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1.
ACS Chem Biol ; 15(11): 3021-3029, 2020 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-33166460

RESUMO

Bacterial tRNA-guanine transglycosylase (Tgt) is involved in the biosynthesis of the modified tRNA nucleoside queuosine present in the anticodon wobble position of tRNAs specific for aspartate, asparagine, histidine, and tyrosine. Inactivation of the tgt gene leads to decreased pathogenicity of Shigella bacteria. Therefore, Tgt constitutes a putative target for Shigellosis drug therapy. Since it is only active as homodimer, interference with dimer-interface formation may, in addition to active-site inhibition, provide further means to disable this protein. A cluster of four aromatic residues seems important to stabilize the homodimer. We mutated residues of this aromatic cluster and analyzed each mutated variant with respect to the dimer and thermal stability or enzyme activity by applying native mass spectrometry, a thermal shift assay, enzyme kinetics, and X-ray crystallography. Our structural studies indicate a strong influence of pH on the homodimer stability. Apparently, protonation of a histidine within the aromatic cluster supports the collapse of an essential structural motif within the dimer interface at slightly acidic pH.

2.
Anal Chem ; 92(19): 12900-12908, 2020 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-32886492

RESUMO

Ion mobility (IM)-based collision-induced unfolding (CIU) has gained increasing attention to probe gas-phase unfolding of proteins and their noncovalent complexes, notably for biotherapeutics. CIU detects subtle conformational changes of proteins and emerges as an attractive alternative to circumvent poor IM resolution. However, CIU still lacks in automation for buffer exchange and data acquisition, precluding its wide adoption. We present here an automated workflow for CIU experiments, from sample preparation to data interpretation using online size exclusion chromatography coupled to native IM mass spectrometry (SEC-CIU). Online automated SEC-CIU experiments offer several benefits over nanoESI-CIU, among which are (i) improved and fast desalting compared to manual buffer exchange used for classical CIU experiments; (ii) drastic reduction of the overall data collection time process; and (iii) maintaining the number of unfolding transitions. We then evaluate the potential of SEC-CIU to distinguish monoclonal antibody (mAb) subclasses, illustrating the efficiency of our method for rapid mAb subclass identification at both intact and middle levels. Finally, we demonstrate that CIU data acquisition time can be further reduced either by setting up a scheduled CIU method relying on diagnostic trap collision voltages or by implementing mAb-multiplexed SEC-CIU analyses to maximize information content in a single experiment. Altogether, our results confirm the suitability of SEC-CIU to automate CIU experiments, particularly for the fast characterization of next-generation mAb-based products.

6.
Anal Chem ; 92(12): 8170-8177, 2020 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-32407621

RESUMO

Conventional antibody-drug conjugate (ADC) manufacturing methods are based on the nonselective bioconjugation of cytotoxic drugs to lysine and cysteine residues. This results in highly heterogeneous mixtures of different drug-antibody ratios (DAR) that can significantly affect the safety and efficacy of the ADC product. Recently, an innovative procedure named GlyCLICK was suggested, consisting of a two-step enzymatic procedure to transform Fc-glycans present on IgG mAbs into two site-specific anchor points for the conjugation of any alkyne-containing payload of choice. Here, we evaluated the conjugation process by comparing trastuzumab and trastuzumab conjugated with DM1, following the GlyCLICK procedure. Complementary reversed phase liquid chromatography (RPLC) and hydrophilic interaction chromatography (HILIC) coupled to high-resolution mass spectrometry (HRMS) were used to analyze the protein subunits (ca. 25-100 kDa) obtained after different levels of enzymatic digestion and chemical reduction. Our results demonstrated that the hydrophobic character of the drug molecule allows to rapidly confirm the Fc-drug conjugation at the chromatographic level. Furthermore, the hyphenation to MS detection provided accurate mass information on the ADC subunits and facilitated the DAR determination of 2.0. Therefore, this work illustrates how middle-up analysis using LC/HRMS can provide accurate and complementary information on the critical quality attributes of these novel site-specific ADC products.

