RESUMO
The major product of reaction of cimetidine in 2 M hydrochloric acid in the prescence of excess sodium nitrite is a mono-nitroso derivative, the structure of which has been determined by the application of field desorption mass and proton magnetic resonance spectrometry. The methylating ability of nitrosocimetidine in phosphate buffer at pH 7 towards 3,4-dichlorobenzenethiol is comparable to that of the known gastric carcinogen, N-methyl-N'-nitro-N-nitrosoguanidine.
Assuntos
Carcinógenos , Cimetidina , Guanidinas , Fenômenos Químicos , Química , Cimetidina/análogos & derivados , Cimetidina/síntese química , Guanidinas/análogos & derivados , Guanidinas/síntese química , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Metilação , Metilnitronitrosoguanidina/toxicidade , Peso Molecular , Compostos Nitrosos/síntese químicaRESUMO
The cyclophosphamide content of urine, serum and spinal fluid of immuno-suppressed multiple sclerosis patients was determined using a newly developed off-line combination of high pressure liquid chromatography and field desorption mass spectrometry. Although urinary excretion of the drug varied considerably between patients, the levels in serum and spinal fluid were in the same range, a relationship that may facilitate control of the dosage.
Assuntos
Ciclofosfamida/metabolismo , Terapia de Imunossupressão , Esclerose Múltipla/metabolismo , Adulto , Barreira Hematoencefálica/efeitos dos fármacos , Ciclofosfamida/uso terapêutico , Feminino , Humanos , Imunoglobulina G/metabolismo , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/imunologia , Prednisona/uso terapêuticoRESUMO
The levels of cyclophosphamide in samples of urine, serum and cerebrospinal fluid of multiple sclerosis patients, who had received the drug orally (4 x 100 mg/day) have been determined by field desorption mass spectrometry using the principle of stable isotope dilution. After thorough preparation of the samples, concentrations of cyclophosphamide of 10 to 60 micrograms/ml in urine and 200 to 400 ng/ml in serum and cerebrospinal fluid have been determined from 0.6-3 ml samples. The first quantitative data for cyclophosphamide in cerebrospinal fluid of multiple sclerosis patients could be established without the use of radioactive material. The relatively high level of the parent drug found in the fluid at the end of a 3-weeks treatment may shed some light on the mechanism of action of this drug in the treatment of the disease.
Assuntos
Ciclofosfamida/urina , Esclerose Múltipla/urina , Ciclofosfamida/sangue , Ciclofosfamida/líquido cefalorraquidiano , Ciclofosfamida/uso terapêutico , Cromatografia Gasosa-Espectrometria de Massas/métodos , Humanos , Esclerose Múltipla/sangue , Esclerose Múltipla/líquido cefalorraquidiano , Esclerose Múltipla/tratamento farmacológicoRESUMO
The combination of pyrolysis (Py) with gas chromatography/mass spectrometry (GC/MS) is already well established for polymer analysis. A first approach is reported using this method for detailed quality monitoring of a complex technical polymer system. Six similar solvent-based paints (one standard and five modifications) have been used for evaluation. The major pyrolysis products were identified and qualitative and quantitative modifications were detected and specified. Principal component analysis (PCA) was applied for visualization of differences and similarities.
RESUMO
It has been proposed that trans-4-acetylaminostilbene (AAS) is an initiator for tumor formation in rat liver and that the metabolically formed hydroxamic acid ester ultimately reacts with nucleic acids in vivo. We have now studied the generation of a major adduct in vitro. trans-4-N-Acetoxy-N-acetylaminostilbene (N-acetoxy-AAS) was reacted with guanosine at pH 7.5 and reaction products were separated by chromatography on Sephadex LH-20 and RP18 HPLC. The major adduct isolated consists of four isomers which have been tentatively identified by mass- and 1H-NMR spectroscopy as (S,S)- and (R,R)-guanosine-N2,beta-N3,alpha-N-acetylaminobibenzyl and the respective regio isomers guanosine-N2,alpha-N3,beta-N-acetylaminobibenzyl. These adducts are formed in a ratio of 9:9:1:1. Under acidic conditions (pH 2) the ribose moiety is removed and two regio isomeric base adducts are formed in the ratio 9:1. Results to be published indicate that the adducts are also formed in vivo in rat liver RNA and DNA.
