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1.
Eur J Pharm Biopharm ; 136: 93-101, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30660692

RESUMO

Continuously manufactured orodispersible films (ODFs) offer a promising approach for individualized therapy with an easy to administer solid dosage form. The aim of this study was to develop a long ODF containing warfarin sodium to enable safe and more flexible dosing. Formulation development was conducted systematically for the continuous film coating process. A continuously working pilot-scale coating bench was used for film manufacturing and the viscosities of the polymer solutions were investigated to obtain processible formulations. The investigation of the mechanical properties of the long film was an integral part of the study, because the handling of the long film during flexible dosing differs distinctly from the handling of a single dosed ODF. The secant modulus and the yield stress were evaluated as parameters with high information value about the deformation behavior of the ODF. A long warfarin ODF was successfully produced using the pilot-scale coating bench equipped with an optical probe for in-line film thickness measurement. It was feasible to use the principle of a tape dispenser for flexible and, therefore, individualized dosing as proof of concept. Combining the long ODF with a dosing device allows individualized therapy with warfarin for all age groups manageable by the patient himself.


Assuntos
Anticoagulantes/síntese química , Composição de Medicamentos/métodos , Sistemas de Liberação de Medicamentos/métodos , Desenvolvimento de Medicamentos/métodos , Varfarina/síntese química , Administração Oral , Anticoagulantes/administração & dosagem , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/síntese química , Composição de Medicamentos/instrumentação , Sistemas de Liberação de Medicamentos/instrumentação , Desenvolvimento de Medicamentos/instrumentação , Varfarina/administração & dosagem
2.
Org Biomol Chem ; 16(35): 6423-6429, 2018 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-30047554

RESUMO

Novel C2-symmetric N,N'-bis(2-amino-1,2-diphenylethyl)squaramides with 1,2-di(pyridin-2-yl)ethane and 1,2-diphenylethane spacer groups were designed and applied as organocatalysts in asymmetric additions of 4-hydroxycoumarin and 4-hydroxy-6-methyl-2H-pyran-2-one to α,ß-unsaturated ketones. Both enantiomers of the anticoagulant warfarin and its analogs were prepared in up to 96% yield and with 96% ee. Recyclability of the developed catalysts and synthetic utility of the prepared Michael adducts for asymmetric synthesis of potential chiral medications via acylation reactions were demonstrated.


Assuntos
Diaminas/química , Quinina/análogos & derivados , Varfarina/química , Varfarina/síntese química , Catálise , Técnicas de Química Sintética , Quinina/química , Estereoisomerismo
3.
Nat Commun ; 8: 15242, 2017 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-28524847

RESUMO

Drugs, usually long acting and metabolically stable molecules, might be the source of adverse effects triggered by complex drug interactions, anaphylaxis and drug-induced coagulopathy. To circumvent this growing drug safety issue, we herein investigate the opportunity offered by bio-orthogonal chemistry for in vivo drug neutralization. We design a small-molecule anticoagulant drug (Warfarin) containing an azide group that acts as a safety pin. It allows drug deactivation and restoration of physiological coagulation via in vivo click reaction with a suitable cyclooctyne-based neutralizing agent. In this strategy, the new molecule formed by reaction of the drug and the antidote is deprived of biological activity and prone to fast renal clearance. This 'Click &Clear' approach lays ground for new strategies in designing drugs with switchable biophysical properties.


Assuntos
Anticoagulantes/administração & dosagem , Anticoagulantes/farmacologia , Azidas/administração & dosagem , Azidas/farmacologia , Varfarina/análogos & derivados , Animais , Anticoagulantes/síntese química , Anticoagulantes/química , Azidas/síntese química , Azidas/química , Cromatografia Líquida , Química Click , Rim/efeitos dos fármacos , Rim/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Espectrometria de Massas em Tandem , Varfarina/administração & dosagem , Varfarina/síntese química , Varfarina/química , Varfarina/farmacologia
4.
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
5.
Ceska Slov Farm ; 62(3): 111-9, 2013 Jun.
Artigo em Tcheco | MEDLINE | ID: mdl-23961812

RESUMO

The review paper deals with some aspects of warfarin history and its use, at the beginning as a rodenticide and later as an anticoagulant. It describes its principal physical-chemical properties and it analyzes schematically the possibilities of its preparation by both selective and non-selective synthesis from coumarin derivatives. A survey of syntheses and its results are tabulated, including the literary references, and the paper is concluded with an evaluation of the prospects of this agent in comparison with alternative anticoagulants and its advantages, disadvantages and prospects.


