RESUMO
BACKGROUND: The interest on magnesium (Mg) has grown since clinical studies have shown the efficacy of Mg-containing phosphate binders. However, some concern has arisen for the potential effect of increased serum Mg on parathyroid hormone (PTH) secretion. Our objective was to evaluate the direct effect of Mg in the regulation of the parathyroid function; specifically, PTH secretion and the expression of parathyroid cell receptors: CaR, the vitamin D receptor (VDR) and FGFR1/Klotho. METHODS: The work was performed in vitro by incubating intact rat parathyroid glands in different calcium (Ca) and Mg concentrations. RESULTS: Increasing Mg concentrations from 0.5 to 2 mM produced a left shift of PTH-Ca curves. With Mg 5 mM, the secretory response was practically abolished. Mg was able to reduce PTH only if parathyroid glands were exposed to moderately low Ca concentrations; with normal-high Ca concentrations, the effect of Mg on PTH inhibition was minor or absent. After 6-h incubation at a Ca concentration of 1.0 mM, the expression of parathyroid CaR, VDR, FGFR1 and Klotho (at mRNA and protein levels) was increased with a Mg concentration of 2.0 when compared with 0.5 mM. CONCLUSIONS: Mg reduces PTH secretion mainly when a moderate low calcium concentration is present; Mg also modulates parathyroid glands function through upregulation of the key cellular receptors CaR, VDR and FGF23/Klotho system.
Assuntos
Cálcio/farmacologia , Compostos de Magnésio/farmacologia , Glândulas Paratireoides/efeitos dos fármacos , Hormônio Paratireóideo/metabolismo , Fosfatos/farmacologia , Receptor Tipo 1 de Hormônio Paratireóideo/metabolismo , Animais , Cálcio/sangue , Células Cultivadas , Modelos Animais de Doenças , Expressão Gênica , Imuno-Histoquímica , Glândulas Paratireoides/metabolismo , RNA Mensageiro/genética , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase em Tempo Real , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Receptor Tipo 1 de Hormônio Paratireóideo/genética , Receptores de Calcitriol/genética , Receptores de Calcitriol/metabolismo , Receptores de Detecção de Cálcio/genética , Receptores de Detecção de Cálcio/metabolismo , Regulação para CimaRESUMO
Calcium-based phosphate binders are used to control hyperphosphatemia; however, they promote hypercalcemia and may accelerate aortic calcification. Here we compared the effect of a phosphate binder containing calcium acetate and magnesium carbonate (CaMg) to that of sevelamer carbonate on the development of medial calcification in rats with chronic renal failure induced by an adenine diet for 4 weeks. After 1 week, rats with chronic renal failure were treated with vehicle, 375 or 750 mg/kg CaMg, or 750 mg/kg sevelamer by daily gavage for 5 weeks. Renal function was significantly impaired in all groups. Vehicle-treated rats with chronic renal failure developed severe hyperphosphatemia, but this was controlled in treated groups, particularly by CaMg. Neither CaMg nor sevelamer increased serum calcium ion levels. Induction of chronic renal failure significantly increased serum PTH, dose-dependently prevented by CaMg but not sevelamer. The aortic calcium content was significantly reduced by CaMg but not by sevelamer. The percent calcified area of the aorta was significantly lower than vehicle-treated animals for all three groups. The presence of aortic calcification was associated with increased sox9, bmp-2, and matrix gla protein expression, but this did not differ in the treatment groups. Calcium content in the carotid artery was lower with sevelamer than with CaMg but that in the femoral artery did not differ between groups. Thus, treatment with either CaMg or sevelamer effectively controlled serum phosphate levels in CRF rats and reduced aortic calcification.