Assuntos
Química , Fígado/metabolismo , Estilbenos/metabolismo , Animais , Fenômenos Químicos , Cromatografia Líquida de Alta Pressão , DNA/metabolismo , Guanosina/metabolismo , RatosRESUMO
The transfer of T1+ cations through the placental barrier of pregnant mice and rats was studied by comparing the thallium concentrations in the maternal brain and kidney and those in fetal tissue at times of 10 min to 50 h after dosage of the animals with 10 mg/kg body wt. T1(2)SO4. The quantitative determinations were performed with field desorption mass spectrometry after dilution of the homogenised tissue samples with enriched stable isotopes of thallium. The total sample quantity required for one complete assay is 1-3 micrograms, the analysis time for one determination about 30 min.
Assuntos
Química Encefálica , Feto/análise , Rim/análise , Troca Materno-Fetal , Tálio/metabolismo , Animais , Feminino , Espectrometria de Massas , Camundongos , Gravidez , Ratos , Ratos Endogâmicos , Especificidade da EspécieRESUMO
The sorption mechanisms and complex formation between humic acid (HA) and a successively increasing number of diethyl phthalate (DEP) molecules have been studied theoretically using molecular mechanics, the number (n) of DEP molecules being varied from 1 to 30. The energy components of the single HA x nDEP complexes have been used as explanatory variables in a principal component analysis for exploring the presence of similarities/dissimilarities in the energetic properties of the individual xenobiotic complexes. The sorption can be explained in terms of a two-step mechanism. Absorption takes place as long as the host humic acid structure offers (a) enough internal docking space and (b) favorable interactions (energy release) with the guest molecule. This takes place for up to 7 DEP molecules. Further increase in the number to 30 DEP molecules will, due to the lack of free available internal voids, lead to surface controlled adsorption. The two-step sorption process apparently results in (a) a linear increase in energy gain by DEP bonds, and similarly (b) a constant incremental rise in molecular properties of the complexes such as volume and surface area. Three outstanding observations emerge: (1) Structural features at the atomic level (nanochemistry), such as partial atomic charges and high aromaticity of the humic acid, are observed to be dominating the intermolecular interactions in the complexes at the specific sorption sites. (2) Torsional relief and favorable changes in bonding energy also prevail for the growing complex. The latter indicates both the structural flexibility of the HA host and the stabilizing effect of DEP on the complex, by filling of the voids within the HA molecule. (3) The intermolecular forces are described mainly by hydrogen bonds (electrostatic energy) and interactions between dipole-dipole, such as carboxylic functions and uncharged moieties such as aromatic rings (van der Waals energy).