Assuntos
Anticoagulantes , Rodenticidas , Varfarina , Animais , Anticoagulantes/síntese química , Anticoagulantes/história , Anticoagulantes/farmacologia , Anticoagulantes/uso terapêutico , Cumarínicos/química , História do Século XX , História do Século XXI , Humanos , Rodenticidas/síntese química , Rodenticidas/história , Rodenticidas/farmacologia , Rodenticidas/uso terapêutico , Varfarina/síntese química , Varfarina/história , Varfarina/farmacologia , Varfarina/uso terapêutico
6.
Org Biomol Chem ; 10(40): 8125-31, 2012 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-22956019

RESUMO

An efficient enantioselective Michael addition of 4-hydroxycoumarin to α,ß-unsaturated ketones catalysed by primary amine-phosphinamide bifunctional catalysts has been developed. This reaction afforded Warfarin and its analogs in moderate to excellent yields (up to 99%) and good to excellent enantioselectivities (up to 99% ee).


Assuntos
Amidas/química , Aminas/química , Compostos Organofosforados/química , Varfarina/síntese química , Catálise , Estrutura Molecular , Estereoisomerismo , Varfarina/química
8.
Bioorg Med Chem ; 15(6): 2414-20, 2007 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-17275317

RESUMO

4-Hydroxycoumarins such as warfarin 1 have been the mainstay of oral anticoagulation therapy for over 20 years. Yet little detail is known about the molecular interactions between 4-hydroxycoumarins with vitamin K epoxide reductase (VKER), inhibition of which produces a deficiency of vitamin K and consequently a deficiency of vitamin K-dependent proteins involved in thrombus formation. Using molecular probes, such as 4-sulfhydrylwarfarin 7 and 4-chlorowarfarin 10 it is shown in vitro that inhibition of VKER by warfarin is dependent on deprotonation of the 4-hydroxycoumarin moiety. In addition, the nature of the substituent on carbon 3 of the 4-hydroxycoumarin modulated inhibition. More specifically, a linear isoprenyl side chain increased inhibition of VKER when compared to cyclical substituents as present in warfarin. An example of a 4-hydroxycoumarin with an isoprenyl side chain is the natural product ferulenol 19 derived from Ferula communis. Ferulenol 19 confers approximately 22 times more potent inhibition than warfarin and is approximately 1.5 more potent than the rodenticide brodifacoum in this in vitro assay. Based on these data it is hypothesized that 4-hydroxycoumarins bind to the active site of VKER thereby mimicking the transition state of the elimination of water from substrate 2-hydroxyvitamin K.


Assuntos
4-Hidroxicumarinas/metabolismo , Anticoagulantes/farmacologia , Inibidores Enzimáticos/farmacologia , Oxigenases de Função Mista/antagonistas & inibidores , Vitamina K/metabolismo , Varfarina/síntese química , Animais , Anticoagulantes/síntese química , Anticoagulantes/química , Sítios de Ligação , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Microssomos/enzimologia , Oxigenases de Função Mista/metabolismo , Ratos , Relação Estrutura-Atividade , Vitamina K Epóxido Redutases , Varfarina/química , Varfarina/farmacologia
9.
Org Lett ; 8(21): 4851-4, 2006 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-17020319

RESUMO

[reaction: see text] We report here the catalytic asymmetric conjugate reduction of enones using ethanol as a hydride source. The reaction was carried out in the presence of a chiral Pd complex at ambient temperature in ethanol, and the desired products were obtained in high chemical yield and high enantioselectivity. We applied this novel reaction to the catalytic asymmetric synthesis of warfarin (96% ee), and on the basis of d-labeling experiments, the reaction mechanism is proposed.


Assuntos
Etanol/química , Paládio/química , Varfarina/síntese química , Catálise , Cetonas/química , Estrutura Molecular , Oxirredução , Estereoisomerismo , Varfarina/química
11.
Pharmazie ; 52(8): 627-31, 1997 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-9292918

RESUMO

Coevaporates of warfarin sodium containing different weight fractions of polyvinylpyrrolidone (Kollidon s5 and 30) polymers of different molecular weights were prepared and their characterization, dissolution properties as well as their bioavailability in rabbits were assessed. UV and IR spectrophotometery revealed a sort of binding between the drug and polymers. Optimum binding tendency appears at polymer weight fractions of 0.7 and 0.5 for Kollidon 25 and Kollidon 30, respectively. Incorporation of the drug with PVP enhances its dissolution properties and improves its bioavailability. Of all the investigated warfarin/PVP systems, the coevaporate of warfarin with an equal weight fraction of Kollidon 30 was found to exhibit optimum biological properties beside highest dissolution rate.


