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1.
Mater Sci Eng C Mater Biol Appl ; 109: 110551, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-32228967

RESUMEN

Accelerated osseointegration is well considered as a critical facilitated factor for titanium scaffold longevity,but immensely limited by bioinert material surfaces and restricted biological responses in vivo. Here, we fabricated three-dimensional printed porous titanium scaffold modified with titanium dioxide (TiO2) nanotubes (p-TNTs), for mimicking the hierarchical trabecular bone structure and building local drug delivery system to accelerate osseointegration. The scaffold at macro and micro gradient was manufactured by selective laser melting process with pure titanium powder according to the computer-aided design (CAD), which could be further anodized to construct nano-gradient frameworks and drug-loading districts. Sequentially, 1α,25-Dihydroxyvitamin D3 (VD3) was loaded into anodized TiO2 nanotubes,thermo-sensitive hydrogel Pluronic F-127 (F-127) was coated and charged as a bio-cap for control release. Biological responses in vitro and in vivo was evaluated, showing significant osteogenesis enhancement of hierarchical structure with local drug delivery. It suggests that a promising bioactive implant system may provide a far-reaching impact on accelerating and enhancing early osseointegration.


Asunto(s)
Calcitriol , Nanotubos/química , Oseointegración/efectos de los fármacos , Andamios del Tejido/química , Titanio/química , Animales , Calcitriol/química , Calcitriol/farmacocinética , Calcitriol/farmacología , Línea Celular , Preparaciones de Acción Retardada/química , Preparaciones de Acción Retardada/farmacocinética , Preparaciones de Acción Retardada/farmacología , Ratones
2.
Pharm Dev Technol ; 25(7): 899-907, 2020 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-32324081

RESUMEN

Calcitriol, as the biologically active form of vitamin D3, is essential for patients with renal osteopathy. The solubilization, stabilization, and content uniformity are key issues in its formulation development. In our previous study, the incomplete release of calcitriol was solved by using the hybrid lipid-based solid dispersion (SD) for calcitriol. However, good stability and content uniformity are still urgently needed. In this study, solid lipid with antioxidant properties and liquid lipid compatible with calcitriol were employed as hybrid lipid carrier (HLC) to establish a solid dispersion. Moreover, the content uniformity of tablets with hybrid lipid carrier based SDs (HLCTs) was further guaranteed due to the multi-dispersion of calcitriol in HLC, solidification, and blank granules. Additionally, the compression of the blank granules was adjusted by the water content. The mixing method of calcitriol-containing and blank granules was also optimized. The obtained HLCTs were evaluated for hardness, disintegration time, in vitro drug dissolution, content uniformity, and stability. Satisfactory HLCTs were developed successfully in this study with superior content uniformity and better stability than the commercial soft capsule (Rocaltrol®). It was proved to be a promising formulation for drugs with poor water-solubility, instability to oxygen and heat, and dose-related toxicity.


Asunto(s)
Conservadores de la Densidad Ósea/síntesis química , Calcitriol/síntesis química , Portadores de Fármacos/síntesis química , Composición de Medicamentos/métodos , Conservadores de la Densidad Ósea/administración & dosificación , Conservadores de la Densidad Ósea/farmacocinética , Calcitriol/administración & dosificación , Calcitriol/farmacocinética , Portadores de Fármacos/administración & dosificación , Portadores de Fármacos/farmacocinética , Liberación de Fármacos/fisiología , Estabilidad de Medicamentos , Comprimidos
3.
Clin Transl Sci ; 12(6): 617-624, 2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-31305024

RESUMEN

Quantum dots (QDs) conjugated with 1,25 dihydroxyvitamin D3 (calcitriol) and Mucin-1 (MUC-1) antibodies (SM3) have been found to target inflammatory breast cancer (IBC) tumors and reduce proliferation, migration, and differentiation of these tumors in mice. A physiologically-based pharmacokinetic model has been constructed and optimized to match experimental data for multiple QDs: control QDs, QDs conjugated with calcitriol, and QDs conjugated with both calcitriol and SM3 MUC1 antibodies. The model predicts continuous QD concentration for key tissues in mice distinguished by IBC stage (healthy, early-stage, and late-stage). Experimental and clinical efforts in QD treatment of IBC can be augmented by in silico simulations that predict the short-term and long-term behavior of QD treatment regimens.


Asunto(s)
Antineoplásicos/farmacocinética , Neoplasias de la Mama/tratamiento farmacológico , Calcitriol/farmacocinética , Modelos Biológicos , Puntos Cuánticos/administración & dosificación , Animales , Antineoplásicos/administración & dosificación , Neoplasias de la Mama/inmunología , Calcitriol/administración & dosificación , Línea Celular Tumoral , Sistemas de Liberación de Medicamentos/métodos , Femenino , Humanos , Inmunoconjugados/administración & dosificación , Inmunoconjugados/farmacocinética , Ratones , Mucina-1/inmunología , Ensayos Antitumor por Modelo de Xenoinjerto
4.
Drug Metab Dispos ; 47(9): 974-982, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-31289106