Assuntos
Acetatos/farmacologia , Doenças da Aorta/prevenção & controle , Quelantes/farmacologia , Hiperfosfatemia/tratamento farmacológico , Falência Renal Crônica/complicações , Magnésio/farmacologia , Fosfatos/sangue , Poliaminas/farmacologia , Uremia/etiologia , Calcificação Vascular/prevenção & controle , Adenina , Animais , Doenças da Aorta/sangue , Doenças da Aorta/etiologia , Doenças da Aorta/genética , Doenças da Aorta/patologia , Proteína Morfogenética Óssea 2/genética , Proteína Morfogenética Óssea 2/metabolismo , Cálcio/sangue , Compostos de Cálcio/farmacologia , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Proteínas da Matriz Extracelular/genética , Proteínas da Matriz Extracelular/metabolismo , Regulação da Expressão Gênica , Hiperfosfatemia/sangue , Hiperfosfatemia/etiologia , Falência Renal Crônica/sangue , Falência Renal Crônica/induzido quimicamente , Masculino , Hormônio Paratireóideo/sangue , Ratos , Ratos Wistar , Fatores de Transcrição SOX9/genética , Fatores de Transcrição SOX9/metabolismo , Sevelamer , Fatores de Tempo , Uremia/sangue , Calcificação Vascular/sangue , Calcificação Vascular/etiologia , Calcificação Vascular/genética , Calcificação Vascular/patologia , Proteína de Matriz GlaRESUMO
This open-label, repeat-dose, fixed-sequence study in healthy subjects examined pharmacokinetic drug-drug interactions between the components of a novel fixed-dose combination product containing ramipril, amlodipine, and atorvastatin. Sequential 5-day monotreatments (MTs) of ramipril (5 mg/d) and atorvastatin (40 mg/d) were followed by a 9-day amlodipine MT (5 mg/d), separated by 96 hours washout intervals. After amlodipine MT, all 3 single-entity drugs were coadministered for 5 days. Blood samples were taken over the dosing intervals and drug concentrations quantified by high-performance liquid chromatography-mass spectrometry. Pharmacokinetic parameters were assessed and compared between the MTs and combination treatments by analysis of variance. Eighteen healthy subjects were enrolled and completed the study. No significant difference in maximum concentration (Cmax ) and area under the plasma concentration-time curve over the dosing interval (AUC0-τ ) for amlodipine and AUC0-τ of atorvastatin was observed upon combination treatments versus MTs. Cmax of atorvastatin was slightly decreased (Cmax ratio, 89.3%) when given in combination. Increased exposure of ramipril and less pronounced exposure of ramiprilat were observed in the presence of amlodipine and atorvastatin, with Cmax ratios for ramipril and ramiprilat of 182.6% and 155.9%, and corresponding AUC0-τ ratios of 150.0% and 112.1%, respectively. These ramiprilat increases are unlikely of clinical relevance, because complete angiotensin-converting enzyme occupation is achieved with ≥5-mg ramipril doses, and free ramiprilat is rapidly eliminated. As ramipril is known to be subject to a site-dependent absorption in the upper small intestine, it is hypothesized that slowing of intestinal motility by atorvastatin or amlodipine or a combined effect of both, increased the residence time of ramipril in its "absorption window," thereby enhancing its bioavailability.
Assuntos
Anlodipino/farmacocinética , Anticolesterolemiantes/farmacocinética , Anti-Hipertensivos/farmacocinética , Atorvastatina/farmacocinética , Interações Medicamentosas , Motilidade Gastrointestinal/efeitos dos fármacos , Absorção Intestinal/efeitos dos fármacos , Ramipril/farmacocinética , Adulto , Anlodipino/farmacologia , Anticolesterolemiantes/farmacologia , Anti-Hipertensivos/farmacologia , Atorvastatina/farmacologia , Disponibilidade Biológica , Combinação de Medicamentos , Voluntários Saudáveis , Humanos , Masculino , Adulto JovemRESUMO
For efficient cardiovascular risk protection antihypertensive treatment is often combined with cholesterol-lowering treatment, although solid data of interaction and side effects are missing. This is a prospective, single-center interaction study conducted in a fixed sequence design at steady state of candesartan, amlodipine, and atorvastatin. Five-day monotherapy of candesartan 8 mg was followed by 5-day atorvastatin 40 mg monotherapy and subsequently 9-day amlodipine 5 mg monotherapy; each treatment separated by washout phases. Immediately after amlodipine monotherapy, all 3 drugs were administered concomitantly for 5 days. Pharmacokinetic parameters as well as safety were assessed. Eighteen healthy subjects enrolled and completed the study. No significant difference in the maximum concentration (Cmax ) and the area the under plasma concentration-time curve (AUC) for amlodipine and AUC of atorvastatin was detected following combination versus monotherapy. Cmax of atorvastatin decreased slightly but clinically not relevantly when given in combination. A statistically significant but not below 0.80-fold decrease between candesartan following combination vs monotherapy was detected for Cmax and AUC. In general, all treatments were well tolerated. Concluding, systemic exposure of candesartan, amlodipine, and atorvastatin is not clinically significantly changed upon coadministration. These data support a fixed-dose combination of the 3 components for dual cardiovascular risk prevention.
