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1.
Artigo em Inglês | MEDLINE | ID: mdl-34823097

RESUMO

Ultrafast affinity extraction (UAE) has recently been developed and employed for measuring non-bound (or free) fractions and binding or rate constants for drugs and other targets with soluble binding agents such as serum proteins. This study examined the long-term stability of 10 mm × 2.1 mm i.d. affinity microcolumns when used in UAE at both low and high flow rates (e.g., 0.5 and 3.5 mL/min) over an extended series of injections. This stability was investigated by using immobilized human serum albumin (HSA) and samples containing the drug warfarin with or without soluble HSA as a model system. The free warfarin fractions measured at 0.5 mL/min in the presence of soluble HSA were stable up to 150 injections and changed by <10% at 3.5 mL/min. The association equilibrium constant for warfarin with HSA that was estimated by UAE at 3.5 mL/min had no significant change over 50 injections and a change of only ∼18-22% over 100-150 injections. The dissociation rate constant for warfarin from HSA was found by combining UAE results at 0.5 and 3.5 mL/min and employing a new two-point approach, with no significant changes in this value being seen even after 200 injections. The effects of extended microcolumn use on the retention time, peak width, and peak asymmetry for warfarin, and on the backpressure of the microcolumn, were also considered. These results indicated that UAE and HSA microcolumns could be used to provide consistent values for free solute fractions, binding constants, and rate constants over a large series of injections. These results should be useful in future work by providing guidelines for the assessment, further development, and use of UAE in characterizing interactions involving other drugs and binding agents in solution-based samples.


Assuntos
Cromatografia de Afinidade/instrumentação , Cromatografia de Afinidade/métodos , Humanos , Modelos Lineares , Modelos Químicos , Ligação Proteica , Reprodutibilidade dos Testes , Albumina Sérica Humana/química , Albumina Sérica Humana/metabolismo , Fatores de Tempo , Varfarina/análise , Varfarina/química , Varfarina/metabolismo
2.
J Chromatogr A ; 1621: 461030, 2020 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-32192705

RESUMO

In the present study, a new generation of water-immiscible natural deep eutectic solvents (DESs) was synthesized using borneol as a hydrogen-bonding acceptor and decanoic acid, oleic acid, and thymol as a hydrogen-bonding donor in different molar ratios. These green hydrophobic solvents which are chemically stable in aqueous solutions were used as extraction solvents for isolation and pre-concentration of warfarin in biological samples. In this method, fine droplets of DESs were dispersed into the sample solution by using the air-assisted liquid-liquid micro-extraction method to accelerate the cloudy emulsion system formation and increase the mass transfer of the analyte to the DES-rich phase. The borneol based deep eutectic solvent is a worthy generation of the extraction solvents in the ALLME method due to low-cost and less toxicity. A Plackett-Burman design was utilized for screening the experimental parameters. The effective parameters were then optimized by Box-Behnken design (BBD). Optimized extraction conditions were pH of sample solution of 3.9, number of aspiration/dispersion cycles of 15, the volume of DES of 60 µL, and rate and time of centrifuge of 6000 rpm and 10 min, respectively. Under the optimized conditions, the developed NADES-ALLME method exhibited a wide linear range of 5-500 µg L - 1 for plasma and urine samples with satisfactory recoveries above 88.80%. Limit of detections (LODs) and Limit of quantifications (LOQs) of warfarin were in the ranges of 0.5-2.7 and 1.65-8.91, respectively. The enrichment factors were obtained in the range of 148-164 and precisions were lower than 5.87%. Finally, the proposed method was successfully employed for the analysis of warfarin in human urine and plasma samples.


Assuntos
Canfanos/química , Microextração em Fase Líquida/métodos , Solventes/química , Varfarina/análise , Varfarina/isolamento & purificação , Adulto , Ar , Ácidos Decanoicos/química , Feminino , Química Verde , Humanos , Ligação de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Limite de Detecção , Ácido Oleico/química , Solventes/síntese química , Timol/química , Varfarina/sangue , Varfarina/urina , Água/química
3.
Acta Pharm ; 70(3): 343-357, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32074068