RESUMEN

Metabolic deactivation of 1,25(OH)2D3 is initiated by modification of the vitamin-D side chain, as carried out by the mitochondrial cytochrome P450 24A1 (CYP24A1). In addition to its role in vitamin-D metabolism, CYP24A1 is involved in catabolism of vitamin-D analogs, thereby reducing their efficacy. CYP24A1 function relies on electron transfer from the soluble ferredoxin protein adrenodoxin (Adx). Recent structural evidence suggests that regioselectivity of the CYP24A1 reaction may correlate with distinct modes of Adx recognition. Here we used nuclear magnetic resonance (NMR) spectroscopy to monitor the structure of 15N-labeled full-length Adx from rat while forming the complex with rat CYP24A1 in the ligand-free state or bound to either 1,25(OH)2D3 or the vitamin-D supplement 1α(OH)D3. Although both vitamin-D ligands were found to induce a reduction in overall NMR peak broadening, thereby suggesting ligand-induced disruption of the complex, a crosslinking analysis suggested that ligand does not have a significant effect on the relative association affinities of the redox complexes. However, a key finding is that, whereas the presence of primary CYP24A1 substrate was found to induce NMR peak broadening focused on the putative recognition site α-helix 3 of rat adrenodoxin, the interaction in the presence of 1α(OH)D3, which is lacking the carbon-25 hydroxyl, results in disruption of the NMR peak broadening pattern, thus indicating a ligand-induced nonspecific protein interaction. These findings provide a structural basis for the poor substrate turnover of side-chain-modified vitamin-D analogs, while also confirming that specificity of the CYP24A1-ligand interaction influences specificity of CYP24A1-Adx recognition. SIGNIFICANCE STATEMENT: Mitochondrial cytochrome P450 enzymes, such as CYP24A1 responsible for catabolizing vitamin-D and its analogs, rely on a protein-protein interaction with a ferredoxin in order to receive delivery of the electrons required for catalysis. In this study, we demonstrate that this protein interaction is influenced by the enzyme-ligand interaction that precedes it. Specifically, vitamin-D missing carbon-25 hydroxylation binds the enzyme active site with high affinity but results in a loss of P450-ferredoxin binding specificity.


Asunto(s)
Adrenodoxina/metabolismo , Calcitriol/farmacocinética , Hidroxicolecalciferoles/farmacocinética , Vitamina D3 24-Hidroxilasa/metabolismo , Adrenodoxina/aislamiento & purificación , Regulación Alostérica , Calcitriol/química , Carbono/metabolismo , Dominio Catalítico , Pruebas de Enzimas , Hidroxicolecalciferoles/química , Hidroxilación , Espectroscopía de Resonancia Magnética , Oxidación-Reducción , Proteínas Recombinantes/aislamiento & purificación , Proteínas Recombinantes/metabolismo , Vitamina D3 24-Hidroxilasa/aislamiento & purificación
5.
Int J Nanomedicine ; 14: 2829-2846, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31114197

RESUMEN

BACKGROUND: Vitamin D3 possesses anti-inflammatory and modulatory properties in addition to its role in calcium and phosphate homeostasis. Upon activation, macrophages (M) can initiate and sustain pro-inflammatory cytokine production in inflammatory disorders and play a pathogenic role in certain cancers. PURPOSE: The main purpose of this study was to encapsulate and specifically target calcitriol to macrophages and investigate the anti-inflammatory properties of calcitriol in vitro and in vivo. METHODS: In this study we have designed and developed near-infrared calcitriol PEGylated nanoparticles (PEG-LNP(Cal)) using a microfluidic mixing technique and modified lipid nanoparticles (LNPs) to target the M specific endocytic receptor CD163. We have investigated LNP cellular uptake and anti-inflammatory effect in LPS-induced M in vitro by flow cytometry, confocal microscopy and gene expression analyses. LNP pharmacodynamics, bio-distribution and organ specific LNP accumulation was also investigated in mice in vivo. RESULTS: In vitro, we observed the specific uptake of PEG-LNP(Cal)-hCD163 in human M, which was significantly higher than the non-specific uptake of control PEG-LNP(Cal)-IgG(h) in M. Pretreatment with encapsulated calcitriol was able to attenuate intracellular TNF-expression, and M surface marker HLA-DR expression more efficiently than free calcitriol in LPS-induced M in vitro. Encapsulated calcitriol diminished mRNA gene levels of TNF-, NF-B, MCP-1 and IL-6, while upregulating IL-10. TNF- and IL-6 protein secretion also decreased. In mice, an in vivo pharmacodynamic study of PEG-LNP(Cal) showed a rapid clearance of IgG and CD163 modified LNPs compared to PEG-LNP(Cal). Antibody modified PEG-LNP(Cal) accumulated in the liver, spleen and kidney, whereas unmodified PEG-LNP(Cal) accumulation was only observed in the liver. CONCLUSION: Our results show that calcitriol can be effectively targeted to M. Our data confirms the anti-inflammatory properties of calcitriol and this may be a potential way to deliver high dose bioactive calcitriol to M during inflammation in vivo.


Asunto(s)
Antiinflamatorios/farmacología , Calcitriol/administración & dosificación , Calcitriol/farmacología , Lípidos/química , Macrófagos/metabolismo , Nanopartículas/química , Animales , Anticuerpos/metabolismo , Antígenos CD/metabolismo , Antígenos de Diferenciación Mielomonocítica/metabolismo , Calcitriol/farmacocinética , Quimiocinas/metabolismo , Composición de Medicamentos , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Inflamación/patología , Mediadores de Inflamación/metabolismo , Macrófagos/efectos de los fármacos , Ratones Endogámicos C57BL , Tamaño de la Partícula , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptores de Superficie Celular/metabolismo , Distribución Tisular/efectos de los fármacos
6.
Eur J Pharm Sci ; 130: 173-180, 2019 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-30654110

