RESUMO
BACKGROUND: Patients with peripheral arterial disease (PAD) are at very high risk for cardiovascular events. How do patients with PAD differ from age- and sex-matched controls in survival, major ischemic events and revascularization procedures when both groups were managed according to the European guidelines on cardiovascular disease prevention? METHODS: Patients with PAD (N.=742) and 713 age and sex-matched control subjects without PAD, both groups aged 65±9 years at inclusion, were managed for 5 years according to the European guidelines on cardiovascular disease prevention and evaluated yearly for occurrence of death, non-fatal major ischemic events and revascularization procedures (minor events). RESULTS: In the PAD group, the 5-year survival was 84.7% (CI 82.1-87.3%) vs. 93.3% (CI 91.5-95.2%) in the control group, P<0.001. In the PAD group the proportion of cardiovascular deaths did not differ significantly from non-cardiovascular deaths (6.9 vs. 8.4%, P=0.14), while in the control group cardiovascular deaths were less frequent (2.4 vs. 4.3%, P=0.05). The groups differed in 5-year major event-free survival: 76.7% (CI 73.7-79.8%) in PAD vs. 89.9% (CI 87.7 -92.2%) in controls, P<0.001, and in event-free survival: 56.2% (CI 52.7-59.9%) in PAD vs. 82.4% (CI 79.9-85.3%) in controls, P<0.001. CONCLUSIONS: Patients with PAD had a higher risk of all-cause death, major and minor non-fatal cardiovascular events compared to control subjects. In our group, cardiovascular events were not the leading cause of death in patients with PAD (ClinicalTrials.gov number NCT00761969.).
Assuntos
Doenças Cardiovasculares/prevenção & controle , Doença Arterial Periférica/complicações , Doença Arterial Periférica/tratamento farmacológico , Idoso , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Doenças Cardiovasculares/mortalidade , Estudos de Casos e Controles , Causas de Morte , Intervalo Livre de Doença , Feminino , Fibrinolíticos/uso terapêutico , Guias como Assunto , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco , Eslovênia , Resultado do TratamentoAssuntos
Testes de Coagulação Sanguínea/métodos , Hemostasia , Heparina/sangue , Anticoagulantes/administração & dosagem , Anticoagulantes/sangue , Hemostasia/efeitos dos fármacos , Hemostáticos , Heparina/administração & dosagem , Antagonistas de Heparina/farmacologia , Humanos , Técnicas In Vitro , Tromboembolia/sangue , Tromboembolia/tratamento farmacológicoRESUMO
INTRODUCTION: In women who suffer venous thrombosis (VT) during oral contraceptive (OC) use, a transient risk factor (OC) is removed during the acute event, while most co-existing forms of thrombophilia persist and presumably continue to maintain hypercoagulability. The aim of this study was to establish if hypercoagulability persists long after OC-related VT and if it could be attributed to thrombophilia. MATERIALS AND METHODS: 60 women (age 33.0 ± 8.5 years) were investigated 5 - 64 (median 33) months after OC-related VT (patients) and compared to 63 apparently healthy women (controls). All women were tested for thrombophilia, activated partial thromboplastin time (APTT), fibrinogen, D-dimer, P-selectin and C-reactive protein. Thrombin generation was measured by Technothrombin® TGA assay. Overall haemostasis potential (OHP) assay with overall coagulation potential (OCP) and overall fibrinolytic potential (OFP) as supplementary parameters were measured by repeated fibrin formation and degradation registration. RESULTS: In patients increased endogenous thrombin potential (4,205 ± 440 nM x min vs 4,015 ± 421 nM x min, p=0.017), increased OCP (22.6 ± 4.6 Abs-sum vs 20.8 ± 4.1 Abs-sum, p=0.025), shorter APTT (30.9 ± 3.8s vs 33.4 ± 3.6s, p<0.001) and lower antithrombin activity (99, 93-105% vs 104, 100-109%, p<0.05) were observed. Thrombophilia was observed in 22/60 (36%) patients and in 5/63 (7.9%, p<0.001) controls. The only significant difference between thrombophilic and non-thrombophilic patients was higher soluble P-selectin in the former subgroup (22, 20-33 µg/L vs 17, 12-22 µg/L, p=0.012). CONCLUSIONS: In women with a history of OC-related VT persistent hypercoagulability was observed, which, however was not augmented by the presence of thrombophilia.