7.
Anal Chem ; 92(13): 8827-8835, 2020 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-32453570

RESUMO

Most of the current FDA and EMA approved therapeutic monoclonal antibodies (mAbs) are based on humanized or human IgG1, 2, or 4 subclasses and engineered variants. On the structural side, these subclasses are characterized by specific interchain disulfide bridge connections. Different analytical techniques have been reported to assess intact IgGs subclasses, with recently special interest in native ion mobility (IM) and collision induced unfolding (CIU) mass spectrometry (MS). However, these two techniques exhibit significant limitations to differentiate mAb subclasses at the intact level. In the present work, we aimed at developing a unique IM-MS-based approach for the characterization of mAb subclasses at the middle level. Upon IdeS-digestion, the unfolding patterns of the F(ab')2 and Fc domains were simultaneously analyzed in a single run to provide deeper structural insights of the mAb scaffold. The unfolding patterns associated with the F(ab')2 domains are completely different in terms of unfolding energies and number of transitions. Thereby, F(ab')2 regions are the diagnostic domain to provide specific unfolding signatures to differentiate IgG subclasses and provide more confident subclass categorization than CIU on intact mAbs. In addition, the potential of middle-level CIU was evaluated through the characterization of eculizumab, a hybrid therapeutic IgG2/4 mAb. The unfolding signatures of both domains were allowed to corroborate, within a single run, the hybrid nature of eculizumab as well as specific subclass domain assignments to the F(ab')2 and Fc regions. Altogether, our results confirm the suitability of middle-level CIU of F(ab')2 domains for subclass categorization of canonical and more complex new generation engineered antibodies and related products.

8.
Methods Mol Biol ; 2078: 197-211, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31643058

RESUMO

Mass spectrometry performed in nondenaturing conditions (native MS) has proven its utility for the quantitative and qualitative analysis of antibody-drug conjugates (ADCs), especially when ADCs' subunits involve noncovalent interactions (i.e., cysteine-conjugated ADCs). Its hyphenation to ion mobility spectrometry (IM-MS) allows differentiation of gas-phase ions based on their rotationally averaged collision cross section providing an additional dimension of conformational characterization of ADCs. More recently, size exclusion chromatography (SEC) appeared as an interesting technique to perform online buffer exchange in an automated way prior to native MS/IM-MS analysis. Online SEC-native MS/IM-MS allows the global structural characterization of ADCs and the assessment of some critical quality attributes (CQAs) required for ADC release on the market, such as drug load distribution (DLD), drug-to-antibody ratio (DAR), the average DAR (DARav), and the relative amount of unconjugated mAb.

9.
J Am Soc Mass Spectrom ; 30(11): 2419-2429, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31429052

RESUMO

Middle-down mass spectrometry (MD MS) has emerged as a promising alternative to classical bottom-up approaches for protein characterization. Middle-level experiments after enzymatic digestion are routinely used for subunit analysis of monoclonal antibody (mAb)-related compounds, providing information on drug load distribution and average drug-to-antibody ratio (DAR). However, peptide mapping is still the gold standard for primary amino acid sequence assessment, post-translational modifications (PTM), and drug conjugation identification and localization. However, peptide mapping strategies can be challenging when dealing with more complex and heterogeneous mAb formats, like antibody-drug conjugates (ADCs). We report here, for the first time, MD MS analysis of a third-generation site-specific DAR4 ADC using different fragmentation techniques, including higher-energy collisional- (HCD), electron-transfer (ETD) dissociation and 213 nm ultraviolet photodissociation (UVPD). UVPD used as a standalone technique for ADC subunit analysis afforded, within the same liquid chromatography-MS/MS run, enhanced performance in terms of primary sequence coverage compared to HCD- or ETD-based MD approaches, and generated substantially more MS/MS fragments containing either drug conjugation or glycosylation site information, leading to confident drug/glycosylation site identification. In addition, our results highlight the complementarity of ETD and UVPD for both primary sequence validation and drug conjugation/glycosylation site assessment. Altogether, our results highlight the potential of UVPD for ADC MD MS analysis for drug conjugation/glycosylation site assessment, and indicate that MD MS strategies can improve structural characterization of empowered next-generation mAb-based formats, especially for PTMs and drug conjugation sites validation.