RESUMEN

The physiological and anti-cancer functions of vitamin D3 are accomplished primarily via 1α,25-dihydroxyvitamin D3 (calcitriol), whereas 20(S)-protopanaxadiol (aPPD) is a ginsenoside, which is isolated from Panax ginseng, with potential anti-cancer benefits. In the present study, we report a pharmacokinetic (PK) herb-nutrient interaction between calcitriol and aPPD in mice. A liquid chromatography mass spectrometry (LC/MS) method was developed using 4-phenyl-1,2,4-triazoline-3,5-dione derivatizing agent and we subsequently used the method to quantitate calcitriol in mouse serum. The limit of quantitation was 0.01 ng/ml which is approximately 100 fold lower than the previously reported assay from our laboratory. Calcitriol PK parameters were determined in non-tumor-bearing or C4-2 human prostate tumor-bearing nude mice following oral co-administration of calcitriol either alone or in combination with aPPD. Mice were pretreated with oral aPPD (70 mg/kg) or vehicle control twice daily for seven consecutive days, followed by a single oral dose of 4 µg/kg calcitriol alone or in combination with aPPD. Our PK results demonstrated that co-administration of calcitriol with aPPD (following pre-treatment with vehicle for seven days) resulted in a 35% increase in the area under the curve (AUC0-24 h) and a 41% increase in the maximum serum concentration (Cmax) compared to the calcitriol only group. aPPD therefore significantly increased calcitriol serum exposure. We also saw a reduction in the time required to reach Cmax. In contrast, calcitriol PK in mice co-administered with calcitriol and aPPD as well as those pretreated seven consecutive days with aPPD was no different than that determined for the mice that received vehicle for seven days as pre-treatment. Co-administration of calcitriol with aPPD therefore could increase health benefits of vitamin D3, however any increased risk of hypercalcemia, resulting from this combination approach, requires further investigation. Lastly, we surmise that a cytochrome P450 inhibition-based mechanism may contribute to the observed PK interaction.


Asunto(s)
Calcitriol/análisis , Calcitriol/farmacocinética , Sapogeninas/análisis , Sapogeninas/farmacocinética , Espectrometría de Masas en Tándem/métodos , Administración Oral , Animales , Calcitriol/administración & dosificación , Hormonas y Agentes Reguladores de Calcio/administración & dosificación , Hormonas y Agentes Reguladores de Calcio/análisis , Hormonas y Agentes Reguladores de Calcio/farmacocinética , Cromatografía Liquida/métodos , Interacciones Farmacológicas/fisiología , Masculino , Ratones , Ratones Desnudos , Sapogeninas/administración & dosificación
7.
Br J Clin Pharmacol ; 85(6): 1095-1102, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-30308088

RESUMEN

Pharmacologists have been interested in vitamin D since its metabolism was elucidated in the early 1970s. Despite the synthesis of thousands of vitamin D analogues in the hope of separating its calcemic and anti-proliferative properties, few molecules have reached the market for use in the treatment of clinical conditions from psoriasis to chronic kidney disease. This review discusses vitamin D drugs, recently developed or still under development, for use in various diseases, but in particular bone disease. In the process we explore the mechanisms postulated to explain the action of these vitamin D analogues including action through the vitamin D receptor, action through other receptors e.g. FAM57B2 and dual action on transcriptional processes.


Asunto(s)
24,25-Dihidroxivitamina D 3/uso terapéutico , Conservadores de la Densidad Ósea/uso terapéutico , Enfermedades Óseas Metabólicas/tratamiento farmacológico , Remodelación Ósea/efectos de los fármacos , Calcifediol/uso terapéutico , Calcitriol/uso terapéutico , Vitaminas/uso terapéutico , 24,25-Dihidroxivitamina D 3/efectos adversos , 24,25-Dihidroxivitamina D 3/farmacocinética , Animales , Conservadores de la Densidad Ósea/efectos adversos , Conservadores de la Densidad Ósea/farmacocinética , Enfermedades Óseas Metabólicas/diagnóstico , Enfermedades Óseas Metabólicas/fisiopatología , Calcifediol/efectos adversos , Calcifediol/farmacocinética , Calcitriol/efectos adversos , Calcitriol/farmacocinética , Humanos , Receptores de Calcitriol/agonistas , Receptores de Calcitriol/metabolismo , Transducción de Señal , Resultado del Tratamiento , Vitaminas/efectos adversos , Vitaminas/farmacocinética
8.
J Steroid Biochem Mol Biol ; 188: 172-184, 2019 04.
Artículo en Inglés | MEDLINE | ID: mdl-30562554

RESUMEN

Calcipotriol (MC903) is a side chain analogue of the biologically active 1,25-dihydroxyvitamin D3 [1,25(OH)2D3]. Due to its anti-inflammatory and anti-proliferative effects on stromal cells, calcipotriol is a promising candidate for the local treatment of arthritis. In this preliminary work, we studied the pharmacokinetics and safety of calcipotriol after an IV (0.1 mg/kg given to one sheep) and intra-articular dose (0.054 mg/kg, 0.216 mg/kg and 0.560 mg/kg given to three sheep). The terminal half-life of calcipotriol was approximately 1 h after an IV dose. After intra-articular dosing, the systemic absorption was between 1 and 13% during the observed 24 h. Hypercalcemia or other clinical adverse effects did not occur in any animal during the study, and no macroscopic or microscopic alterations were seen in the synovium of the calcipotriol-injected knees compared to the vehicle knees. The in vitro metabolism of calcipotriol was analyzed with LC-MS from human synovial and mesenchymal stromal cell cultures. Both cell types were able to metabolize calcipotriol with MC1080 and MC1046 as the main metabolites. CYP24A1 transcripts were strongly induced by a 48-hour calcipotriol exposure in mesenchymal stromal cells, but not consistently in synovial stromal cells, as determined by RT-qPCR. Calcipotriol proved to be safe after a single intra-articular dose with applied concentrations, and it is metabolized by the cells of the joint. Slow dissolution of calcipotriol crystals in the joint can extend the pharmaceutical impact on the synovium, cartilage and subcortical bone.