Assuntos
Anticoncepcionais Orais/efeitos adversos , Trombina/metabolismo , Trombofilia/complicações , Trombose Venosa/induzido quimicamente , Trombose Venosa/complicações , Adulto , Testes de Coagulação Sanguínea , Feminino , Humanos , Trombofilia/sangue , Trombose Venosa/sangue , Trombose Venosa/metabolismoRESUMO
Thrombophilia can be identified in about half of all patients presenting with venous thromboembolism (VTE). Thrombophilia screening for various indications has increased tremendously, but whether the results of such tests help in the clinical management of patients is uncertain. Here, current recommendations for thrombophilia screening in selected groups of patients, and considerations whether other high-risk subjects should be tested are reviewed. The methods for determination of the most common thrombophilic defects (antithrombin, protein C, protein S deficiencies, Factor V Leiden and prothrombin G20210A) associated with strong to moderate risk of VTE are described, indicating the timing and location of thrombophilia screening. Circumstances when a positive result of thrombophilia screening helps clinicians decide if adjustments of the anticoagulant regime are needed are discussed. Finally, psychological, social and ethical dilemmas associated with thrombophilia screening are indicated.
Assuntos
Trombofilia/diagnóstico , Criança , Feminino , Humanos , Gravidez , Complicações Hematológicas na Gravidez/diagnóstico , Fatores de Risco , Trombofilia/complicaçõesRESUMO
BACKGROUND: Although light transmittance aggregometry is considered the gold standard for platelet function testing, it is poorly standardized. The effect of several pre-analytical variables on this assay was investigated. METHODS: Light transmittance aggregometry was performed with an automated coagulation analyzer using arachidonic acid (1.6 mmol/L), adenosine-5-diphosphate (ADP) (11 µmol/L) and collagen (11 mg/L, all final concentrations). The results were reported as maximum aggregation (in %) in 10 min. Twenty apparently healthy subjects were tested three times on two consecutive days: on day 1, fasting samples were collected in the morning and mid-day; on day 2, samples were collected in the morning after a light breakfast. Light transmittance aggregometry was performed immediately after preparation of platelet-rich-plasma (PRP), after stabilization (30 min) of non-adjusted and platelet count (225-275×10(9)/L) adjusted PRP, and at 2 and 4 h after blood collection. RESULTS: Maximum aggregation was higher in the non-adjusted compared to the adjusted PRP with all three agonists used (all p<0.05). Arachidonic acid and ADP, but not collagen, induced maximal aggregation was significantly decreased after 4 h (arachidonic acid from 84%, 73%-90% to 71%, 28%-85%, p<0.001; ADP from 79%, 62%-87% to 66%, 50%-79%, p<0.001, medians with inter-quartile ranges). Short-term stabilization of PRP, consumption of breakfast and sampling at mid-day had no significant effect on maximal aggregation. CONCLUSIONS: Blood collection and plasma preparation can be simplified by omitting short-term stabilization of PRP and adjustment for platelet count. The subjects can be tested from morning to mid-day, and a light breakfast is acceptable. However, the analyses should not be postponed for more than 2 h if arachidonic acid or ADP are used as agonists.
