced generation of thrombin in an ex-vivo in-vitro model, the liberation of arachidonic acid (AA), and induces platelet aggregation in a Ca2+-dependent manner. In contrast to beta-BA, the 11-keto-BAs (KBA or AKBA) evoke only moderate Ca2+ mobilisation and activate p38 MAPK, but fail to induce phosphorylation of ERK2 or Akt, and do not cause aggregation or significant generation of thrombin. In summary, beta-BA potently induces Ca2+ mobilisation as well as the activation of pivotal protein kinases, and elicits functional platelet responses such as thrombin generation, liberation of AA, and aggregation.


Assuntos
Anti-Inflamatórios/farmacologia , Plaquetas/efeitos dos fármacos , Sinalização do Cálcio/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Triterpenos/farmacologia , Análise de Variância , Anti-Inflamatórios/química , Ácido Araquidônico/metabolismo , Plaquetas/fisiologia , Relação Dose-Resposta a Droga , Humanos , Técnicas In Vitro , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Fosforilação/efeitos dos fármacos , Agregação Plaquetária/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Trombina/metabolismo , Fatores de Tempo , Triterpenos/química , Fosfolipases Tipo C/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Quinases da Família src/metabolismo
18.
Thromb Haemost ; 91(6): 1137-45, 2004 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-15175800

RESUMO

Treatment with the direct thrombin inhibitor argatroban (ARG) is often followed by vitamin K-antagonist treatment (VKA). Phenprocoumon (PC) and acenocoumarol (AC) are frequently used in Europe. The standard monitoring test for VKA, pro-thrombin time (PT), is prolonged by direct thrombin inhibitors. Therefore the International Normalized Ratio (INR) obtained during combined treatment does not reflect the true effect of the VKA. A similar interference of the VKA on the activated partial thromboplastin time (aPTT), a monitoring assay for direct thrombin inhibitors, can occur. In 39 healthy volunteers the effect of ARG alone or combined with PC or AC on PT, INR, aPTT, and Ecarin Clotting Time (ECT) was investigated. 6 groups each of 6-8 volunteers received a 5-hour infusion of either 1.0, 2.0 or 3.0 microg/kg/min ARG (days 1, 3, 4 and 5) before initiation of either PC or AC (day 1) and during continued VKA dosing (target INR 2-3). A linear relationship (INR(ARG+VKA) = intercept + slope * INR (VKA alone)) was observed between the INR measured "on" and "off" ARG. The slope depended on the argatroban dose and on the International Sensitivity Index (ISI) of the PT reagent, the steepest slope (i.e., the largest difference between INR (ARG+VKA) and INR (VKA alone)) was seen with the highest ARG dose and the PT reagent with an ISI of 2.13. There was a close correlation between plasma levels of ARG and aPTT or ECT. Under VKA the ARG-aPTT relationship indicated an increased sensitivity of the aPTT to ARG, VKA treatment had no effect on the prolongation of the ECT induced by argatroban. In conclusion, ARG at doses up to 2 microg/kg/min can be discontinued at an INR of 4.0 on combined therapy with VKA, as this would correspond to an INR between 2.2 and 3.7 for the VKA. If it is necessary to monitor ARG in the critical transition period, the ECT which is not influenced by VKA can be used as an alternative to the aPTT.


Assuntos
Anticoagulantes/administração & dosagem , Coagulação Sanguínea/efeitos dos fármacos , Acenocumarol/administração & dosagem , Administração Oral , Adulto , Anticoagulantes/sangue , Testes de Coagulação Sanguínea , Monitoramento de Medicamentos/métodos , Monitoramento de Medicamentos/normas , Quimioterapia Combinada , Endopeptidases , Humanos , Coeficiente Internacional Normatizado , Masculino , Tempo de Tromboplastina Parcial , Femprocumona/administração & dosagem , Ácidos Pipecólicos/administração & dosagem , Tempo de Protrombina , Análise de Regressão , Distribuições Estatísticas
19.
Thromb Res ; 113(5): 295-302, 2004.
Artigo em Inglês | MEDLINE | ID: mdl-15183041