RESUMO

In this study, high-performance liquid chromatography with fluorescence detection (HPLC-FLD) has been used for the first time, for direct determination of warfarin and its major metabolite, 7-hydroxywarfarin, in rat plasma. The simple and sensitive method was developed using Fortis® reversed-phase diphenyl column (150 × 4.6 mm, 3 µm) and a mobile phase composed of phosphate buffer (25 mmol L-1)/methanol/acetonitrile (70:20:10, V/V/V), adjusted to pH 7.4, at a flow rate of 0.8 mL min-1. The diphenyl chemistry of the stationary phase provided a unique selectivity for separating the structurally related aromatic analytes, warfarin and 7-hydroxywarfarin, allowing their successful quantification in the complex plasma matrix. The method was linear over the range 0.01-25 µg mL-1, for warfarin and 7-hydroxywarfarin, and was found to be accurate, precise and selective in accordance with US FDA guidance for bioanalytical method validation. The method was sensitive enough to quantify 0.01 µg mL-1 of warfarin and 7-hydroxywarfarin (LLOQ) using only 100 µL of plasma. The applicability of this method was demonstrated by analyzing samples obtained from rats after oral administration of a single warfarin dose, and studying warfarin and 7-hydroxywarfarin pharmacokinetics.


Assuntos
Anticoagulantes/análise , Cromatografia Líquida de Alta Pressão/métodos , Varfarina/análogos & derivados , Administração Oral , Animais , Anticoagulantes/farmacocinética , Masculino , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Varfarina/análise , Varfarina/farmacocinética
4.
Am J Emerg Med ; 38(6): 1226-1232, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32029342

RESUMO

BACKGROUND: Coagulation panels are ordered for a variety of conditions in the emergency department (ED). OBJECTIVE: This narrative review evaluates specific conditions for which a coagulation panel is commonly ordered but has limited utility in medical decision-making. DISCUSSION: Coagulation panels consist of partial thromboplastin time (PTT) or activated partial thromboplastin time (aPTT), prothrombin time (PT), and international normalized ratio (INR). These tests evaluate the coagulation pathway which leads to formation of a fibrin clot. The coagulation panel can monitor warfarin and heparin therapy, evaluate for vitamin K deficiency, evaluate for malnutrition or severe systemic disease, and assess hemostatic function in the setting of bleeding. The utility of coagulation testing in chest pain evaluation, routine perioperative assessment, prior to initiation of anticoagulation, and as screening for admitted patients is low, with little to no change in patient management based on results of these panels. Coagulation testing should be considered in systemically ill patients, those with a prior history of bleeding or family history of bleeding, patients on anticoagulation, or patients with active hemorrhage and signs of bleeding. Thromboelastography and rotational thromboelastometry offer more reliable measures of coagulation function. CONCLUSIONS: Little utility for coagulation assessment is present for the evaluation of chest pain, routine perioperative assessment, initiation of anticoagulation, and screening for admitted patients. However, coagulation panel assessment should be considered in patients with hemorrhage, patients on anticoagulation, and personal history or family history of bleeding.


Assuntos
Anticoagulantes/análise , Testes de Coagulação Sanguínea/normas , Medicina de Emergência/métodos , Anticoagulantes/uso terapêutico , Testes de Coagulação Sanguínea/métodos , Testes de Coagulação Sanguínea/estatística & dados numéricos , Dor no Peito/sangue , Dor no Peito/diagnóstico , Serviço Hospitalar de Emergência/organização & administração , Heparina/análise , Heparina/uso terapêutico , Humanos , Coeficiente Internacional Normatizado/métodos , Coeficiente Internacional Normatizado/normas , Complicações Intraoperatórias/sangue , Complicações Intraoperatórias/diagnóstico , Tempo de Tromboplastina Parcial/métodos , Tempo de Tromboplastina Parcial/normas , Tempo de Protrombina/métodos , Tempo de Protrombina/normas , Varfarina/análise , Varfarina/uso terapêutico
5.
Toxicol Mech Methods ; 29(7): 518-530, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31099292

RESUMO

In this study, an analytical strategy to identify brucine, strychnine, methomyl, carbofuran (alkaline compounds), phenobarbital, and warfarin (acid compounds) using thin-layer chromatography (TLC) screening with ultraviolet (UV) detection at 254 nm in stomach content is shown. The optimum mobile phase was found to be a chloroform: ethyl acetate: diethylamine (0.5:8.5:1) mixture for alkaline substances while a mixture of chloroform: acetone (9:1) has given better results for acidic substances. As for extraction, an equal proportion between distillated water and crude material (1:1) is required. For alkaline compounds, a filtration system was created in order to avoid any interferences from the biological matrix while for acidic compounds only centrifugation (4000 rpm/10 minutes) was required to obtain an appropriate sample. After the respective pretreatments, a one-step liquid-liquid extraction (LLE) has been employed for alkaline substances using a 3 mL of chloroform: ethyl ether (2:1) mixture for 2 min while acidic analytes used 3 mL of chloroform only during 5 min. For both methodologies described, the respective organic layers were dried down and re-suspended with 50 µL of methanol for further TLC plate application. The methodologies have been developed, successfully validated and applied to gastric contents from real case samples of suspected animal poisoning. Positive results from TLC/UV screening were confronted with HPLC-UV and confirmed by GC-MS.