Assuntos
Substâncias Húmicas/química , Modelos Moleculares , Ácidos Ftálicos/química , Absorção , Adsorção , Poluentes Ambientais , Cinética , Relação Estrutura-AtividadeRESUMO
Residues of pharmaceutical antibiotics are found in the environment, whose fate and effects are governed by sorption. Thus, the extent and mechanisms of the soil sorption of p-aminobenzoic acid and five sulfonamide antibiotics (sulfanilamide, sulfadimidine, sulfadiazine, sulfadimethoxine, and sulfapyridine) were investigated using topsoils of fertilized and unfertilized Chernozem and their organic-mineral particle-size fractions. Freundlich adsorption coefficients (K(f)) ranged from 0.5 to 6.5. Adsorption increased with aromaticity and electronegativity of functional groups attached to the sulfonyl-phenylamine core. Adsorption to soil and particle-size fractions increased in the sequence: coarse silt < whole soil < medium silt < sand < clay < fine silt and was influenced by pH. Sorption nonlinearity (1/n = 0.76) indicated specific interactions with functional groups of soil organic matter (SOM). Phenolic and carboxylic groups, N-heterocyclic compounds, and lignin decomposition products were tentatively assigned as preferred binding sites using statistical analysis of pyrolysis-mass spectra and adsorption coefficients. Adsorption of sulfonamides to mineral soil colloids was weaker and resulted in a stronger desorption from clay-size fractions. Moreover, steric accessibility of organic-mineral complexes in clay-size fractions was significantly reduced. With a quantitative structure-property relationship (QSPR) model, combining the organic carbon concentration, the sulfonamides' chromatographic capacity factor (k'), and nondissociated species concentration (CF(a)), distribution coefficients (K(d)) were estimated with a cross-validated regression coefficient Q(2) = 0.71. Modeling and molecular mechanics calculations of antibiotic-SOM complexes showed preferred site-specific sorption via hydrogen bonds and van der Waals interactions. Distinct chemical structural properties, such as aromaticity and van der Waals volumes, correlated with the sorption data.
Assuntos
Anti-Infecciosos/química , Modelos Teóricos , Poluentes do Solo/análise , Sulfonamidas/química , Adsorção , Anti-Infecciosos/análise , Monitoramento Ambiental , Tamanho da Partícula , Sulfonamidas/análiseAssuntos
Espectrometria de Massas , Preparações Farmacêuticas/análise , Animais , Líquidos Corporais/análise , Química Clínica/métodos , Técnicas de Laboratório Clínico/métodos , Computadores , Ciclofosfamida/metabolismo , Desipramina/sangue , Dextropropoxifeno/metabolismo , Estudos de Avaliação como Assunto , Cromatografia Gasosa-Espectrometria de Massas/métodos , Humanos , Imipramina/sangue , Isótopos , Cinética , Espectrometria de Massas/métodos , Preparações Farmacêuticas/metabolismo , Técnica de Diluição de Radioisótopos/métodosAssuntos
Espectrometria de Massas/métodos , Aminoácidos/análise , Animais , Carboidratos/análise , DNA/análise , Espectrometria de Massas/instrumentação , Microscopia Eletrônica de Varredura , Peptídeos/análise , Preparações Farmacêuticas/análise , Polirribonucleotídeos , RNA/análise , Ribonucleosídeos/análise , Ribonucleotídeos/análise , Esteroides/análise , Ácidos Sulfúricos/análise , TemperaturaAssuntos
Azatioprina/análise , Animais , Azatioprina/urina , Espectrometria de Massas/métodos , Peso Molecular , RatosRESUMO
The potential of field-desorption mass spectrometry (FD-MS) coupled with photoplate detection for qualitative and quantitative studies on cyclophosphamide (CP) and its metabolites is reviewed. The characteristic features of this ionization mode are minimal fragmentation of the molecular ion coupled with the capacity to produce such ions from thermally unstable or nonvolatile samples. Since CP is itself extensively fragmented in the electron-impact ionization mode, and since it possesses both thermally unstable (eg, 4-hydroxycyclophosphamide, carboxyphosphamide) as well as ionic and hence nonvolatile metabolites (eg, phosphorodiamidic acid), the FD technique has potential value for the detection and quantitation of the drug and its metabolites in underviatized mixtures. Some of the factors which influence the reproducibility of FD spectra are enumerated. In order to improve the FD technique for quantitative results a device for emission-controlled FD was constructed and its use is described. Three different modes of operation are discussed using the FD spectra of CP conjugates typical for each. Preliminary investigations into the use of the d6 analog of CP for quantitation of the drug by FD-MS are also reported.