Assuntos
Testes de Coagulação Sanguínea/instrumentação , Plasma Rico em Plaquetas , Coagulação Sanguínea , Testes de Coagulação Sanguínea/métodos , Humanos , Contagem de Plaquetas , Testes de Função Plaquetária , Valores de Referência , Sensibilidade e EspecificidadeRESUMO
The clinical efficacy of antiplatelet therapy (aspirin, P2Y12 and glycoprotein IIb/IIIa receptor antagonists) to prevent occlusive arterial events in patients with atherothrombotic disease is well established. Despite the proven benefits of antiplatelet therapy, many patients continue to experience arterial events. Many factors may influence the response of platelets to antiplatelet therapy and some patients with adequate compliance to the treatment may exhibit failure of platelet inhibition as determined by ex vivo laboratory tests, a phenomenon termed "resistance" to antiplatelet therapy. Platelet function can be measured by numerous platelet function tests, with which various parameters of platelet activation, secretion, adhesion and aggregation can be determined. These tests include light transmission (optical) and whole blood aggregometry, point-of-care devices, such as platelet function analyzers PFA-100, and VerifyNow, flow cytometry, serum thromboxane B2 and urinary levels of the thromboxane B2 metabolite 11-dehyro-thromboxane B2. Other tests, such as whole blood platelet aggregation measured by platelet counting, thrombelastography and devices such as the cone and plate(let) analyzer, Plateletworks and thrombotic status analyzer have also been used to determine platelet inhibition by antiplatelet drugs, but their use is not widespread and therefore experience is limited. Further studies need to be carried out to answer basic questions on the clinical utility and cost-effectiveness of laboratory monitoring of antiplatelet therapy before it can be recommended in clinical practice.
Assuntos
Inibidores da Agregação Plaquetária/uso terapêutico , Testes de Função Plaquetária , Aspirina/uso terapêutico , Clopidogrel , Resistência a Medicamentos , Humanos , Ticlopidina/análogos & derivados , Ticlopidina/uso terapêuticoRESUMO
3,4-Dihydro-2 H-1,4-benzoxazine derivatives possessing both thrombin inhibitory and glycoprotein IIb/IIIa (GPIIb/IIIa) receptor antagonistic activities were obtained by combining mimetics of the d-Phe-Pro-Arg pharmacophore of thrombin inhibitors and the Arg-Gly-Asp pharmacophore of GPIIb/IIIa receptor antagonists in the same low molecular weight peptidomimetic compound. Systematic variation of the position of substituents around the 3,4-dihydro- 2H-1,4-benzoxazine nucleus, the distance between the carboxylate and amidine moieties, together with additional substituents to fill the thrombin S 2 and S 3 pockets resulted in compounds displaying submicromolar inhibition constants ( K i) for thrombin and submicromolar IC 50 for inhibition of binding of fibrinogen to platelet GPIIb/IIIa receptor. Some of these compounds, such as 17a, 17b, 17d, and 17h possessing a well balanced activity at both targets, are a good starting point for further optimization. Incorporation of anticoagulant and platelet antiaggregatory activity in the same molecule constitutes a promising approach toward novel antithrombotic agents.
Assuntos
Antitrombinas/farmacologia , Benzoxazinas/farmacologia , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/antagonistas & inibidores , Antitrombinas/química , Antitrombinas/metabolismo , Benzoxazinas/química , Benzoxazinas/metabolismo , Desenho de Fármacos , Humanos , Técnicas In Vitro , Espectroscopia de Ressonância Magnética , Masculino , Modelos Moleculares , Mimetismo Molecular , Espectrometria de Massas por Ionização por Electrospray , Trombina/metabolismoRESUMO
Thrombophilia is considered to increase the risk of venous thrombosis (VT) due to hemostasis activation. To determine the level of hemostasis activation in thrombophilic subjects with or without a history of VT, hemostasis activation markers prothrombin fragment 1 and 2 (F1+2), thrombin-antithrombin complex (TAT), and cross-linked fibrin degradation products (D-dimer) were measured in 94 subjects with (patients) and 101 subjects without a history of VT (controls). A total of 34.8% of patients and 14.8% of controls (P= .002) had at least 1 thrombophilic defect (protein C deficiency, activated protein C [APC] resistance, presence of lupus anticoagulants, or prothrombin G20210A polymorphism). The subjects were divided into 4 subgroups: patients with (TF(+) patients) and without (TF(-) patients) thrombophilia, and controls with (TF(+) controls) and without (TF(-) controls) thrombophilia. Hemostasis activation was comparable between all patients and controls (TAT: 2.1 vs 2.6 microg/L; F1+2: 1.0 vs 0.9 nmol/L; D-dimer: 36 vs 37 microg/L, respectively) and between TF(+) and TF(- ) patients. However, TF(+) controls had a significantly higher prevalence of increased hemostasis activation markers compared with TF(-) controls (TAT>4.4 microg/L, 38.4 vs 7.3%; F1+2>1.1 nmol/L, 53.8 vs 22.0%; D-dimer >78 microg/L, 30.7 vs 8.8% of subjects, respectively; all P< .05). After stratification for thrombophilic defects, hemostasis activation was associated with APC resistance in controls and with protein C deficiency in patients. To conclude, thrombophilia was associated with hemostasis activation in controls. We assumed that, in patients, the differences in hemostasis activation between subjects with or without thrombophilia were blurred due to undetermined and unidentified thrombophilic defects.