Assuntos
Imunoconjugados/química , Imunoconjugados/metabolismo , Espectrometria de Massas/métodos , Mapeamento de Peptídeos/métodos , Sítios de Ligação , Humanos
10.
Expert Rev Proteomics ; 16(4): 337-362, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30706723

RESUMO

INTRODUCTION: The development and optimization of antibody drug conjugates (ADCs) rely on improving their analytical and bioanalytical characterization, by assessing critical quality attributes (CQAs). Among the CQAs, the glycoprofile, drug load distribution (DLD), the amount of unconjugated antibody (D0), the average drug-to-antibody ratio (DAR), the drug conjugation sites and the residual drug-linker and related product proportions (SMDs) in addition to high and low molecular weight species (H/LMWS), and charge variants are the most important ones. Areas covered: The analytical and structural toolbox for the characterization of 1st, 2d and 3d generation ADCs was significantly extended in the last 3 years. Here, we reviewed state-of-the-art techniques, such as liquid chromatography, high resolution native and ion mobility mass spectrometry, multidimensional liquid chromatography and capillary electrophoresis hyphenated to mass spectrometry, reported mainly since 2016. Expert commentary: These emerging techniques allow a deep insight into important CQAs that are related to ADC Chemistry Manufacturing and Control (CMC) as well as an improved understanding of in vitro and in vivo ADC biotransformations. This knowledge and the development of quantitative bioanalytical assays will continue to contribute to early-developability assessment for the optimization of all the ADC components (i.e. antibody, drug, and linker) and help to bring next-generation ADCs into late clinical development and to the market.


Assuntos
Imunoconjugados/análise , Imunoconjugados/química , Sequência de Aminoácidos , Cromatografia , Eletroforese , Humanos , Interações Hidrofóbicas e Hidrofílicas , Espectrometria de Massas
11.
Anal Chem ; 90(23): 13929-13937, 2018 12 04.
Artigo em Inglês | MEDLINE | ID: mdl-30371058

RESUMO

The determination of size variants is a major critical quality attribute of a therapeutic monoclonal antibody (mAb that may affect the drug product safety, potency, and efficacy. Size variant characterization often relies on size-exclusion chromatography (SEC), which could be hampered by difficult identification of peaks. On the other hand, mass spectrometry (MS)-based techniques performed in nondenaturing conditions have proven to be valuable for mAb-related compound characterization. On the basis of the observation that limited SEC performance was observed in nondenaturing MS compatible ammonium acetate buffer compared with classical phosphate salts, a multidimensional analytical approach was proposed. It combines comprehensive online two-dimensional chromatography (SEC×SEC), with ion mobility and mass spectrometry (IM-MS) in nondenaturing conditions for the characterization of a variety of mAbs. We first exemplify the versatility of our approach for simultaneous detection, identification, and quantitation of adalimumab size variants. Benefits of the SEC×SEC-native IM×MS were further highlighted on forced degraded pembrolizumab and bevacizumab samples, for which the 4D setup was mandatory to obtain an extensive and unambiguous identification, and accurate quantitation of unexpected high/low molecular weight species (HMWS and LMWS). In this specific context, monomeric conformers were detected by IM-MS as HMWS or LMWS. Altogether, our results emphasize the power of comprehensive 2D LC×LC setups hyphenated to IM×MS in nondenaturing conditions with unprecedented performance including: (i) maintaining optimal SEC performance (under classical nonvolatile salt conditions), (ii) performing online native MS identification, and (iii) providing IM-MS conformational characterization of all separated size variants.


Assuntos
Anticorpos Monoclonais Humanizados/análise , Anticorpos Monoclonais/análise , Antineoplásicos Imunológicos/análise , Bevacizumab/análise , Cromatografia em Gel , Espectrometria de Massas
12.
Anal Chem ; 90(15): 8865-8872, 2018 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-29956914