Assuntos
Alcaloides/análise , Carbamatos/análise , Conteúdo Gastrointestinal/química , Fenobarbital/análise , Intoxicação/veterinária , Varfarina/análise , Alcaloides/intoxicação , Animais , Carbamatos/intoxicação , Doenças do Gato/induzido quimicamente , Gatos , Cromatografia em Camada Fina/veterinária , Doenças do Cão/induzido quimicamente , Cães , Fenobarbital/intoxicação , Intoxicação/etiologia , Varfarina/intoxicação
6.
Int J Pharm ; 561: 314-323, 2019 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-30877029

RESUMO

Individualized medicine is relevant to ensure safe and efficient pharmacotherapy. It requires a suitable dosage form and a matching dosing device to enable flexible dosing serving the needs of individual dose requirements. For oral films no flexible dosing option is available until today. This study covers the development of a dosing device that enables flexible dosing of films within the pharmacopoeial requirements. The prototype was produced with the 3D-printing technique fused filament fabrication. The developed and produced prototype of the device was tested for the uniformity of doses according to Ph.Eur. 2.9.27 and 2.9.40. A ribbon as model film and an oral film with HPMC as polymer matrix met the specifications for both tests for three different lengths dispensed with the prototype of the dosing device (HPMC film: AV = 11.30 (1 cm), 12.04 (2 cm) and 10.19 (5 cm)). A second oral film with a polymer matrix from PVA and HPMC exceeded the threshold for the shortest piece of 1 cm (AV = 26.54) because of slight splintering during the cutting process, likely due to too little plasticizer in the formulation. A successful device development and a use within the specifications of the European Pharmacopoeia is demonstrated.


Assuntos
Composição de Medicamentos/métodos , Sistemas de Liberação de Medicamentos/instrumentação , Medicina de Precisão/métodos , Impressão Tridimensional , Varfarina/administração & dosagem , Administração Oral , Sistemas de Liberação de Medicamentos/métodos , Derivados da Hipromelose/química , Álcool de Polivinil/química , Varfarina/análise
7.
Chem Res Toxicol ; 32(1): 168-178, 2019 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-30585484

RESUMO

The effects measured with in vitro cell-based bioassays are typically reported as nominal effect concentrations ( Cnom), but the freely dissolved concentration in the exposure medium ( Cw) and the total cellular concentration ( Ccell) are considered more quantitative dose metrics that allow extrapolation to the whole-organism level. To predict Cw and Ccell, the partitioning of the test chemicals to medium proteins and lipids and cells has to be known. In this study, we developed a solid-phase microextraction (SPME) method based on C18-coated fibers to quantify the partitioning of diclofenac, 2,4-dichlorophenoxyacetic acid (2,4-D), ibuprofen, naproxen, torasemide, warfarin, and genistein to bovine serum albumin (BSA), phospholipid liposomes, fetal bovine serum (FBS), and cells. For ibuprofen, 2,4-D, naproxen, and warfarin, the partitioning to the SPME fibers was found to be concentration dependent, which had to be considered for the calculation of distribution ratios to biological materials. The sorption isotherms to FBS were nonlinear for diclofenac, 2,4-D, ibuprofen, naproxen, and warfarin. The FBS isotherms could be described by assuming that the total amount of chemical bound to FBS is the sum of the amount specifically bound to the binding sites of albumin and nonspecifically bound to all medium proteins and lipids. The determined cell-water distribution ratios ( Dcell/w) differed considerably between four different cell lines (up to 1.83 log-units) and also between different batches of the same cell line (up to 0.48 log-units). The relative importance of protein and lipid content for Dcell/w was evaluated with a mass balance model and different types of cellular proteins and lipids as input parameters. Existing in vitro mass balance models may underestimate Cw because they do not account for saturable protein binding and overestimate Ccell for organic acids, if BSA is used as surrogate for cellular proteins.