Asunto(s)
Antiinflamatorios/metabolismo , Antiinflamatorios/farmacocinética , Calcitriol/análogos & derivados , Células Madre Mesenquimatosas/metabolismo , Membrana Sinovial/metabolismo , Animales , Antiinflamatorios/administración & dosificación , Antiinflamatorios/sangre , Artritis/tratamiento farmacológico , Calcitriol/administración & dosificación , Calcitriol/sangre , Calcitriol/metabolismo , Calcitriol/farmacocinética , Células Cultivadas , Femenino , Humanos , Masculino , Células Madre Mesenquimatosas/citología , Ovinos , Membrana Sinovial/citología
9.
Clin Interv Aging ; 13: 2367-2374, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30532527

RESUMEN

OBJECTIVE: This study aimed to determine the effect of calcitriol on serum concentrations of fibroblast growth factor-23 (FGF-23), sclerostin, intact parathyroid hormone (PTH), and handgrip strength in postmenopausal women with low bone mass. METHODS: A randomized, double-blind controlled trial was carried out among 141 postmenopausal women with low bone mass. Participants were randomized into two groups: 75 participants received calcitriol 0.5 µg/day and 66 participants received a placebo for 12 weeks. RESULTS: After 12-week calcitriol treatment, significant decreases in serum intact PTH (P=0.035) and sclerostin (P=0.039), as well as significant increases in serum creatinine (P=0.027), uric acid (P=0.032), 24-hour urinary calcium (P=0.0026), and left handgrip strength (P=0.03), were observed, compared to placebo group. Level of serum sclerostin was weakly but significantly positively correlated with serum PTH (r=0.277; P=0.01) and negatively correlated with 24-hour urinary calcium (r=-0.221; P=0.04) and left handgrip strength (r=-0.338; P=0.03) after calcitriol treatment. Multiple regression analysis demonstrated that decrease in serum sclerostin was associated with decrease in PTH serum level after calcitriol treatment (OR, 7.90; 95% CI, 2.28-27.42; P=0.002). However, no significant change in FGF-23 level was observed after calcitriol treatment. CONCLUSION: Calcitriol treatment yields a considerable decrease in serum sclerostin and significant increase of handgrip strength, and the change in serum sclerostin is regulated by serum PTH and by muscle strength.


Asunto(s)
Proteínas Morfogenéticas Óseas , Calcitriol , Factores de Crecimiento de Fibroblastos , Marcadores Genéticos , Fuerza Muscular , Hormona Paratiroidea , Posmenopausia , Proteínas Adaptadoras Transductoras de Señales , Anciano , Proteínas Morfogenéticas Óseas/sangre , Proteínas Morfogenéticas Óseas/metabolismo , Calcitriol/administración & dosificación , Calcitriol/farmacocinética , Calcio/sangre , Calcio/metabolismo , Hormonas y Agentes Reguladores de Calcio/administración & dosificación , Hormonas y Agentes Reguladores de Calcio/farmacocinética , Método Doble Ciego , Monitoreo de Drogas , Femenino , Factor-23 de Crecimiento de Fibroblastos , Factores de Crecimiento de Fibroblastos/sangre , Factores de Crecimiento de Fibroblastos/metabolismo , Fuerza de la Mano/fisiología , Humanos , Persona de Mediana Edad , Fuerza Muscular/efectos de los fármacos , Fuerza Muscular/fisiología , Hormona Paratiroidea/sangre , Hormona Paratiroidea/metabolismo , Posmenopausia/sangre , Posmenopausia/efectos de los fármacos , Resultado del Tratamiento
10.
G Ital Dermatol Venereol ; 153(6): 872-876, 2018 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-30261718

RESUMEN

The fixed-combination of Cal/BD aerosol foam is now entering the Italian market. This drug was developed with a technology that allows an enhanced penetration of the active ingredients into the skin. This enhanced penetration improves local bioavailability and, consequently, Cal/BD aerosol foam therapy is associated with improved clinical outcomes if compared with other products with the same components. The efficacy and safety of Cal/BD aerosol foam were confirmed both in clinical trials and in "field-practice" studies. This short review discusses current evidence on the Cal/BD aerosol foam combination; some preliminary data collected in the Italian clinical practice will be also presented.


Asunto(s)
Betametasona/análogos & derivados , Calcitriol/análogos & derivados , Fármacos Dermatológicos/administración & dosificación , Psoriasis/tratamiento farmacológico , Administración Cutánea , Aerosoles , Betametasona/administración & dosificación , Betametasona/efectos adversos , Betametasona/farmacocinética , Disponibilidad Biológica , Calcitriol/administración & dosificación , Calcitriol/efectos adversos , Calcitriol/farmacocinética , Fármacos Dermatológicos/efectos adversos , Fármacos Dermatológicos/farmacocinética , Combinación de Medicamentos , Humanos , Italia , Psoriasis/patología , Absorción Cutánea , Resultado del Tratamiento
11.
Actual. osteol ; 14(1): 10-21, Ene - Abr. 2018. ilus, graf, tab
Artículo en Español | LILACS | ID: biblio-1116424