RESUMO

Although the majority of FDA and EMA approved therapeutic monoclonal antibodies (mAbs) are IgG1, the number of IgG4-based formats reaching the market is increasing. IgG4 differs from other mAb isotypes by its specificity to form half mAbs that recombine into bispecific (bsAbs) molecules, through a process termed fab-arm exchange (FAE). We report here the complementarity of native mass spectrometry (MS), ion mobility (IM), and collision-induced unfolding (CIU) experiments for the structural characterization of members of the IgG4 subfamily (wild-type (wt), hinge-stabilized (hs, S228P mutation), and the resulting bsAb IgG4s). Native MS allows confirming/invalidating the occurrence of FAE as a function of these different types of IgG4. While IM-MS was unable to distinguish iso-cross-section IgG4 species, CIU experiments provide unique specific structural signatures of each individual IgG4 based on their specific unfolding pathways. Common CIU features of IgG4 formats include the observation of three conformational states and two transitions. In addition, CIU experiments demonstrated that S228P mutation stabilizes gas phase conformations of hsIgG4, in agreement with increased stability related to more rigid hinge regions. CIU patterns also appear to be more informative than IM-MS for bsAb structural characterization, unfolding signature of the bsAb being intermediate to the ones of the former parent wt-IgG4s, highlighting that bsAb CIU profiles keep the memory of their origins. Altogether, our results demonstrate that CIU patterns can serve as mAb specific structural signatures and are mature to be included in MS-based analytical workflows for conformational/structural characterization of mAb formats in early development phases and for multiple attribute monitoring.


Assuntos
Anticorpos Monoclonais Humanizados/química , Imunoglobulina G/química , Espectrometria de Mobilidade Iônica/métodos , Natalizumab/química , Nivolumabe/química , Anticorpos Monoclonais Humanizados/genética , Humanos , Imunoglobulina G/genética , Espectrometria de Massas , Modelos Moleculares , Natalizumab/genética , Nivolumabe/genética , Mutação Puntual , Conformação Proteica , Estabilidade Proteica , Desdobramento de Proteína
13.
Inorg Chem ; 57(10): 6095-6106, 2018 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-29746120

RESUMO

A series of polynuclear assemblies based on ligand L (1,4,7-tris[hydrogen (6-methylpyridin-2-yl)phosphonate]-1,4,7-triazacyclononane) has been developed. The coordination properties of ligand L with LnIII (Ln = La, Eu, Tb, Yb, Lu) have been studied in water (pH = 7.0) and in D2O (pD = 7.0) by UV-absorption spectrometry, spectrofluorimetry, 1H and 31P NMR, DOSY, ESI-mass spectrometry, and X-ray diffraction. This nonadentate ligand forms highly stable mononuclear complexes in water and provides a very efficient shielding of the Ln cations, as emphasized by the very good luminescence properties of the Yb complex in D2O, especially regarding its lifetime (τD2O = 10.2 µs) and quantum yield (ϕD2O = 0.42%). In the presence of excess LnIII cation, polynuclar complexes of [(LnL)2Ln x] stoichiometry (x = 1 and x = 2) are observed in solution. In the solid state, a dinuclear complex of La could be isolated and structurally characterized by X-ray diffraction, unraveling the presence of strong hydrogen bonding interactions between a La(H2O)93+ cation and the [LaL]3- complex.

14.
Artigo em Inglês | MEDLINE | ID: mdl-29684909

RESUMO

Mass spectrometry performed in non-denaturing conditions (native MS), and its hyphenation to ion mobility spectrometry (IM-MS), have gained interest for the qualitative and quantitative characterization of intact monoclonal antibody-related (mAb) products. However, one main drawback is the manual sample preparation, which hampers its routine use in high throughput automated environments. Size exclusion chromatography (SEC) appears as an interesting technique to perform online buffer exchange in an automated way. We present here an exhaustive and systematic evaluation of the possibilities and versatility of SEC direct hyphenation to native MS or IM-MS (SEC-nativeMS/IM-MS) for the characterization of a variety of mAb-formats (IgGs, ADCs, bispecific mAbs and Fc-fusion proteins). First, online SEC-native MS allows automated sample preparation, resulting in high resolution mass spectra and improved mass accuracies (<80 ppm) compared to manual buffer exchange procedures. When hyphenated to ion mobility, SEC-native IM-MS can deliver conformational characterization through collision cross section (CCS) measurements within few minutes without affecting mAb structures. Finally, benefits of online SEC-nativeIM-MS compared to standalone SEC-UV or native MS techniques are demonstrated for higher order structure characterization of mAb forced degraded samples. While SEC provides separation of high/low molecular weight species from the main mAb peak along with precise quantification of the species, native MS affords complementary unambiguous identification of SEC peaks, even when poor SEC separation is achieved. The synergic online coupling of SEC to native MS/IM-MS is envisioned to definitely push native MS approaches at the forefront of mAb characterization in quality-controlled environments and as multiple monitoring method.