Assuntos
Fosfolipídeos/química , Soroalbumina Bovina/química , Microextração em Fase Sólida , Ácido 2,4-Diclorofenoxiacético/análise , Animais , Bovinos , Células Cultivadas , Diclofenaco/análise , Genisteína/análise , Células HEK293 , Humanos , Ibuprofeno/análise , Cinética , Lipossomos/química , Naproxeno/análise , Torasemida/análise , Varfarina/análise
8.
N Engl J Med ; 379(13): 1216-1223, 2018 09 27.
Artigo em Inglês | MEDLINE | ID: mdl-30280655

RESUMO

BACKGROUND: In March and April 2018, more than 150 patients presented to hospitals in Illinois with coagulopathy and bleeding diathesis. Area physicians and public health organizations identified an association between coagulopathy and synthetic cannabinoid use. Preliminary tests of patient serum samples and drug samples revealed that brodifacoum, an anticoagulant, was the likely adulterant. METHODS: We reviewed physician-reported data from patients admitted to Saint Francis Medical Center in Peoria, Illinois, between March 28 and April 21, 2018, and included in a case series adult patients who met the criteria used to diagnose synthetic cannabinoid-associated coagulopathy. A confirmatory anticoagulant poisoning panel was ordered at the discretion of the treating physician. RESULTS: A total of 34 patients were identified as having synthetic cannabinoid-associated coagulopathy during 45 hospitalizations. Confirmatory anticoagulant testing was performed in 15 of the 34 patients, and superwarfarin poisoning was confirmed in the 15 patients tested. Anticoagulant tests were positive for brodifacoum in 15 patients (100%), difenacoum in 5 (33%), bromadiolone in 2 (13%), and warfarin in 1 (7%). Common symptoms at presentation included gross hematuria in 19 patients (56%) and abdominal pain in 16 (47%). Computed tomography was performed to evaluate abdominal pain and revealed renal abnormalities in 12 patients. Vitamin K1 (phytonadione) was administered orally in all 34 patients and was also administered intravenously in 23 (68%). Red-cell transfusion was performed in 5 patients (15%), and fresh-frozen plasma infusion in 19 (56%). Four-factor prothrombin complex concentrate was used in 1 patient. One patient died from complications of spontaneous intracranial hemorrhage. CONCLUSIONS: Our data indicate that superwarfarin adulterants of synthetic cannabinoids can lead to clinically significant coagulopathy. In our series, in most of the cases in which the patient presented with bleeding diathesis, symptoms were controlled with the use of vitamin K1 replacement therapy. The specific synthetic cannabinoid compounds are not known.


Assuntos
Anticoagulantes/efeitos adversos , Transtornos da Coagulação Sanguínea/epidemiologia , Canabinoides/efeitos adversos , Vitamina K/uso terapêutico , 4-Hidroxicumarinas/efeitos adversos , 4-Hidroxicumarinas/análise , Dor Abdominal/induzido quimicamente , Adulto , Transtornos da Coagulação Sanguínea/induzido quimicamente , Transtornos da Coagulação Sanguínea/tratamento farmacológico , Transtornos da Coagulação Sanguínea/terapia , Transfusão de Sangue , Canabinoides/síntese química , Canabinoides/química , Feminino , Hematúria/induzido quimicamente , Hemorragia/induzido quimicamente , Hemorragia/tratamento farmacológico , Humanos , Illinois/epidemiologia , Coeficiente Internacional Normatizado , Masculino , Pessoa de Meia-Idade , Readmissão do Paciente , Varfarina/efeitos adversos , Varfarina/análise
9.
Dalton Trans ; 46(31): 10205-10209, 2017 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-28748979

RESUMO

Warfarin, a commercial anticoagulant drug, is extensively used to prevent blood clots in the blood vessel but lack of adequate analytical techniques poses serious monitoring issues. This work illustrates the application of Pd(ii) complexes not only in the excellent sensing of warfarin in organic but also in aqueous medium.