Assuntos
Hemostasia , Trombofilia/sangue , Trombose Venosa/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Deficiência de Proteína CRESUMO
The objective of our study was to investigate the prevalence of the polymorphisms factor V Leiden (FVL), prothrombin G20210A (PT G20210A), methylenetetrahydrofolate reductase C677T (MTHFR C677T), plasminogen activator inhibitor type 1 -675 4G/5G (PAI-1 4G/5G) and factor XII -4 C/T (FXII -4 C/T) in 295 Slovenian patients with venous thrombosis (VT) and 223 healthy controls in order to establish their contribution to the risk for VT. The major genetic risk factor was FVL, while PT G20210A, MTHFR 677 C/T, PAI-1 4G/5G and FXII -4 C/T polymorphisms were not. However, PT G20210A increased the risk of recurrent VT, MTHFR C677T increased the risk in older patients, while the FXII -4 T allele suggested a possible protective effect in younger patients. The risk of VT increased with increasing number of genetic defects.
Assuntos
Trombofilia/genética , Trombose Venosa/genética , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Fator V , Fator XII , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2) , Pessoa de Meia-Idade , Mutação , Inibidor 1 de Ativador de Plasminogênio , Polimorfismo de Nucleotídeo Único , Protrombina , Recidiva , Risco , Eslovênia/epidemiologia , Adulto JovemRESUMO
INTRODUCTION: An increased demand for monitoring aspirin treatment by platelet function tests has been observed, but data on the biological variation of these tests are insufficient. The aim of this study was to assess the biological variation of optical platelet aggregometry and closure time in healthy subjects without aspirin and after aspirin ingestion. SUBJECTS AND METHODS: In 20 healthy subjects, blood was sampled 4 times: on 2 consecutive mornings a day after aspirin ingestion (100 mg/daily) and on 2 consecutive days of no treatment. In all samples, arachidonic acid-, ADP- and collagen-induced optical platelet aggregation was measured, and closure times were determined by collagen/epinephrine (CEPI) and collagen/ADP (CADP) cartridges in a platelet function analyzer-100. RESULTS: Aspirin significantly reduced arachidonic acid- and ADP-induced platelet aggregation and significantly prolonged CEPI closure time, but had no significant effect on collagen-induced platelet aggregation and CADP closure time. Aspirin increased both within- and between-subject coefficients of variation. Arachidonic acid-induced platelet aggregation was the most sensitive to aspirin and no aspirin-resistant subjects were detected on either day after aspirin. According to ADP-induced platelet aggregation or CEPI closure time, 25 and 30% of healthy subjects, respectively, changed from aspirin resistant to aspirin responsive or vice versa from one day to another. There was no agreement between platelet function tests in determining aspirin resistance. CONCLUSIONS: A significant variation in optical platelet aggregometry and closure time exists and is presumed to have a major effect on determination of aspirin resistance.