Assuntos
Anticorpos Monoclonais/análise , Anticorpos Monoclonais/química , Cromatografia em Gel/métodos , Espectrometria de Massas/métodos , Agregados Proteicos
15.
J Sep Sci ; 41(1): 20-67, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29024509

RESUMO

Ion mobility spectrometry is an analytical technique known for more than 100 years, which entails separating ions in the gas phase based on their size, shape, and charge. While ion mobility spectrometry alone can be useful for some applications (mostly security analysis for detecting certain classes of narcotics and explosives), it becomes even more powerful in combination with mass spectrometry and high-performance liquid chromatography. Indeed, the limited resolving power of ion mobility spectrometry alone can be tackled when combining this analytical strategy with mass spectrometry or liquid chromatography with mass spectrometry. Over the last few years, the hyphenation of ion mobility spectrometry to mass spectrometry or liquid chromatography with mass spectrometry has attracted more and more interest, with significant progresses in both technical advances and pioneering applications. This review describes the theoretical background, available technologies, and future capabilities of these techniques. It also highlights a wide range of applications, from small molecules (natural products, metabolites, glycans, lipids) to large biomolecules (proteins, protein complexes, biopharmaceuticals, oligonucleotides).


Assuntos
Cromatografia Líquida/métodos , Espectrometria de Mobilidade Iônica/métodos , Espectrometria de Massas em Tandem/métodos , Animais , Produtos Biológicos/análise , Glucuronídeos/análise , Humanos , Íons , Ligantes , Lipídeos/análise , Oligonucleotídeos/análise , Peptídeos/análise , Polissacarídeos/análise , Ligação Proteica , Proteínas/análise , Reprodutibilidade dos Testes , Software , Temperatura
16.
Anal Chem ; 90(3): 1578-1586, 2018 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-29260862

RESUMO

There are currently two main techniques allowing the analytical characterization of interchain cysteine-linked antibody drug conjugates (ADCs) under native conditions, namely, hydrophobic interaction chromatography (HIC) and native mass spectrometry (MS). HIC is a chromatographic technique allowing the evaluation of drug load profile and calculation of average drug-to-antibody ratio (DAR) in quality control laboratories. Native MS offers structural insights into multiple ADC critical quality attributes, thanks to accurate mass measurement. However, both techniques can lead to misinterpretations or incomplete characterization when used as standalone methods. Online coupling of both techniques can thus potentially be of great interest, but the presence of large amounts of nonvolatile salts in HIC mobile phases makes it not easily directly compatible with native MS. Here, we present an innovative multidimensional analytical approach combining comprehensive online two-dimensional (2D)-chromatography that consists of HIC and size-exclusion chromatography (SEC), to ion mobility and mass spectrometry (IM-MS) for performing analytical characterization of ADCs under nondenaturing conditions. This setup enabled comprehensive and streamlined characterization of both native and forced degraded ADC samples. The proposed 4D methodology might be more generally adapted for online all-in-one HIC×SEC-IM×MS analysis of single proteins or analysis of protein complexes in nondenaturing conditions.


Assuntos
Cromatografia em Gel , Imunoconjugados/química , Interações Hidrofóbicas e Hidrofílicas , Espectrometria de Massas
17.
MAbs ; 9(5): 801-811, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28406343

RESUMO

Antibody-drug conjugates (ADCs) have emerged as a family of compounds with promise as efficient immunotherapies. First-generation ADCs were generated mostly via reactions on either lysine side-chain amines or cysteine thiol groups after reduction of the interchain disulfide bonds, resulting in heterogeneous populations with a variable number of drug loads per antibody. To control the position and the number of drug loads, new conjugation strategies aiming at the generation of more homogeneous site-specific conjugates have been developed. We report here the first multi-level characterization of a site-specific ADC by state-of-the-art mass spectrometry (MS) methods, including native MS and its hyphenation to ion mobility (IM-MS). We demonstrate the versatility of native MS methodologies for site-specific ADC analysis, with the unique ability to provide several critical quality attributes within one single run, along with a direct snapshot of ADC homogeneity/heterogeneity without extensive data interpretation. The capabilities of native IM-MS to directly access site-specific ADC conformational information are also highlighted. Finally, the potential of these techniques for assessing an ADC's heterogeneity/homogeneity is illustrated by comparing the analytical characterization of a site-specific DAR4 ADC to that of first-generation ADCs. Altogether, our results highlight the compatibility, versatility, and benefits of native MS approaches for the analytical characterization of all types of ADCs, including site-specific conjugates. Thus, we envision integrating native MS and IM-MS approaches, even in their latest state-of-the-art forms, into workflows that benchmark bioconjugation strategies.