Assuntos
Anticoagulantes/análise , Técnicas de Química Analítica/instrumentação , Compostos Organometálicos/química , Paládio/química , Varfarina/análise , Anticoagulantes/química , Modelos Moleculares , Conformação Molecular , Varfarina/química , Água/química
10.
Talanta ; 171: 25-31, 2017 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-28551136

RESUMO

In the current study, poly(MImEO8BS)-Ni nanocomposite was synthesized and applied to modify a glassy carbon electrode along with conductive polymeric ionic liquids. The electrochemical investigation of the modified electrode as well as its efficiency for voltammetric oxidation of warfarin is elucidated. The electrode was used to study the voltammetric oxidation of warfarin by employing cyclic voltammetry (CV), linear sweep voltammetry (LSV), chronoamperometry, and square wave voltammetry (SWV) as diagnostic techniques. It has been observed that warfarin oxidation at the surface of modified electrode occurs at a potential of about 230mV which is less positive than that of an unmodified glassy carbon electrode. SWV demonstrated a linear dynamic range from 1.0×10-6 to 1.0×10-4M and a detection limit of 1.5×10-7M for warfarin. In addition, this modified electrode was utilized for simultaneous determination of warfarin and tramadol. Finally, the modified electrode was employed for determination of warfarin and tramadol in pharmaceutical compounds.


Assuntos
Condutividade Elétrica , Líquidos Iônicos/química , Nanocompostos/química , Níquel/química , Polímeros/síntese química , Tramadol/química , Varfarina/análise , Calibragem , Técnicas de Química Sintética , Eletroquímica , Limite de Detecção , Oxirredução , Polímeros/química , Varfarina/química
11.
J Pharm Biomed Anal ; 139: 156-164, 2017 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-28284080

RESUMO

In this paper a novel electrochemical sensor based on nickel carbide (Ni3C) nanoparticles as a new modifier was constructed. Ni3C nanoparticle was synthesized and characterized by scanning electron microscopy, X-ray diffraction and first-principles study. Electrochemical impedance spectroscopy (EIS) and cyclic voltammetry (CV) studies confirmed the electrode modification. Afterwards, the new electrode for the first time was used for interaction study between vitamin K1 and warfarin as an anticoagulant drug by differential pulse voltammetry. The adduct formation between the drug and vitamin K1 was improved by decreasing in anodic peak current of warfarin in the presence of different amounts of vitamin K1. The binding constant between warfarin and vitamin K1 was obtained by voltammetric and UV-vis and fluorescence spectroscopic methods. The molecular modeling method was also performed to explore the structural features and binding mechanism of warfarin to vitamin K1. The different aspects of modeling of vitamin K1 and warfarin and their adduct structures confirmed the adduct formation by hydrogen bonding.


Assuntos
Carbono/química , Nanopartículas Metálicas/química , Modelos Moleculares , Níquel/química , Vitamina K 1/metabolismo , Varfarina/metabolismo , Interações Medicamentosas/fisiologia , Eletrodos , Vitamina K 1/análise , Varfarina/análise , Difração de Raios X
12.
Spectrochim Acta A Mol Biomol Spectrosc ; 176: 183-188, 2017 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-28095360

RESUMO

A sensitive fluorescence sensor for warfarin was proposed via quenching the fluorescence of l-tryptophan due to the interaction between warfarin and l-tryptophan. Warfarin, as one of the most effective anticoagulants, was designed and synthesized via lipase from porcine pancreas (PPL) as a biocatalyst to catalyze the Michael addition of 4-hydroxycoumarin to α, ß-unsaturated enones in organic medium in the presence of water. Furthermore, the spectrofluorometry was used to detect the concentration of warfarin with a linear range and detection limit (3σ/k) of 0.04-12.0µmolL-1 (R2=0.994) and 0.01µmolL-1, respectively. Herein, this was the first application of bio-catalytic synthesis and fluorescence for the determination of warfarin. The proposed method was applied to determine warfarin of the drug in tablets with satisfactory results.


Assuntos
Biocatálise , Lipase/metabolismo , Triptofano/química , Varfarina/análise , Varfarina/síntese química , Animais , Cromatografia Líquida de Alta Pressão , Concentração de Íons de Hidrogênio , Cinética , Espectrometria de Fluorescência , Sus scrofa , Comprimidos , Fatores de Tempo , Varfarina/química
13.
Drug Des Devel Ther ; 10: 2173-80, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27462142