RESUMEN

La suplementación con calcio reduciría, sola o asociada a otra medicación para osteoporosis, la pérdida de masa ósea y el riesgo de fracturas. Sin embargo, su tasa de adherencia es baja debido a la poca tolerancia. Objetivo: comparar la tasa de absorción neta de calcio entre dos formulaciones distintas de carbonato de calcio (500 mg): comprimidos vs. mousse. Material y métodos: 11 pruebas fueron realizadas en mujeres posmenopáusicas de 58,9±3 años. El diseño fue exploratorio abierto, aleatorizado, prospectivo cruzado de fase 4. Intervención: las participantes fueron aleatorizadas en dos grupos para recibir las dos formulaciones previa suplementación con vitamina D3. La tasa de absorción neta de calcio fue estudiada por la prueba de inhibición de hormona paratiroidea (PTH). Se obtuvieron muestras de sangre: basal y en la 1a, 2a y 3a hora posadministración del calcio asignado, y de orina de 2 horas basal y al final de la prueba. Determinaciones bioquímicas: calcio, fósforo, albúmina, 25-hidroxivitamina D y hormona paratiroidea intacta y calciuria. Análisis estadístico: método de los trapecios para calcular el área bajo la curva (AUC) de la concentración de calcio en el tiempo (R Development Core Team (2008). http://www.Rp-project.org) y Anova con dos términos de error para evaluar el efecto secuencia, período y formulación. Resultados: la mayor inhibición de PTH se observó a dos horas de la toma de ambas formulaciones (comprimidos -39,2% vs. mousse -38,0%; p=ns), con similar AUC0-3 h (comprimidos 3,35; IC 95%: 3,32; 3,37 vs. mousse 3,36; IC 95%: 3,33; 3,38). Cuando analizamos tolerancia y preferencias no se observaron diferencias estadísticamente significativas entre ambas formulaciones. Conclusión: el carbonato de calcio en mousse mostró similar tasa de absorción intestinal, preferencia y tolerancia gastrointestinal que en comprimido. (AU)


Calcium supplementation, administered alone or in combination with a specific medication for osteoporosis, would reduce bone mass loss and fracture risk in postmenopausal women. However, the adherence rate to calcium supplements is low, mainly due to low tolerance. Objective: comparisson of net calcium absorption rate between two different pharmaceutical formulations of calcium carbonate (PFCa) in postmenopausal women. Materials and Methods: 11 tests were performed in postmenopausal women aged 58.9±3 yrs. Design: Comparative, randomized, prospective, open-label exploratory crossover study of calcium mousse versus calcium pills. Intervention: Participants were randomized in 2 groups to receive the 2 different PFCa (500mg): pills vs. mousse, with previous vitamin D3 supplementation. The parathyroid hormone (PTH) inhibition test and the area-under-thecurve (AUC) of calcium were analyzed. Blood samples were taken at baseline and 1, 2 and 3 hrs after intake of the assigned PFCa. Urine samples (2hs) were obtained at -baseline, after 2hs of PFCa intake and at the end of the test. Biochemical Determinations: Serum: calcium, phosphorus, albumin, 25-hydroxyvitamin D, and intact PTH. In urine: calcium. Statistical Analysis: The trapezoid rule was applied to assess AUC in time (R Development Core Team (2008). http://www.Rp-project.org). An ANOVA model with 2 error terms was used to assess the effect of sequence, period, and formulation. Results: The highest inhibition PTH rates were observed after 2 hrs of PFCa (pills -39.2% vs. mousse -38.0%; p=ns). The AUC0-3hrs for both PFCa was similar (pills 3.35; 95%CI: 3.32; 3.37 vs. mousse 3.36; 95%CI: 3.33; 3.38). No statistically significant differences were observed when we analyze tolerance and predilection. Conclusion: The calcium carbonate in mousse showed an adequate rate of intestinal absorption, similarly predilection and gastrointestinal tolerance than the pill presentation. (AU)


Asunto(s)
Humanos , Femenino , Persona de Mediana Edad , Carbonato de Calcio/farmacocinética , Osteoporosis Posmenopáusica/prevención & control , Calcio/farmacocinética , Hormona Paratiroidea/análisis , Aclorhidria , Calcitriol/farmacocinética , Carbonato de Calcio/administración & dosificación , Carbonato de Calcio/uso terapéutico , Índice de Masa Corporal , Densidad Ósea , Evaluación Nutricional , Osteoporosis Posmenopáusica/dietoterapia , Osteoporosis Posmenopáusica/tratamiento farmacológico , Tamizaje Masivo , Calcio/deficiencia , Posmenopausia/efectos de los fármacos , Posmenopausia/sangre , Colecalciferol/administración & dosificación , Colecalciferol/efectos adversos , Estudios Cruzados , Citrato de Calcio/uso terapéutico , Fracturas Óseas/prevención & control , Estrógenos/deficiencia , Absorción Gastrointestinal/efectos de los fármacos , Cumplimiento y Adherencia al Tratamiento , Anabolizantes/uso terapéutico
12.
G Ital Dermatol Venereol ; 153(3): 375-382, 2018 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-27982547

RESUMEN

Psoriasis is a chronic-relapsing skin disorder which requires long-term treatments. Therapeutic options for psoriasis include topical treatments, phototherapy and systemic therapy. However, those treatments, and particularly the topical drug therapies, may present some limitations, including poor efficacy/tolerability ratio and lack of adherence. Recently, the supersaturated aerosol foam formulation of the fixed combination calcipotriene plus betamethasone dipropionate (Cal/BD) has gained major attention because it overcomes some of the limitations associated with other topical treatments. This fixed-combination has increased efficacy compared with its individual components. Moreover, the alcohol-free aerosol foam formulation allows a higher penetration of the active ingredients into the skin, resulting in enhanced bioavailability and, consequently, in better clinical outcomes than other products with the same components. Given the short duration of therapy course and the fast onset of action, a reduced amount of Cal/BD foam formulation would be required for the treatment of psoriasis patients, resulting also in cost saving. Therefore this novel formulation could represent an alternative to other topical agents and a first-line therapy in the treatment of mild and mild-to-moderate psoriasis.