Assuntos
Anlodipino/administração & dosagem , Atorvastatina/administração & dosagem , Benzimidazóis/administração & dosagem , Compostos de Bifenilo/administração & dosagem , Tetrazóis/administração & dosagem , Adolescente , Adulto , Anlodipino/efeitos adversos , Anlodipino/farmacocinética , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/efeitos adversos , Anti-Hipertensivos/farmacocinética , Área Sob a Curva , Atorvastatina/efeitos adversos , Atorvastatina/farmacocinética , Benzimidazóis/efeitos adversos , Benzimidazóis/farmacocinética , Compostos de Bifenilo/efeitos adversos , Compostos de Bifenilo/farmacocinética , Interações Medicamentosas , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacocinética , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Tetrazóis/efeitos adversos , Tetrazóis/farmacocinética , Adulto JovemRESUMO
The major light-harvesting chlorophyll a/b complex (LHCII) greatly enhances the efficiency of photosynthesis in green plants. Recombinant LHCII can be assembled in vitro from its denatured, bacterially expressed apoprotein and plant pigments. This makes it an interesting candidate for biomimetic light-harvesting in photovoltaic applications. Due to its almost 20 pigments bound per apoprotein, LHCII absorbs efficiently in the blue and red spectral domains of visible light but less efficiently in the green domain, the so-called "green gap" in its absorption spectrum. Here we present a hybrid complex of recombinant LHCII with organic dyes that add to LHCII absorption in the green spectral region. One or three Rhodamine Red dye molecules were site-specifically attached to cysteine side chains in the apoprotein and did not interfere with LHCII assembly, function and stability. The dyes transferred their excitation energy virtually completely to the chlorophylls in LHCII, partially filling in the green gap. Thus, organic dyes can be used to increase the absorption cross section and, thus, the light-harvesting efficiency of recombinant LHCII.
Assuntos
Clorofila/química , Corantes Fluorescentes/química , Rodaminas/química , Clorofila A , Dobramento de ProteínaRESUMO
Employing the utility of the native chemical ligation, site-specific attachment of an ultrastable perylene dye to a derivative of the major light-harvesting complex (LHCII) was demonstrated. Biochemical analysis of the conjugate indicated that the structure and function of LHCII remain largely unaffected by the N-terminal modification.
Assuntos
Corantes Fluorescentes/química , Complexos de Proteínas Captadores de Luz/química , Perileno/química , Proteínas de Plantas/química , Complexos de Proteínas Captadores de Luz/metabolismo , Dados de Sequência Molecular , Proteínas de Plantas/metabolismo , Plantas/química , Plantas/metabolismoRESUMO
AIMS: To investigate the role of FGF-23 and magnesium in relation to the albumin-to-creatinine ratio in type 2 diabetics with chronic kidney disease (CKD) stages 2-4. METHODS: In a cross-sectional study we included all eligible type 2 diabetic patients with CKD stages 2-4, followed in our outpatient Diabetic Kidney clinic. We used descriptive statistics, the Student'st-test, ANOVA and the chi-square tests. Our population was divided according to the UACR (G1 30-300 mg/g and G2≥300 mg/g), and compared these groups regarding several biological and laboratorial parameters. We employed a multiple regression model to identify risk factors of increased UACR. RESULTS: The patients in G2 displayed a lower eGFR (p=0.0001) and, had lower levels of magnesium (p=0.004) as well as higher levels of FGF-23 (p=0.043) compared to patients in G1. FGF-23 (ß=0.562, P=0.0001) and the magnesium (ß=- 8.916, p=0.0001) were associated with increased UACR. CONCLUSIONS: A dysregulation of mineral metabolism, reflected by altered levels of magnesium and FGF-23, correlates with an increased UACR in type 2 diabetic patients with CKD stages 2-4.