Assuntos
Anticoagulantes/síntese química , Varfarina/análogos & derivados , Varfarina/síntese química , Animais , Anticoagulantes/farmacocinética , Anticoagulantes/farmacologia , Área Sob a Curva , Disponibilidade Biológica , Cristalização , Meia-Vida , Técnicas In Vitro , Masculino , Povidona/química , Coelhos , Espectrofotometria Infravermelho , Espectrofotometria Ultravioleta , Varfarina/farmacocinética
12.
Eksp Med Morfol ; 31(3-4): 49-60, 1993.
Artigo em Búlgaro | MEDLINE | ID: mdl-7805620

RESUMO

4-hydroxy-3-(3-oxo-1-phenyl butyl)-2H-1-benzopyran-2-one (warfarin) has been synthesised by an original method. The influence of a phase-transfer catalyst of ammonium type with alkyl substituents containing eight carbon atoms upon the reaction of Michael addition has been investigated. It has been found out that when elongating the hydrocarbon chain of the substituents to the nitrogen atom in the quaternary ammonium salt the yield of the product decreased. The acute (LD50) and subchronic (lasting for 30 days) toxicity was determined when taking warfarin orally. The experimental data show that LD50 is 500 mg/kg for mice and 420 mg/kg body mass for rats. The subchronic toxicity at experiments made with rabbits (each day taking orally respectively 25 and 100 mg/kg) does not reveal any humoral and tissue toxic influence of warfarin. The results from the comparative cytogenetic analysis of warfarin and Niffcumar are the basis of the conclusion cytogenetic analysis of warfarin and Niffcumar are the basis of the conclusion that warfarin damages chromosomes of mice's marrow cells (used as a model) less than Niffcumar. Moreover warfarin has a slight influence on these cells in the first place changing the orientation of chromosomes one towards the other and unlike other drugs it does not damage nuclear chromatin strongly.


Assuntos
Aberrações Cromossômicas , Varfarina/síntese química , Varfarina/toxicidade , Animais , Anticoagulantes/toxicidade , Relação Dose-Resposta a Droga , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Coelhos , Ratos , Ratos Wistar , Fatores de Tempo
14.
Acta Crystallogr C ; 45 ( Pt 8): 1182-4, 1989 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-2604944

RESUMO

A derivative of warfarin, racemic C19H14O4, Mr = 306.32, monoclinic, Cc, a = 9.594 (2), b = 20.437 (4), c = 7.793 (2) A, beta = 109.94 (3) degree, V = 1436.4 (11) A3, Z = 4, Dx = 1.416 g cm-3, lambda(CuK alpha) = 1.5418 A, mu = 7.742 cm-1, F(000) = 640, T = 293 K, final R = 0.053 for 1224 observations. The title molecule, formed by spontaneous dehydration of 2'-hydroxy-warfarin, is a cyclic ketal in which the side-chain phenyl is disposed pseudoaxially and is linked through a 2'-oxygen to the ketal carbon in a fixed cis 1,3-diaxial configuration. Two dihydropyran rings are formed; one fused with the benzopyran ring adopts an e,f-diplanar conformation, the other is a chroman and is in a similar conformation.


Assuntos
Varfarina/análogos & derivados , Fenômenos Químicos , Físico-Química , Cristalização , Cristalografia , Conformação Molecular , Estrutura Molecular , Varfarina/síntese química
17.
J Med Chem ; 21(10): 1054-9, 1978 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-722713

RESUMO

The metabolism of the clinically utilized, anticoagulant warfarin [4-hydroxy-3-(3-oxo-1-phenylbutyl)-2H-1-benzopyran-2-one] by rat liver microsomes has been investigated. The structure of a new warfarin metabolite [4-hydroxy-3-(3-oxo-1-phenyl-1-butenyl)-2H-1-benzopyran-2-one] (dehydrowarfarin) has been determined by mass spectral comparison with the chemically synthesized compound. The formation of dehydrowarfarin is catalyzed by cytochrome P-450 and is unusual in that the final product is effectively dehydrogenated warfarin.


Assuntos
Varfarina/metabolismo , Animais , Coagulação Sanguínea/efeitos dos fármacos , Fenômenos Químicos , Química , Sistema Enzimático do Citocromo P-450/metabolismo , Indução Enzimática/efeitos dos fármacos , Técnicas In Vitro , Microssomos Hepáticos/metabolismo , Mutagênicos , Ratos , Salmonella/efeitos dos fármacos , Salmonella/genética , Estereoisomerismo , Vitamina K 1/antagonistas & inibidores , Varfarina/síntese química , Varfarina/farmacologia
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