Asunto(s)
Betametasona/análogos & derivados , Calcitriol/análogos & derivados , Fármacos Dermatológicos/administración & dosificación , Psoriasis/tratamiento farmacológico , Administración Cutánea , Betametasona/administración & dosificación , Betametasona/farmacocinética , Calcitriol/administración & dosificación , Calcitriol/farmacocinética , Fármacos Dermatológicos/farmacocinética , Combinación de Medicamentos , Humanos , Fototerapia/métodos , Psoriasis/patología , Índice de Severidad de la Enfermedad , Absorción Cutánea , Resultado del Tratamiento
13.
Drugs R D ; 17(4): 597-605, 2017 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-28905271

RESUMEN

BACKGROUND: 2-Methylene-19-nor-(20S)-1α,25-dihydroxyvitamin D3 (DP001 or 2MD) is a novel, potent 1α-hydroxylated vitamin D analog that binds to the vitamin D receptor and suppresses parathyroid hormone synthesis and secretion with potential for an improved safety profile compared to existing active vitamin D analogs. The purpose of this study was to evaluate the pharmacokinetics of DP001 given orally after hemodialysis. METHODS: DP001 (550 ng) was given orally to 11 hemodialysis patients with secondary hyperparathyroidism after each dialysis session (3 times/week) for 4 weeks. Pharmacokinetic analyses were performed after the first and final dose. RESULTS: After the first and final dose, the half-life of DP001 was similar (55.8 ± 13.0 and 50.8 ± 8.2 h, respectively). At 4 weeks, the time to maximum plasma concentration was 4.0 ± 0.8 h, with a concentration maximum of 3.4 ± 0.3 pg/mL. The area under the curve (0 to infinity) after the final dose was 204.3 ± 23.9 pg h/mL, and apparent volume of distribution was 2.03 ± 0.22 L/kg. At week 4, mean intact parathyroid hormone was suppressed 33% from the baseline (pre-dose) value (313 ± 52 vs 462 ± 39 pg/mL, respectively). No clinically significant changes from baseline values were found for vital signs, electrocardiogram measurements, or other laboratory parameters, including serum calcium and phosphorus. CONCLUSIONS: In hemodialysis patients, DP001 has a longer half-life than existing vitamin D therapies and enables control of parathyroid hormone when administered every 2-3 days on the day of dialysis. It is effective at a lower concentration maximum and area under the curve than other clinically available vitamin D compounds. DP001 may represent a therapeutic improvement over existing compounds due to rapid and extensive distribution to its target and its long half-life enabling sustained parathyroid hormone suppression. These studies support further evaluation of DP001 in longer-term treatment of secondary hyperparathyroidism.


Asunto(s)
Calcitriol/análogos & derivados , Hiperparatiroidismo Secundario/tratamiento farmacológico , Receptores de Calcitriol/agonistas , Diálisis Renal , Insuficiencia Renal Crónica/sangre , Administración Oral , Adulto , Anciano , Área Bajo la Curva , Calcitriol/administración & dosificación , Calcitriol/farmacocinética , Calcitriol/uso terapéutico , Femenino , Semivida , Humanos , Hiperparatiroidismo Secundario/sangre , Masculino , Persona de Mediana Edad , Hormona Paratiroidea/sangre , Insuficiencia Renal Crónica/terapia
14.
Int Urol Nephrol ; 49(2): 325-328, 2017 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-27822674

RESUMEN

PURPOSE: The optimal vitamin D3 therapy for the treatment of secondary hyperparathyroidism (SHPT) in chronic hemodialysis patients is still controversial. Recent studies suggest that uremia in end-stage renal disease is associated with enzymatic hepatic dysfunction altering 25-hydroxylation of vitamin D3. The goal of our study was to compare the efficacy of calcitriol, the fully hydroxylated active form of vitamin D3, to alfacalcidol which needs 25-hydroxylation to be effective, for the treatment of SHPT in chronic hemodialysis patients. METHODS: We retrospectively reviewed 45 chronic hemodialysis patients who were switched from oral alfacalcidol to oral calcitriol for the treatment of SHPT. Parathyroid hormone (PTH), serum calcium and serum phosphorus levels were compared pre- and post-conversion using paired Student's t tests. RESULTS: The mean dose of active vitamin D3 decreased from 3.50 mcg/week at baseline to 2.86 mcg (P < 0001) after the switch from alfacalcidol to calcitriol. PTH significantly decreased from 94.4 to 82.6 pmol/L (-11.8 pmol/L, P = 0.02). The mean corrected calcium increased from 2.17 to 2.25 mmol/L (+0.08 mmol/L, P < 0.001) without any clinically significant hypercalcemia, and phosphorus levels were stable. Results were similar in a subgroup of patients (n = 17) for whom the medication was administrated during the hemodialysis session, ensuring a complete compliance. CONCLUSIONS: According to our study, calcitriol in equal dosage is more effective than alfacalcidol in lowering serum PTH level in chronic hemodialysis patients. This suggests that calcitriol may be the optimal active vitamin D3 for the treatment of SHPT in chronic hemodialysis patients.