Assuntos
Aspirina/farmacocinética , Resistência a Medicamentos , Agregação Plaquetária/efeitos dos fármacos , Testes de Função Plaquetária/normas , Adulto , Aspirina/administração & dosagem , Tempo de Sangramento , Erros de Diagnóstico , Monitoramento de Medicamentos , Feminino , Humanos , Masculino , Nefelometria e Turbidimetria , Reprodutibilidade dos TestesRESUMO
BACKGROUND: Closure time measured by a platelet function analyser (PFA-100) was examined for its usefulness in assessing the efficacy of platelet membrane glycoprotein IIb/IIIa antagonists in vitro, and was compared to optical platelet aggregometry. METHODS: Three known glycoprotein IIb/IIIa antagonists [H-Arg-Gly-Asp-Ser-OH (RGDS), tirofiban and eptifibatide] and six new peptidomimetic glycoprotein IIb/IIIa antagonists (DKT-59, DPS-172, SMA-101, SMA-104, SMA-179 and SKN-191) were assessed. The concentration of antagonist which doubled closure time in collagen/ADP and collagen/epinephrine cartridges (IC200) or decreased ADP- or collagen-induced platelet aggregation by 50% (IC50) was used to assess the efficacy of the glycoprotein IIb/IIIa antagonist in inhibiting platelet function. RESULTS: IC200 for collagen/ADP and collagen/epinephrine closure times and IC50 for ADP- and collagen-induced platelet aggregation were highly associated (correlation coefficients 0.97-1.00, all p<0.001). Therefore, according to both methods, the most efficient glycoprotein IIb/IIIa antagonist was tirofiban (IC200=0.030-0.034 micromol/L, IC50=0.005-0.027 micromol/L) and the least efficient was RGDS (IC200=875-1100 micromol/L, IC50=124-377 micromol/L; all data are means), while the new peptidomimetic glycoprotein IIb/IIIa antagonists exhibited intermediate efficacies. CONCLUSIONS: Closure time represents a fast, simple and sensitive method of assessing glycoprotein IIb/IIIa antagonism in vitro, is comparable to optical aggregometry, and suitable for testing larger numbers of glycoprotein IIb/IIIa antagonists.
Assuntos
Complexo Glicoproteico GPIIb-IIIa de Plaquetas/antagonistas & inibidores , Adulto , Técnicas de Laboratório Clínico , Feminino , Humanos , Técnicas In Vitro , MasculinoRESUMO
BACKGROUND: Measurement of some haemostatic factors and products formed during activation of haemostasis seems to be promising in the determination of hypercoagulability. METHODS: The fibrinolytic variables euglobulin clot lysis time, tissue-type plasminogen activator, plasminogen activator inhibitor-1 and the haemostasis activation markers prothrombin fragment 1+2, thrombin-antithrombin complex and D-dimer were determined in 101 apparently healthy men and women aged 20-92 years (58+/-18 years, mean+/-SD) to establish variability due to several demographic, behavioural and metabolic factors. RESULTS: None of the fibrinolytic variables were affected by smoking, while tissue-type plasminogen activator antigen was significantly lower in women compared to men. Multiple regression analysis revealed several independent associations between tissue-type plasminogen activator, plasminogen activator inhibitor, body mass index and lipid levels, describing up to 40% of the variance in fibrinolytic variables. For haemostasis activation markers, no gender difference or effect of smoking was observed. Only D-dimer was independently associated with age. The haemostasis activation markers determined proved to be extremely sensitive to blood sampling procedure and were significantly higher in samples obtained by an untrained nurse compared to a trained nurse. CONCLUSIONS: Fibrinolytic variables are predominantly modulated by age, body mass index and blood lipids, while haemostasis activation markers are mainly un-influenced by these factors.