Assuntos
Imunoconjugados/análise , Espectrometria de Massas/métodos , Humanos
18.
ChemSusChem ; 8(21): 3605-16, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26212854

RESUMO

The ageing phenomena occurring in various diethyl carbonate/LiPF6 solutions are studied using gamma and pulse radiolysis as a tool to generate similar species as the ones occurring in electrolysis of Li-ion batteries (LIBs). According to picosecond pulse radiolysis experiments, the reaction of the electron with (Li(+), PF6(-)) is ultrafast, leading to the formation of fluoride anions that can then precipitate into LiF(s). Moreover, direct radiation-matter interaction with the salt produces reactive fluorine atoms forming HF(g) and C2H5F(g). The strong Lewis acid PF5 is also formed. This species then forms various R(1)R(2)R(3) P=O molecules, where R is mainly -F, -OH, and -OC2H5. Substitution reactions take place and oligomers are slowly formed. Similar results were obtained in the ageing of an electrochemical cell filled with the same model solution. This study demonstrates that radiolysis enables a description of the reactivity in LIBs from the picosecond timescale until a few days.


Assuntos
Fontes de Energia Elétrica , Eletrólitos/química , Compostos de Lítio/química , Eletrólise , Espectrometria de Massas , Radiólise de Impulso , Soluções , Fatores de Tempo , Viscosidade
19.
Rev. colomb. obstet. ginecol ; 42(4): 305-15, oct.-dic. 1991. tab
Artigo em Espanhol | LILACS | ID: lil-293176

RESUMO

Se analizan 64 pacientes postmenopáusicas de la Clínica del Hospital Materno Infantil y del Hospital San Juan de Dios de Bogotá con el fin de evaluar el grado de Osteoporosis y la respuesta al tratamiento. Para cumplir el primer objetivo se conformaron 5 grupos. Grupo O o control con 20 pacientes menores de 20 años. Grupo 1: 5 pacientes 20 y 30 años. Grupo 2: 6 pacientes entre 31 y 40 años. Grupo 3: 21 pacientes entre 41 y 50 años. grupo 4: 23 pacientes entre 51 y 60 años. Grupo 5: 8 pacientes mayores de 60 años. Para el diagnóstico de Osteroporosis se dispone de marcadores plasmáticos como la PTH, Orteocalcina, Fosfatasa Alcalina, además, de los estudios radiológicos , radiografía de columna(TAC Densitometría de doble fotón). En este estudio aplicando la PTH, Osteocalcina, Fosfatasa Alcalina y Fósforo Sérico. Valores de (P menor 001) en el calcio sérico y proteínas totales. No hubo diferencia significativa en el sérico y proteínas totales. No hubo diferencia significativa en el Fósforo urinario. El índice de deformidad para radiografía de columna mostró una clara tendencia de lesión a nivel de T7 y L1. Para el objetivo No.2 se conformaron 4 grupos terapéuticos: grupo 1: Fluoruro de Sodio + Calcio (N=12) Grupo 2: terapia Secuncial Hormonal (N=11) Grupo 3 : Calcio (N=4) Grupo 4: Placebo (N=8) Un corte a los 6 meses muestra en el grupo 1 cambios significativos en la Fosfatasa Alcalina y osteocalcina (P menor 0.01), Grupo 2: disminución de calcio sérico (P menor 0.01) y aumento de la Fosfatasa Alcalina (P menor 0.01). En el grupo 3 no hubo variación. Con esta información el tratamiento con Fluoruro de Sodio + el calcio se presenta como una alternativa a la terapia hormonal de sustitución en pacientes postmenopáusicas


Assuntos
Humanos , Feminino , Adulto , Pessoa de Meia-Idade , Osteoporose Pós-Menopausa/complicações , Osteoporose Pós-Menopausa/diagnóstico , Osteoporose Pós-Menopausa/etiologia , Osteoporose Pós-Menopausa/prevenção & controle , Osteoporose Pós-Menopausa/terapia
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