Asunto(s)
Calcitriol , Sustitución de Medicamentos/métodos , Hidroxicolecalciferoles , Hiperparatiroidismo Secundario , Fallo Renal Crónico/terapia , Diálisis Renal/efectos adversos , Adulto , Anciano , Calcitriol/administración & dosificación , Calcitriol/farmacocinética , Calcio/sangre , Canadá , Monitoreo de Drogas/métodos , Femenino , Humanos , Hidroxicolecalciferoles/administración & dosificación , Hidroxicolecalciferoles/farmacocinética , Hiperparatiroidismo Secundario/diagnóstico , Hiperparatiroidismo Secundario/tratamiento farmacológico , Hiperparatiroidismo Secundario/etiología , Fallo Renal Crónico/diagnóstico , Fallo Renal Crónico/metabolismo , Fallo Renal Crónico/fisiopatología , Masculino , Persona de Mediana Edad , Hormona Paratiroidea/sangre , Evaluación del Resultado de la Atención al Paciente , Fósforo/sangre , Diálisis Renal/métodos , Estudios Retrospectivos
16.
Mol Cell Endocrinol ; 404: 75-81, 2015 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-25614971

RESUMEN

Vitamin D deficiency or insufficiency is an independent risk factor for diabetic peripheral neuropathy (DPN), but the relationship between 1,25(OH)2D3 and DPN remains unknown. We found that 1,25(OH)2D3 stimulated the secretion of nerve growth factor (NGF) in rat Schwann cell line RSC96, but ability of 1,25(OH)2D3 to increase NGF protein was impaired under high glucose conditions. High glucose upregulated the expression of CYP24A1 protein, which catalyzes the conversion of 1,25(OH)2D3 into inactive products, further impairing the ability of 1,25(OH)2D3 to upregulate NGF secretion in Schwann cells. Inhibition of CYP24A1 protein expression ameliorated the secretion of NGF in response to 1,25(OH)2D3. The findings of this study suggest that CYP24A1 protein plays an important role in the relationship between DPN and 1,25(OH)2D3.


Asunto(s)
Calcitriol/farmacocinética , Glucosa/farmacología , Factor de Crecimiento Nervioso/metabolismo , Células de Schwann/enzimología , Vitamina D3 24-Hidroxilasa/metabolismo , Animales , Calcitriol/farmacología , Línea Celular , Proliferación Celular/efectos de los fármacos , Neuropatías Diabéticas/enzimología , Genisteína/farmacología , Ratas , Especies Reactivas de Oxígeno/metabolismo , Células de Schwann/citología , Células de Schwann/efectos de los fármacos , Regulación hacia Arriba
17.
Expert Opin Drug Deliv ; 11(12): 1833-47, 2014 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-25078031

RESUMEN

AIM: The primary aim of present work was to develop effective combination drug therapy for topical treatment of psoriasis. METHODS: Betamethasone dipropionate and calcipotriol loaded solid lipid nanoparticles (CT-BD-SLNs) were prepared by hot melt high shear homogenization technique, which were then incorporated in Carbopol gel matrix. The anti-psoriatic potential was tested by sequential in vitro (skin permeation and dermal distribution, anti-proliferative effect in HaCaT cells) and in vivo (Draize patch irritation, transepidermal water loss (TEWL) and anti-psoriatic mouse tail studies) experiments. RESULTS: A negligible amount in receptor compartment, yet confined distribution of drugs to epidermal and dermal region of skin was observed in case of SLNs, which is essential for safe and effective anti-psoriatic therapy. Draize patch test and TEWL demonstrated negligible skin irritation and better skin tolerability of SLNs. The in vitro HaCaT cell line study demonstrated that SLNs delayed the abrupt growth of keratinocytes, while in vivo mouse tail model showed that SLNs gel significantly decreased the epidermal thickness and increased melanocyte count in comparison to commercial Daivobet® ointment. CONCLUSIONS: The developed SLNs gel is expected to be potential strategies for treatment of psoriasis and other topical diseases.


Asunto(s)
Betametasona/análogos & derivados , Calcitriol/análogos & derivados , Diglicéridos/administración & dosificación , Portadores de Fármacos/administración & dosificación , Nanopartículas/administración & dosificación , Psoriasis/tratamiento farmacológico , Administración Tópica , Animales , Betametasona/administración & dosificación , Betametasona/química , Betametasona/farmacocinética , Calcitriol/administración & dosificación , Calcitriol/química , Calcitriol/farmacocinética , Línea Celular , Proliferación Celular/efectos de los fármacos , Dermis/efectos de los fármacos , Dermis/metabolismo , Diglicéridos/química , Diglicéridos/farmacocinética , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Combinación de Medicamentos , Evaluación Preclínica de Medicamentos , Estabilidad de Medicamentos , Epidermis/efectos de los fármacos , Epidermis/metabolismo , Geles , Humanos , Ratones Endogámicos BALB C , Nanopartículas/química , Ratas Sprague-Dawley , Solubilidad
18.
J Biomed Nanotechnol ; 9(10): 1707-15, 2013 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-24015500

RESUMEN

Vitamin D3 is an essential vitamin that has been extensively studied due to its potential role as therapeutic for many diseases, including breast cancer. Previous research has indicated that calcitriol, the active form of Vitamin D3 has a negative effect on the metastatic ability of Inflammatory Breast Cancer (IBC) cells however the mechanism is not fully understood. The effect of calcitriol on IBC cells starting from cellular uptake must be investigated in order to understand these therapeutic effects. Calcitriol bound Quantum Dots (CalQDs) are a novel nanoparticle conjugated probe that can be used to directly examine the distribution, uptake, and signaling of calcitriol in live cells. Therefore we used these conjugated probes to directly investigate the uptake of calcitriol into live IBC cells. Interestingly, calcitriol uptake was observed to decrease when caveolae mediated endocytosis is disrupted. A luciferase assay confirmed that caveolae function is necessary; since calcitriol mediated activity decreases when caveolae mediated endocytosis is disrupted in IBC cells. In vitro examination of the localization of the probe indicated colocalization between caveolae and CalQDs. Additionally, Vitamin D Receptor (VDR) colocalization was observed with caveolae and calcitriol. This study demonstrates that in IBC cells calcitriol enters cells via caveolae mediated endocytosis and that caveolae are required for calcitriol to be uptaken at the increased rate.