Assuntos
Albuminas/análise , Creatinina/sangue , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/sangue , Fatores de Crescimento de Fibroblastos/sangue , Magnésio/sangue , Insuficiência Renal Crônica/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Albuminas/metabolismo , Albuminúria/sangue , Albuminúria/complicações , Estudos Transversais , Feminino , Fator de Crescimento de Fibroblastos 23 , Humanos , Masculino , Pessoa de Meia-Idade , Insuficiência Renal Crônica/complicações , Fatores de RiscoRESUMO
Background. Mitral valve calcification and intima media thickness (IMT) are common complications of chronic kidney disease (CKD) implicated with high cardiovascular mortality. Objective. To investigate the implication of magnesium and fibroblast growth factor-23 (FGF-23) levels with mitral valve calcification and IMT in CKD diabetic patients. Methods. Observational, prospective study involving 150 diabetic patients with mild to moderate CKD, divided according to Wilkins Score. Carotid-echodoppler and transthoracic echocardiography were used to assess calcification. Statistical tests used to establish comparisons between groups, to identify risk factors, and to establish cut-off points for prediction of mitral valve calcification. Results. FGF-23 values continually increased with higher values for both IMT and calcification whereas the opposite trend was observed for magnesium. FGF-23 and magnesium were found to independently predict mitral valve calcification and IMT (P < 0.05). Using Kaplan-Meier analysis, the number of deaths was higher in patients with lower magnesium levels and poorer Wilkins score. The mean cut-off value for FGF-23 was 117 RU/mL and for magnesium 1.7 mg/dL. Conclusions. Hypomagnesemia and high FGF-23 levels are independent predictors of mitral valve calcification and IMT and are risk factors for cardiovascular mortality in this population. They might be used as diagnostic/therapeutic targets in order to better manage the high cardiovascular risk in CKD patients.
RESUMO
BACKGROUND: The aim of our study was to evaluate the relevance of magnesium and FGF-23 in terms of cardiovascular disease in a population of type 2 diabetic patients with nephropathy. METHODS: In a cross-sectional study, we included 80 type 2 diabetic patients with chronic kidney disease (CKD) stages 2, 3 and 4. We analysed mineral metabolism, inflammation, oxidative stress and insulin resistance. Our population was divided into two groups according to their pulse pressure (PP) as follows: G-1 with PP < 50 mmHg (n = 34) and G-2 with PP ≥ 50 mmHg (n = 46). RESULTS: We found that G-2 patients showed lower calcium (P = 0.004), eGFR (P = 0.001), magnesium (P = 0.0001), osteocalcin (P = 0.0001) and 25(OH)D3 (P = 0.001), and higher iPTH (P = 0.001), FGF-23 (P = 0.0001), malonaldehyde (P = 0.0001), interleukin 6 (P = 0.001) and HOMA-IR (P = 0.033). No differences were found between the two groups regarding age, duration of disease, haemoglobin, HgA1c and phosphorus. In a multivariate analysis, we found that FGF-23 and magnesium independently influenced the PP [OR = 1.239 (1.001-2.082), P = 0.039 and OR = 0.550 (0.305-0.727), P = 0.016, respectively]. CONCLUSIONS: In our diabetic population with early stages of CKD, FGF-23 as well as lower magnesium levels were significantly and independently associated with higher PP levels, an established marker of cardiovascular morbidity and mortality.