RESUMO

According to previous research studies, warfarin can be detected in human bile after oral administration. Ferulic acid (FA) is the main bioactive component of many Chinese herbs for the treatment of cardiovascular disease. To elucidate the effects of FA on the pharmacokinetics of warfarin in rats after biliary drainage is necessary. Twenty rats were randomly divided into four groups: Group 1 (WN): healthy rats after the administration of warfarin sodium, Group 2 (WO): a rat model of biliary drainage after the administration of warfarin sodium, Group 3 (WFN): healthy rats after the administration of warfarin sodium and FA, and Group 4 (WFO): a rat model of biliary drainage after the administration of warfarin sodium and FA. Blood samples were collected at different time points after administration. The concentrations of blood samples were determined by ultraperformance liquid chromatography-tandem mass spectrometry. Comparisons between groups were performed according to the main pharmacokinetic parameters calculated by the DAS 2.1.1 software. The pharmacokinetic parameters showed a significant difference between the WN and WO groups, the WO group showed a decrease of 51% and 41.6% in area under the curve from 0 to time (AUC0- t ) and peak plasma concentration (C max), respectively, whereas time to C max (T max) was delayed 3.27 folds. There were significant differences between the WFO and WFN groups, the WFO group showed a decrease of 63.8% and 70% in AUC0- t and C max, respectively; the delay in T max between the WN and WFN groups (mean, from 132-432 minutes) was significantly different; the mean retention time from 0 to time (MRT0- t ) between the WO and WFO groups (mean, from 718.31-606.13 minutes) also showed a significant difference. Enterohepatic circulation markedly influences the disposition of warfarin in rats, and FA significantly affected the warfarin disposition in rat plasma.


Assuntos
Ácidos Cumáricos/química , Medicamentos de Ervas Chinesas/análise , Circulação Êntero-Hepática/efeitos dos fármacos , Espectrometria de Massas em Tandem/métodos , Varfarina/análise , Varfarina/farmacocinética , Administração Oral , Animais , Ácidos Cumáricos/farmacologia , Drenagem , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/química , Humanos , Ratos , Varfarina/química
14.
Ann N Y Acad Sci ; 1374(1): 111-22, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27244102

RESUMO

Superwarfarins were developed following the emergence of warfarin resistance in rodents. Compared to warfarin, superwarfarins have much longer half-lives and stronger affinity to vitamin K epoxide reductase and therefore can cause death in warfarin-resistant rodents. By the mid-1970s, the superwarfarins brodifacoum and difenacoum were the most widely used rodenticides throughout the world. Unfortunately, increased use was accompanied by a rise in accidental poisonings, reaching >16,000 per year in the United States. Risk of exposure has become a concern since large quantities, up to hundreds of kilograms of rodent bait, are applied by aerial dispersion over regions with rodent infestations. Reports of intentional use of superwarfarins in civilian and military scenarios raise the specter of larger incidents or mass casualties. Unlike warfarin overdose, for which 1-2 days of treatment with vitamin K is effective, treatment of superwarfarin poisoning with vitamin K is limited by extremely high cost and can require daily treatment for a year or longer. Furthermore, superwarfarins have actions that are independent of their anticoagulant effects, including both vitamin K-dependent and -independent effects, which are not mitigated by vitamin K therapy. In this review, we summarize superwarfarin development, biology and pathophysiology, their threat as weapons, and possible therapeutic approaches.


Assuntos
Varfarina/efeitos adversos , Varfarina/análise , Animais , Anticoagulantes/efeitos adversos , Anticoagulantes/análise , Anticoagulantes/química , Biomarcadores/análise , Exposição Ambiental/análise , Humanos , Rim/efeitos dos fármacos , Rim/patologia , Sistema Nervoso/efeitos dos fármacos , Sistema Nervoso/patologia , Varfarina/química , Varfarina/intoxicação
15.
J Pharm Biomed Anal ; 126: 60-5, 2016 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-27160739

RESUMO

In this work cyclodextrin-assisted enantioseparation of warfarin and 10-hydroxywarfarin by CE has been studied from the analytical and thermodynamic points of view. The role of cyclodextrin concentration and temperature has been analyzed in reference to three different analytical parameters, corresponding to selectivity, resolution and resolution/analysis time ratio. The optimal conditions for enantioseparation have been found, they have been selected on the basis of critical difference in electrophoretic mobility and possibly short analysis time. The values of complexation percentage have also been calculated, to provide a link between the state of complexation equilibrium and the effectiveness of enantioseparation. In the optimal conditions the difference in complexation degree between enantiomers reaches 2.5% and 7.3% for warfarin and 10-hydroxywarfarin, respectively. At each temperature the highest enantioresolution is observed when the average complexation degree is close to 50%. In each case complexation is exothermic and driven by some enthalpically favorable process. 10-hydroxywarfarin exerts the stronger affinity to cyclodextrin and the stronger stereoselective effect. The presented results may be helpful in optimization and understanding of chiral separations by CE.