Assuntos
Biomarcadores/metabolismo , Fibrinólise/fisiologia , Hemostasia/fisiologia , Trombofilia/diagnóstico , Adulto , Idoso , Antropometria , Antitrombina III/metabolismo , Comportamento , Demografia , Feminino , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/metabolismo , Peptídeo Hidrolases/metabolismo , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Protrombina/metabolismo , Trombofilia/metabolismo , Ativador de Plasminogênio Tecidual/metabolismoRESUMO
INTRODUCTION: Young subjects with acute cerebral ischaemia - stroke or transient ischaemic attack - form an etiologically heterogeneous and often not clearly explained group of patients. The aim was to investigate possible disturbances in haemostasis and inflammation long after an acute cerebral ischaemic event. MATERIALS AND METHODS: Forty-four consecutive patients referred after having suffered from acute cerebral ischaemia before the age of 45 participated 1 to 9 years (median value 5 years) after the event. At the time of blood sampling 33 (75%) patients were receiving antithrombotic treatment. Forty-six apparently healthy subjects of the same age group served as controls. In all subjects global haemostasis parameters (overall haemostasis, coagulation and fibrinolytic potential), thrombophilia, several markers of haemostasis activation and inflammation were determined. RESULTS: Patients did not differ from controls in most of the conventional risk factors and the presence of most forms of thrombophilia, although in seven (17.5%) patients the weak presence of lupus anticoagulants was observed. Patients had significantly increased overall haemostasis and coagulation potential, increased soluble P-selectin and D-dimer, decreased overall fibrinolysis potential and increased fibrinogen and C-reactive protein compared to controls. The subgroups of patients receiving antiplatelet treatment, with thrombophilia and recurrent acute cerebral ischaemia, did not differ significantly from the other patients. CONCLUSIONS: In young patients long after acute cerebral ischaemia an imbalance in the haemostatic system and a minor, but significant degree of inflammation was detected. The mechanisms behind haemostatic imbalance seem to be enhanced thrombin generation, platelet activation and depressed fibrinolysis.
Assuntos
Transtornos da Coagulação Sanguínea/sangue , Isquemia Encefálica/sangue , Mediadores da Inflamação/sangue , Inflamação/sangue , Doença Aguda , Adulto , Transtornos da Coagulação Sanguínea/complicações , Testes de Coagulação Sanguínea , Isquemia Encefálica/etiologia , Estudos de Casos e Controles , Feminino , Hemostasia , Humanos , Inflamação/complicações , Ataque Isquêmico Transitório/sangue , Ataque Isquêmico Transitório/etiologia , Masculino , Pessoa de Meia-Idade , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/etiologia , Fatores de TempoRESUMO
The degree of interpatient variability in the warfarin dose required to achieve the desired anticoagulant response can only partly be explained by polymorphisms in the CYP2C9 gene, suggesting that additional genetic factors such as polymorphisms in genes involved in blood coagulation may influence warfarin dose requirement. In total, 165 Caucasian outpatients on stable maintenance warfarin treatment previously genotyped for CYP2C9 were analysed for common polymorphisms in FVII, GGCX and VKORC1 genes. The -402G > A polymorphism and a variable number of repeats in intron 7 of FVII gene did not significantly influence warfarin dose. The mean warfarin doses increased with the number of (CAA) repeats in the GGCX gene, but the differences were significant only in the CYP2C9*1/*1 subgroup of patients (p = 0.032). Common polymorphism (6484C > T) in intron 1 of the VKORC1 gene led to lower warfarin dose requirement; the means were 5.70 (95% C.I. 4.95-6.45), 3.49 (3.07-3.90) and 2.11 (1.80-2.42) mg/day for 6484 CC, CT and TT genotypes, respectively (p < 0.001). In contrast, 9041G > A polymorphism in 3'UTR of theVKORC1 gene led to higher warfarin dose requirement; the means were 3.09 (2.58- 3.60), 4.26 (3.69-4.82) and 5.86 (4.53-7.19) mg/day for 9041 GG, GA and AA genotypes, respectively (p < 0.001). With a regression model we explained 60.0% of variability in warfarin dose, which was due to gene polymorphisms (CYP2C9, VKORC1), age and body-surface-area. When aiming for individualised warfarin therapy, at least VKORC1 polymorphisms should be included in predictive genotyping besides CYP2C9.