RESUMO
The alternative phosphate binder calcium acetate/magnesium carbonate (CaMg) effectively reduces hyperphosphatemia, the most important inducer of vascular calcification, in chronic renal failure (CRF). In this study, the effect of low dose CaMg on vascular calcification and possible effects of CaMg on bone turnover, a persistent clinical controversy, were evaluated in chronic renal failure rats. Adenine-induced CRF rats were treated daily with 185 mg/kg CaMg or vehicle for 5 weeks. The aortic calcium content and area% calcification were measured to evaluate the effect of CaMg. To study the effect of CaMg on bone remodeling, rats underwent 5/6th nephrectomy combined with either a normal phosphorus diet or a high phosphorus diet to differentiate between possible bone effects resulting from either CaMg-induced phosphate deficiency or a direct effect of Mg. Vehicle or CaMg was administered at doses of 185 and 375 mg/kg/day for 8 weeks. Bone histomorphometry was performed. Aortic calcium content was significantly reduced by 185 mg/kg/day CaMg. CaMg ameliorated features of hyperparathyroid bone disease. In CRF rats on a normal phosphorus diet, the highest CaMg dose caused an increase in osteoid area due to phosphate depletion. The high phosphorus diet combined with the highest CaMg dose prevented the phosphate depletion and thus the rise in osteoid area. CaMg had no effect on osteoblast/osteoclast or dynamic bone parameters, and did not alter bone Mg levels. CaMg at doses that reduce vascular calcification did not show any harmful effect on bone turnover.
Assuntos
Osso e Ossos/efeitos dos fármacos , Osso e Ossos/metabolismo , Falência Renal Crônica/metabolismo , Magnésio/farmacologia , Fosfatos/metabolismo , Calcificação Vascular/metabolismo , Acetatos/metabolismo , Acetatos/farmacologia , Animais , Biomarcadores/sangue , Biomarcadores/metabolismo , Biomarcadores/urina , Remodelação Óssea/efeitos dos fármacos , Compostos de Cálcio/metabolismo , Compostos de Cálcio/farmacologia , Dieta , Modelos Animais de Doenças , Magnésio/metabolismo , Masculino , Fósforo/metabolismo , RatosRESUMO
Magnesium reduces vascular smooth muscle cell (VSMC) calcification in vitro but the mechanism has not been revealed so far. This work used only slightly increased magnesium levels and aimed at determining: a) whether inhibition of magnesium transport into the cell influences VSMC calcification, b) whether Wnt/ß-catenin signaling, a key mediator of osteogenic differentiation, is modified by magnesium and c) whether magnesium can influence already established vascular calcification. Human VSMC incubated with high phosphate (3.3 mM) and moderately elevated magnesium (1.4 mM) significantly reduced VSMC calcification and expression of the osteogenic transcription factors Cbfa-1 and osterix, and up-regulated expression of the natural calcification inhibitors matrix Gla protein (MGP) and osteoprotegerin (OPG). The protective effects of magnesium on calcification and expression of osteogenic markers were no longer observed in VSMC cultured with an inhibitor of cellular magnesium transport (2-aminoethoxy-diphenylborate [2-APB]). High phosphate induced activation of Wnt/ß-catenin pathway as demonstrated by the translocation of ß-catenin into the nucleus, increased expression of the frizzled-3 gene, and downregulation of Dkk-1 gene, a specific antagonist of the Wnt/ß-catenin signaling pathway. The addition of magnesium however inhibited phosphate-induced activation of Wnt/ß-catenin signaling pathway. Furthermore, TRPM7 silencing using siRNA resulted in activation of Wnt/ß-catenin signaling pathway. Additional experiments were performed to test the ability of magnesium to halt the progression of already established VSMC calcification in vitro. The delayed addition of magnesium decreased calcium content, down-regulated Cbfa-1 and osterix and up-regulated MGP and OPG, when compared with a control group. This effect was not observed when 2-APB was added. In conclusion, magnesium transport through the cell membrane is important to inhibit VSMC calcification in vitro. Inhibition of Wnt/ß-catenin by magnesium is one potential intracellular mechanism by which this anti-calcifying effect is achieved.