Assuntos
Ciclofosfamida , Ciclofosfamida/análogos & derivados , Fenômenos Químicos , Química , Ciclofosfamida/análise , Ciclofosfamida/metabolismo , Íons , Espectrometria de Massas/métodos , TemperaturaRESUMO
Field desorption mass spectrometry (FD-MS), which is applicable to analyses of compounds of low volatility and thermal instability, is used as a sensitive, specific and fast detection method for high-performance liquid chromatography (HPLC). Owing to its simplicity and efficiency, off-line combination is the preferred technique for the analysis of substances in chromatographic effuents. The principles of identification, purity control and quantification are presented. Characteristic examples of mental, medical and pharmaceutical areas are given. Qualitative and quantitative results for drugs and endogenous compounds, e.g., tranquillizers, immunosuppressive and antitumour agents and free amino acids, in human body fluids, biocides, e.g., phenylureas, carbamates, organophosphorus and organometallic compounds, in river water, and natural and synthetic products, e.g., saponins, chlorophyll and deoxyribonucleotides, are presented.
Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Barbitúricos/urina , Carbamatos/análise , Ciclofosfamida/metabolismo , Humanos , Espectrometria de Massas , Fenilalanina/sangue , Compostos de Fenilureia/análise , Valores de Referência , Tiocarbamatos/análise , Tirosina/sangueRESUMO
The off-line combination of high pressure liquid chromatography and field desorption mass spectrometry has been used for the simultaneous isolation, identification and determination of cyclophosphamide and two of its metabolites, 4-ketocyclophosphamide and carboxyphosphamide in urine from a patient suffering from multiple sclerosis. Cyclophosphamide and its metabolites were separated using reverse phase liquid chromatography. Field desorption mass spectrometry was employed for identification and quantification. The technique applied needs no derivatization for analysis. The limits of detection by field desorption mass spectrometry for 1, 2 and 3 are factor of about 4 X 10(3)-10(5) lower than those of a common variable ultraviolet detector. Quantitative determination was carried out using the method of stable isotope dilution with deuterated analogues of 1, 2 and 3. In a pilot study, the ratio of 1:2:3 was determined to 1:0.02:0.6. One ml of urine is sufficient for simultaneous analysis of the three compounds. The typical analysis time, including separation by liquid chromatography and field desorption measurement, is about 30 minutes.
Assuntos
Ciclofosfamida/isolamento & purificação , Esclerose Múltipla/urina , Cromatografia Líquida de Alta Pressão , Ciclofosfamida/administração & dosagem , Ciclofosfamida/análogos & derivados , Ciclofosfamida/urina , Esquema de Medicação , Humanos , Espectrometria de Massas/métodos , Esclerose Múltipla/tratamento farmacológico , Mostardas de Fosforamida/urina , Projetos PilotoRESUMO
The possibilities for the application of field desorption mass spectrometry in quantitative analyses are described and evaluated. The advantages of and the sources of errors in the use of different standards as well as in the application of different methods such as photographic detection, single ion monitoring, repetitive scanning, selected ion monitoring, and double ion detection are illustrated by representative examples. Sensitivity and precision of the different techniques are evaluated. Most importantly, the use of stable isotope labelled compounds as internal standards has enabled quantitative determination with good precision, accuracy, and sensitivity. In order to demonstrate the capabilities of the methods, examples of applications are presented and the scope of quantitative analysis with field desorption mass spectrometry is discussed.
Assuntos
Espectrometria de Massas/métodos , Humanos , Espectrometria de Massas/instrumentação , Fenilcetonúrias/urina , Tirosina/urinaRESUMO
It is shown that the production of field desorption mass spectra with an emission-controlled emitter heating device is a useful tool in obtaining information about molecular structures. Since the structurally significant signals are sometimes missing in the corresponding electron impact spectra but not in the field desorption spectra the use of field desorption mass spectrometry appears to be more advantages. This will be especially true for substances that are thermally labile, unvolatile or unstable upon electron impact (both at high and low electron energy), the latter being the case for some of the compounds presently investigated which are derivatives of a drug with antitumour and antiepileptic effects. Further, emission-controlled desorption improves the reproducibility of the spectra obtained and thus appears to be a prerequisite for quantification in biomedical and pharmacokinetic studies.