RESUMO

BACKGROUND: In pharmacodynamic studies with antiplatelet agents, platelets are usually activated in vitro with single agonists (e.g., ADP) solely. We questioned whether differences occur between single and combined stimulation of platelets [involving the major thrombin-receptors, protease-activated receptors (PAR)1 and PAR4], and whether the pharmacodynamic response to common antiplatelet drugs vary when a combined stimulus is applied instead of a single agonist. METHODS: We investigated the influence of different antiplatelet agents (aspirin [500 mg]) in vivo, the P2Y12-antagonist AR-C 69931MX (4 nM) and the GPII/IIIa-antagonist (abciximab ([5 microg/ml] in vitro) on the degranulation response (CD62) and expression of the activated GPIIb/IIIa-receptor (PAC-1) after stimulation with ADP (2 microM), collagen (4 microg/ml), a PAR1-activating peptide (3 microM TRAP) and a PAR4-activating peptide (200 microM AYPGKF) alone or in a combination of each two agonists by flow cytometry in healthy subjects. RESULTS: (1) Combined activation of TRAP with AYPGKF resulted in synergistic CD62 and PAC-1 expression. Only AYPGKF but neither TRAP nor ADP acted synergistically with collagen. (2) AR-C 69931MX inhibited platelet degranulation (CD62) in all inducer combinations with ADP or the combination TRAP with AYPGKF. The effect was considerably smaller or absent for the combination of collagen with a second inducer. (3) Aspirin intake reduced platelet degranulation and PAC-1 expression only for AYPGKF costimulation with collagen. CONCLUSION: Because a variety of different agonists influence platelet activation and its distinct functions at a time, investigations which regard the concert of these agonists might be closer to the in vivo situation and better reflect the pharmacodynamic profile of an antiplatelet agent than using one single inducing agent.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Inibidores da Agregação de Plaquetas/farmacologia , Abciximab , Difosfato de Adenosina/administração & dosagem , Monofosfato de Adenosina/administração & dosagem , Anticorpos Monoclonais/administração & dosagem , Aspirina/administração & dosagem , Plaquetas/efeitos dos fármacos , Plaquetas/fisiologia , Degranulação Celular/efeitos dos fármacos , Colágeno/administração & dosagem , Interações de Medicamentos , Humanos , Fragmentos Fab das Imunoglobulinas/administração & dosagem , Proteínas de Membrana/antagonistas & inibidores , Oligopeptídeos/administração & dosagem , Ativação Plaquetária/efeitos dos fármacos , Inibidores da Agregação de Plaquetas/administração & dosagem , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/antagonistas & inibidores , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Antagonistas do Receptor Purinérgico P2 , Receptores Purinérgicos P2Y12
20.
Br J Clin Pharmacol ; 56(3): 321-6, 2003 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-12919181

RESUMO

AIMS: To investigate the pharmacodynamic interaction of unfractionated heparin (UFH) and acetylic salicylic acid (ASA) on YM337, a monoclonal humanized antibody of the platelet GPIIb/IIIa receptor. METHODS: In a randomized, placebo-controlled study three treatment groups each with six healthy volunteers received the following medication: group 1, ASA (3 days) + UFH + YM337 (placebo); group 2, ASA (placebo) + UFH (placebo) + YM337; group 3, ASA + UFH + YM337. Assessments were made over 24 h and included bleeding time (BT), ADP (20 microm)- and collagen (5 microg ml-1)-induced platelet aggregation and PAC1 and CD62 expression measured by flow cytometry. RESULTS: In group 3 BT was prolonged to 35 [median, 16-45 min (1,3 quartile)] after UFH administration, increasing to 45 [median, 42-45 min (1,3 quartile)] after YM infusion (6 h). BT remained elevated to 26 [median, 14-45 min (1,3 quartile)] at 24 h, while groups 1 and 2 returned to normal values. Collagen-induced aggregation was 73% [median, 70-80% (1,3 quartile)] under YM337 alone, 79% [median, 72-80% (1,3 quartile)] under ASA + UFH and reduced only in group 3 to 24% [median, 18-29% (1,3 quartile)]. In both groups receiving active YM337, PAC1 expression showed a reduction to < 20% after 6 h of infusion. CD62 expression was not significantly affected by any treatment. CONCLUSION: UFH and YM337 have strong synergistic effects on BT, while coadministration of ASA strongly augments inhibitory effects of YM337 on collagen-induced platelet aggregation.


Assuntos
Anticoagulantes/farmacologia , Aspirina/farmacologia , Heparina/farmacologia , Inibidores da Agregação de Plaquetas/farmacologia , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/antagonistas & inibidores , Adolescente , Adulto , Anticorpos Monoclonais/farmacologia , Tempo de Sangramento , Interações de Medicamentos , Fosfatase 2 de Especificidade Dupla , Selectina E/metabolismo , Feminino , Humanos , Masculino , Agregação Plaquetária , Proteína Fosfatase 2 , Proteínas Tirosina Fosfatases/metabolismo
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