Asunto(s)
Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/ultraestructura , Calcitriol/farmacocinética , Caveolas/metabolismo , Endocitosis , Línea Celular Tumoral , Humanos
19.
Biopharm Drug Dispos ; 34(7): 402-16, 2013 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-23897575

RESUMEN

Previous studies have shown that 1α,25-dihydroxyvitamin D3 [1,25(OH)2 D3 ] treatment in mice resulted in induction of intestinal and renal Cyp24a1 and Trpv6 expression, increased hepatic Cyp7a1 expression and activity, as well as higher renal Mdr1/P-gp expression. The present study compared the equimolar efficacies of 1α-hydroxyvitamin D3 [1α(OH)D3 ] (6 nmol/kg i.p. q2d × 4), a lipophilic precursor with a longer plasma half-life that is converted to 1,25(OH)2 D3 , and 1,25(OH)2 D3 on vitamin D receptor (VDR) target genes. To clarify whether changes in VDR genes was due to VDR and not secondary, farnesoid X receptor (FXR)-directed effects, namely, lower Cyp7a1 expression in rat liver due to increased bile acid absorption, wildtype [fxr(+/+)] and FXR knockout [fxr(-/-)] mice were used to distinguish between VDR and FXR effects. With the exception that hepatic Sult2a1 mRNA was increased equally well by 1α(OH)D3 and 1,25(OH)2 D3 , 1α(OH)D3 treatment led to higher increases in hepatic Cyp7a1, renal Cyp24a1, VDR, Mdr1 and Mrp4, and intestinal Cyp24a1 and Trpv6 mRNA expression in both fxr(+/+) and fxr(-/-) mice compared to 1,25(OH)2 D3 treatment. A similar induction in protein expression and microsomal activity of hepatic Cyp7a1 and renal P-gp and Mrp4 protein expression was noted for both compounds. A higher intestinal induction of Trpv6 was observed, resulting in greater hypercalcemic effect following 1α(OH)D3 treatment. The higher activity of 1α(OH)D3 was explained by its rapid conversion to 1,25(OH)2 D3 in tissue sites, furnishing higher plasma and tissue 1,25(OH)2 D3 levels compared to following 1,25(OH)2 D3 -treatment. In conclusion, 1α(OH)D3 exerts a greater effect on VDR gene induction than equimolar doses of 1,25(OH)2 D3 in mice.


Asunto(s)
Calcitriol/farmacología , Hidroxicolecalciferoles/farmacología , Receptores de Calcitriol/genética , Receptores Citoplasmáticos y Nucleares/genética , Animales , Calcitriol/sangre , Calcitriol/farmacocinética , Calcio/sangre , Sistema Enzimático del Citocromo P-450/genética , Sistema Enzimático del Citocromo P-450/metabolismo , Hidroxicolecalciferoles/farmacocinética , Íleon/efectos de los fármacos , Íleon/metabolismo , Riñón/efectos de los fármacos , Riñón/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Proteínas de Transporte de Membrana/genética , Ratones , Ratones Noqueados , Fósforo/sangre , Sulfotransferasas/genética
20.
Biomed Chromatogr ; 27(12): 1714-9, 2013 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-23847087

RESUMEN

A rapid and sensitive liquid chromatography-tandem mass spectrometric method to evaluate the permeation and retention of calcipotriol in excised samples of pig, rat and mouse skin after application of a calcipotriol ointment has been developed and validated. After sample preparation of ointment, skin homogenate and receptor medium by liquid-liquid extraction, chromatography was performed on an Extend-C18 column using isocratic elution. Detection was by electrospray ionization in the negative ion mode using multiple-reaction monitoring of the precursor to product ion transitions of calcipotriol at m/z 411.1 → 393.5, and of lovastatin (internal standard) at m/z 403.2 → 101.2. The assay was linear in all matrices with LLOQs of 1, 0.5 and 40 ng/mL for skin homogenate, receptor medium and ointment samples respectively. In terms of the permeation profiles, it was found that calcipotriol permeated through all skins to only a limited extent over 20 h after application but was efficiently retained in all skins at a level at 20 h of between 40% (pig) and 60% (rat and mouse) of the applied dose. This indicates that calcipotriol ointment has the potential to provide sustained therapeutic benefit in the treatment of psoriasis with minimal systemic side effects.


Asunto(s)
Calcitriol/análogos & derivados , Cromatografía Liquida/métodos , Absorción Cutánea , Piel/metabolismo , Espectrometría de Masas en Tándem/métodos , Administración Tópica , Animales , Calcitriol/administración & dosificación , Calcitriol/análisis , Calcitriol/farmacocinética , Masculino , Ratones , Ratas , Ratas Wistar , Sensibilidad y Especificidad , Piel/química , Porcinos
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