Assuntos
Carbono-Carbono Ligases/genética , Fator VII/genética , Oxigenases de Função Mista/genética , Farmacogenética , Polimorfismo Genético , Varfarina/administração & dosagem , Sequência de Aminoácidos , Hidrocarboneto de Aril Hidroxilases/genética , Citocromo P-450 CYP2C9 , Feminino , Genótipo , Humanos , Masculino , Vitamina K Epóxido RedutasesRESUMO
AIMS: Warfarin is a frequently used anticoagulant drug with narrow therapeutic index and high interindividual variability in the dose requirement. We have previously shown that warfarin dose is influenced by cytochrome P450 (CYP) 2C9 genotype, age, body weight and co-treatment with drugs that interfere with warfarin metabolism. As, in many patients, drug co-treatment cannot be avoided, we investigated the effect of co-treatment with carbamazepine, amiodarone and statins on warfarin metabolism and maintenance dose. METHODS: Caucasian patients on stable maintenance warfarin therapy with CYP2C9*1/*1 genotype (n=82) were included in the study. Plasma concentrations of (S)- and (R)-warfarin as well as warfarin hydroxylated metabolites were determined using HPLC assay and corresponding clearances of (S)- and (R)-warfarin were calculated. RESULTS: Patients co-treated with carbamazepine (n=5) had significantly higher plasma 10-hydroxywarfarin concentrations than patients not taking any interacting drugs (n=54) (median: 0.327 microg/ml vs 0.030 microg/ml, p=0.003). (S)- and (R)-warfarin clearances were also higher in the carbamazepine co-treated group (p=0.003), as were warfarin dose requirements (median: 9.00 mg/day vs 3.86 mg/day, p=0.003). Under the conditions of this study, patients co-treated with amiodarone (n=6) did not differ significantly regarding any measured characteristic from patients with no interacting drug treatment, while patients co-treated with simvastatin or lovastatin (n=17) had lower 10-hydroxywarfarin concentration (p=0.02). CONCLUSIONS: We confirmed important interaction between carbamazepine and warfarin metabolism which can be of major clinical importance. If treatment with carbamazepine cannot be avoided, patients taking warfarin should be frequently monitored, especially when initiating or stopping carbamazepine therapy.
Assuntos
Hidrocarboneto de Aril Hidroxilases/metabolismo , Varfarina/administração & dosagem , Varfarina/metabolismo , Idoso , Idoso de 80 Anos ou mais , Amiodarona/administração & dosagem , Amiodarona/farmacologia , Hidrocarboneto de Aril Hidroxilases/genética , Carbamazepina/administração & dosagem , Carbamazepina/farmacologia , Citocromo P-450 CYP2C9 , Relação Dose-Resposta a Droga , Interações Medicamentosas/genética , Quimioterapia Combinada , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Masculino , Pessoa de Meia-Idade , Farmacocinética , Varfarina/análogos & derivados , Varfarina/sangueAssuntos
Anticoagulantes/uso terapêutico , Hidrocarboneto de Aril Hidroxilases/genética , Administração Oral , Idoso , Idoso de 80 Anos ou mais , Anticoagulantes/administração & dosagem , Anticoagulantes/farmacocinética , Hidrocarboneto de Aril Hidroxilases/metabolismo , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/metabolismo , Citocromo P-450 CYP2C9 , Monitoramento de Medicamentos , Éxons/genética , Feminino , Genótipo , Humanos , Pessoa de Meia-Idade , Mutação , Varfarina/administração & dosagem , Varfarina/farmacocinética , Varfarina/uso terapêuticoRESUMO
The design, synthesis and biological activity of new thrombin inhibitors with a pyridinone or pyrazinone core and different heterobicyclic P(1) arginine side-chain mimetics are described. The arginine side-chain mimetics used in this study are (+/-)-4,5,6,7-tetrahydro-2H-indazol-5-ylmethanamine and both enantiomers thereof, (+/-)-4,5,6,7-tetrahydro-1,3-benzothiazole-2,6-diamine and the corresponding R enantiomer. Compound 25, the most potent in the series of pyrazinone inhibitors, exhibited a K(i) of 41 nM in vitro and high selectivity against trypsin and factor Xa.