Assuntos
Ciclodextrinas/química , Eletroforese Capilar/métodos , Termodinâmica , Varfarina/análogos & derivados , Estereoisomerismo , Temperatura , Varfarina/análise , Varfarina/química
16.
Environ Sci Pollut Res Int ; 23(15): 15739-48, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27146526

RESUMO

The occurrence of 10 commonly used anticoagulant rodenticides in centrifuged sludge of 27 wastewater treatment plants was evaluated using solid-liquid extraction (SLE) and liquid chromatography-tandem mass spectrometry (LC-MS/MS). Activated carbon, alumina, and Florisil cartridges with methanol/dichloromethane as eluting solvents were tested in combination with primary-secondary amine (PSA) to optimize an efficient sample cleanup. PSA in combination with Florisil was the best methodology to extract anticoagulant rodenticides in sludge providing recoveries between 42 ± 0.5 and 100 ± 2 %. Warfarin, bromadiolone, ferulenol, and coumachlor were the most ubiquitous compounds in sludge at concentrations up to 84.2 ng g(-1) for the latter. Coumatetralyl, dicoumarol, and brodifacoum were detected sporadically at levels between 6.1 and 17.4 ng g(-1). On the contrary, acenocoumarol, difenacoum, and flocoumafen were not detected in any sample. Finally, we estimated the amount of anticoagulant rodenticides discharged via sludge in order to determine the potential impact to agricultural soil according to different sludge usage practices in the region investigated. This study demonstrates that anticoagulant rodenticides are accumulated in sludge during activated sludge treatment and that the application of sludge as fertilizers may pose a future environmental risk, if not controlled.


Assuntos
Anticoagulantes/análise , Esgotos/química , 4-Hidroxicumarinas/análise , Cromatografia Líquida de Alta Pressão/métodos , Cumarínicos/análise , Rodenticidas/análise , Espectrometria de Massas em Tandem/métodos , Varfarina/análise , Águas Residuárias/química
17.
Ceska Slov Farm ; 65(6): 211-215, 2016.
Artigo em Tcheco | MEDLINE | ID: mdl-28079385

RESUMO

Warfarin is a drug with narrow therapeutic index. Individualization of dose and thorough therapy monitoring is compensated by long time use in praxis and low therapy cost. Considering the low dose usually administered, critical parameter of solid dosage form is its uniformity of content. It has to not only meet the criteria set by pharmacopoeia, but to meet them on statisticall significant level also.This experimental study asseses impact of warfarin concentration and blending time after adition of lubricant on uniformity of content of mixtures and tablets made of them. It concludes, that concentration in 2-2,7% range is optimal and its increase or decrease has a negative effect on uniformity of content. It also confirms 5 minutes of blending after lubricant addition to be adequate, as employing longer blending times leads to mixture overblending.Key words: content uniformity warfarin blending time narrow therapeutic index.


Assuntos
Tecnologia Farmacêutica , Varfarina/análise , Composição de Medicamentos , Lubrificantes/administração & dosagem , Comprimidos , Varfarina/administração & dosagem
18.
Drug Dev Ind Pharm ; 42(4): 584-94, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26161939

RESUMO

Monitoring of the physical state of warfarin sodium (WS) in products is essential for minimizing product quality variability in order to ensure consistent clinical performance. This study reports the development of chemometric models for quantifying the crystalline and amorphous fractions of WS in commercial drug products using NIR spectroscopy. Formulations based on commercially available products with different API to excipient ratio were used for the study. For each content, two formulations containing either lactose monohydrate or lactose anhydrous as the predominant formulation excipient were prepared. Two formulations containing either 100% amorphous WS (AWS) or crystalline WS (CWS) were prepared and mixed in various ratios to obtain sample matrices containing AWS/CWS 0-100%. The uniformity of the samples was confirmed by near infrared chemical imaging. Data were mathematically pretreated by multiplicative signal correction and Savitzky-Golay second derivative. Principal component regression and partial least square regression models were developed from mathematically treated data. All the models showed linear trend for amorphous and crystalline fractions of the WS as indicated by correlation and R(2) > 0.99 and >0.98, respectively. The models demonstrated good performance parameters with a low-root mean squared error, standard error and bias. The model predicted CWS and AWS contents were in very close agreement with the actual values. The study indicated the utility of NIR chemometric methods in quantification of the crystalline and/or amorphous fraction of WS in its products.