Assuntos
Antitrombinas/química , Antitrombinas/farmacologia , Arginina/química , Arginina/farmacologia , Materiais Biomiméticos/farmacologia , Pirazinas/química , Piridonas/química , Piridonas/uso terapêutico , Materiais Biomiméticos/química , Concentração de Íons de Hidrogênio , EstereoisomerismoRESUMO
A novel class of potential antithrombotic compounds with moderate thrombin inhibitory and fibrinogen receptor antagonistic activity is described. Combination of anticoagulant and antiaggregatory activity in the same molecular entity is presented as a new promising approach in the search for novel antithrombotic agents.
Assuntos
Anticoagulantes/síntese química , Benzoxazinas/síntese química , Fibrinolíticos/síntese química , Inibidores da Agregação Plaquetária/síntese química , Receptores de Fibrinogênio/antagonistas & inibidores , Trombina/antagonistas & inibidores , Anticoagulantes/química , Anticoagulantes/farmacologia , Benzoxazinas/química , Benzoxazinas/farmacologia , Inibidores do Fator Xa , Fibrinogênio/metabolismo , Fibrinolíticos/química , Fibrinolíticos/farmacologia , Modelos Moleculares , Mimetismo Molecular , Peso Molecular , Oligopeptídeos/química , Peptídeos/química , Inibidores da Agregação Plaquetária/química , Inibidores da Agregação Plaquetária/farmacologia , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/antagonistas & inibidores , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismoAssuntos
Modelos Animais de Doenças , Trombose Venosa/tratamento farmacológico , Animais , Testes de Coagulação Sanguínea , Cloretos , Feminino , Compostos Férricos/uso terapêutico , Hemostasia/efeitos dos fármacos , Masculino , Nadroparina/uso terapêutico , Ratos , Ratos Wistar , Análise de Regressão , Sensibilidade e Especificidade , Tromboplastina/uso terapêutico , Trombose/tratamento farmacológicoRESUMO
The antithrombotic potential of new direct thrombin inhibitors built on the azaphenylalanine scaffold (LK-732, LK-639 and LK-731) and their amidoxime prodrugs (LK-658, LK-633 and LK-730) was studied in comparison to argatroban and nadroparin in two rat models of venous thrombosis, induced either by complete stasis combined with hypercoagulability (model 1) or by partial stasis combined with vessel injury (model 2). In initial experiments LK-732 was established as the most promising antithrombotic of the LK inhibitors and as such was further tested. In model 1, intravenous bolus administration of LK-732 produced a dose-dependent inhibition of thrombus formation with an ID50 value of 1.3 mg/kg. This ID50 value was approximately four times higher than the ID50 value of argatroban (0.3 mg/kg; p=0.011). However, in model 2, LK-732 and argatroban decreased thrombus weight by 50% at similar ID50 values (3.8 mg/kg vs 3.0 mg/kg, respectively; p=0.726). The ex vivo anticoagulant effect of LK-732 was substantially weaker compared to argatroban at doses that produced comparable antithrombotic effects. After subcutaneous administration, in vivo thrombus weight reduction of LK inhibitors (10 mg/kg) ranged between 22 to 48%. However, their oral antithrombotic effect at a dose of 30 mg/kg was rather low. LK amidoxime prodrugs failed to produce a substantial antithrombotic effect after subcutaneous (10 mg/kg) as well as after oral administration (30 mg/kg). In conclusion, thrombin inhibitors built on the azaphenylalanine scaffold represent a new group of intravenously effective antithrombotics. However, optimisation of the oral antithrombotic effect of amidoxime prodrug LK-658 of the lead inhibitor LK-732 is required for justifying further development of these inhibitors.