Assuntos
Anticoagulantes/análise , Anticoagulantes/química , Espectroscopia de Luz Próxima ao Infravermelho/métodos , Varfarina/análise , Varfarina/química , Química Farmacêutica , Cristalização
19.
Crit Rev Food Sci Nutr ; 56 Suppl 1: S149-61, 2016 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-26507574

RESUMO

The discovery of bioactive molecules from botanical sources is an expanding field, preferentially oriented to plants having a tradition of use in medicine and providing high yields and availability. Temperate forage legumes are Fabaceae species that include worldwide-important crops. These plants possess therapeutic virtues that have not only been used in veterinary and folk medicine, but have also attracted the interest of official medicine. We have examined here Medicago sativa (alfalfa), Trifolium pratense and T. repens (clovers), Melilotus albus and M. officinalis (sweet clovers), Lotus corniculatus (birdsfoot trefoil), Onobrychis viciifolia (sainfoin), Lespedeza capitata (roundhead lespedeza), and Galega officinalis (goat's rue). The phytochemical complexes of these species contain secondary metabolites whose pharmacological potentials deserve investigation. Major classes of compounds include alkaloids and amines, cyanogenic glycosides, flavonoids, coumarins, condensed tannins, and saponins. Some of these phytochemicals have been related to antihypercholesterolemia, antidiabetic, antimenopause, anti-inflammatory, antiedema, anthelmintic, and kidney protective effects. Two widely prescribed drugs have been developed starting from temperate forage legumes, namely, the antithrombotic warfarin, inspired from sweet clover's coumarin, and the antidiabetic metformin, a derivative of sainfoin's guanidine. Available evidence suggests that temperate forage legumes are a potentially important resource for the extraction of active principles to be used as nutraceuticals and pharmaceuticals.


Assuntos
Fabaceae/química , Compostos Fitoquímicos/farmacologia , Plantas Medicinais/química , Animais , Anti-Inflamatórios/análise , Anti-Inflamatórios/farmacologia , Ensaios Clínicos como Assunto , Cumarínicos/análise , Cumarínicos/farmacologia , Modelos Animais de Doenças , Fibrinolíticos/análise , Fibrinolíticos/farmacologia , Flavonoides/análise , Flavonoides/farmacologia , Galega/química , Humanos , Hipoglicemiantes/análise , Hipoglicemiantes/farmacologia , Lespedeza/química , Lotus/química , Medicago/química , Medicago sativa/química , Melilotus/química , Compostos Fitoquímicos/análise , Proantocianidinas/análise , Proantocianidinas/farmacologia , Saponinas/análise , Saponinas/farmacologia , Trifolium/química , Varfarina/análise , Varfarina/farmacologia
20.
Pharm Dev Technol ; 21(5): 546-53, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26465269

RESUMO

The adsorption of the anticoagulant warfarin onto unmodified (UMS) and modified (phenyl (PhMS), methyl (MMS), mercaptopropyl (MPMS)) mesoporous silica materials was studied at pH 1.6 and 7.4 and in the temperature range of 293-325 K. The silica materials were prepared by sol-gel method for further characterization by FTIR spectroscopy, N2 adsorption/desorption method, transmission electron microscopy and zeta potential measurements. The effects of medium pH, temperature and surface modification of mesoporous silica material on their adsorption characteristics (adsorption capacity, thermodynamic parameters of adsorption) relative to anticoagulant warfarin were investigated. It was found that medium acid-base properties strongly affect the adsorption of warfarin due to the pH-dependent structural diversity of the drug and ionization state of the silica surfaces. The adsorption capacity of the silica materials at pH 1.6 decreases in the order: MMS > MPMS > UMS > PhMS. The influence of various non-covalent interactions on the adsorption capacity of the silica materials and energy of the drug-silica interactions is discussed. These results may be useful for the development of a novel delivery system of warfarin.


Assuntos
Anticoagulantes/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Dióxido de Silício/metabolismo , Varfarina/metabolismo , Anticoagulantes/análise , Anticoagulantes/química , Porosidade , Dióxido de Silício/análise , Dióxido de Silício/química , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Propriedades de Superfície , Varfarina/análise , Varfarina/química
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