Effects of ergosteroside combined risedronate on fracture healing and BMP-2, BMP-7 and VEGF expression in rats

Purpose To evaluate the effect of ergosterol combined with risedronate on fracture healing. Methods Sixty male Sprague Dawley fracture model rats were assigned into group A (n=20), group B (n=20), and group C (n=20) at random. All rats were fed by gavage until their sacrifice as it follows: group A with ergosteroside and risedronate, group B with risedronate, and group C with saline solution. At weeks 2 and 4, 10 rats of each group were sacrificed. Healing effect and bone tissue changes in the fractures site were assessed by using hematoxylin and eosin stain histology. Enzyme-linked immunosorbent assay was used to detect the expression of serum bone morphogenetic protein-2 (BMP-2), bone morphogenetic protein-7 (BMP-7), and vascular endothelial growth factor (VEGF). Reverse transcriptase polymerase chain reaction was applied to detect the expression of osteoprotegerin (OPG) mRNA, osteocalcin (OCN) mRNA and core-binding factor subunit-?1 (CBF-?1) mRNA. Results In terms of serum BMP-2, BMP-7, and VEGF expression at weeks 2 and 4 after gavage, group A < group B < group C (P<0.05). At week 4 after gavage, serum VEGF expression in the three groups harbored positive relationship with serum BMP-2 and BMP-7 expression (P<0.05). Regarding serum OPG, OCN and CBF-?1 mRNA expression at weeks 2 and 4 after gavage, group A

Plasmodium falciparum parasites overexpressing farnesyl diphosphate synthase/geranylgeranyl diphosphate synthase are more resistant to risedronate.

Farnesyl diphosphate synthase/geranylgeranyl diphosphate synthase (FPPS/GGPPS) is a key enzyme in the synthesis of isoprenic chains. Risedronate, a bisphosphonate containing nitrogen (N-BP), is a potent inhibitor of blood stage Plasmodium. Here, we show that P. falciparum parasites overexpressing FPPS/GGPPS are more resistant to risedronate, suggesting that this enzyme is an important target, and bisphosphonate analogues can be used as potential antimalarial drugs.

Plasmodium falciparum parasites overexpressing farnesyl diphosphate synthase/geranylgeranyl diphosphate synthase are more resistant to risedronate

Farnesyl diphosphate synthase/geranylgeranyl diphosphate synthase (FPPS/GGPPS) is a key enzyme in the synthesis of isoprenic chains. Risedronate, a bisphosphonate containing nitrogen (N-BP), is a potent inhibitor of blood stage Plasmodium. Here, we show that P. falciparum parasites overexpressing FPPS/GGPPS are more resistant to risedronate, suggesting that this enzyme is an important target, and bisphosphonate analogues can be used as potential antimalarial drugs.

Polymer-ceramic Monolithic In-Needle Extraction (MINE) device: Preparation and examination of drug affinity.

Polymer-ceramic materials were placed in the in-needle device. Polymer-ceramic Monolithic In-Needle Extraction (MINE) device is an extraction device used in sample preparation step but, on the other hand, it can be a tool for examination of interactions between potential antiresorptive drugs and bones. MINE device was used as tool for determination of bisphosphonate affinity to hydroxyapatite. Spectra of prepared materials containing different proportion of the ceramic part were performed with the use of Fourier transform infrared spectroscopy. The extraction of sodium risedronate as standard compound from simulated body fluids was carried out by pumping liquid samples through the MINE device. The amount of sodium risedronate in solutions was examined using UV-VIS spectroscopy. The sorption results of sodium risedronate obtained for monolithic materials containing different amount of hydroxyapatite were compared to the values determined for pure (bulk) hydroxyapatite. Sorption capacity for polymer-ceramic materials placed in the in-needle extraction device was about 0.39mg of sodium risedronate. The complete desorption process was carried out at the level over 95% using various eluents. The results of sorption-desorption experiments allow to deduce on the affinity of sodium risedronate to the ceramic part of sorbent (hydroxyapatite).

Estudio PERSIRIS: estudio observacional, postautorización, prospectivo, para evaluar la persistencia al tratamiento con risedronato mensual en mujeres con osteoporosis / PERSIRIS study: observational study, postmarketing, prospective, to evaluate the persistence to treatment with monthly risedronate in women with osteoporosis

OBJETIVO: Evaluar la persistencia del tratamiento con risedronato mensual y conocer los motivos de persistencia y no persistencia terapéutica y el perfil de las pacientes no persistentes. DISEÑO: Estudio observacional, postautorización y prospectivo. Emplazamiento: Consultas de atención primaria, traumatología, reumatología, ginecología y geriatría de Cataluña. PARTICIPANTES: Mujeres con osteoporosis en tratamiento con risedronato mensual que previamente hubiesen abandonado el tratamiento con bifosfonato semanal. MEDICIONES PRINCIPALES: Porcentaje de pacientes bajo risedronato mensual persistentes al año de su prescripción, motivos de persistencia y no persistencia y perfil de pacientes no persistentes en relación a datos biodemográficos, datos clínicos y factores de riesgo de fractura. RESULTADOS: Doscientos ochenta y nueve pacientes valorables con una edad media de 68,3. A los 12 meses de inicio de risedronato mensual, un 58,1% de las pacientes persistía con el tratamiento. Motivos más frecuentes de abandono: miedo a tener efectos secundarios y creencia de que la enfermedad es propia de la edad. Motivos de persistencia destacables: comodidad/facilidad y posología. Se observaron diferencias significativas entre pacientes persistentes y no persistentes en relación a: situación laboral, número de tratamientos concomitantes y talla; sin embargo los resultados de posibles factores asociados deben contextualizarse dentro de las características del estudio y la diferencia de talla no parece clínicamente relevante. CONCLUSIONES: La administración de pautas terapéuticas más cómodas, como risedronato mensual en la osteoporosis, podría facilitar la persistencia en los pacientes mejorando la efectividad del fármaco. Sin embargo, en dicha persistencia pueden influir también variables biodemográficas y clínicas de diversa índole

OBJECTIVE: To assess the persistence of treatment with monthly risedronate and know the reasons of persistence and nontherapeutic persistence and the profile of the non-persistent patients. Desing: Observational, postmarketin and prospective study. LOCATION: Primary care, traumatology, rheumatology, gynecology and geriatrics of Catalonia. PARTICIPANTS: Women with osteoporosis treated with monthly risedronate that previously had abandoned weekly bisphosphonate therapy. MAIN MEASUREMENTS: Percentage of patients on persistent monthly risedronate year of their prescription, reasons for persistent and non persistent and profile of non persistent patients in relation to biodemographic data, clinical data and risk factors for fracture. RESULTS: 289 evaluable patients with a mean age of 68.3. At 12 months of initiation with monthly risedronate, 58.1% of patients remained on treatment. Most frequent reasons for leaving: fear of having side effects and belief that the disease is typical of the age. Reasons remarkable persistence: comfort/ease and dosage. Significant differences were observed between persistent and non-persistent patients relative to: employment status, number of concomitant therapy and height; however the results of possible associated factors must be contextualized within the study characteristics and the difference in size does not seem clinically relevant. CONCLUSIONS: The administration of therapeutic patterns more comfortable as monthly risedronate in osteoporosis, could facilitate persistence in patients improving the effectiveness of the drug. However in that persistence can also influence biodemographic and clinical variables and diverse of various kinds

On-cartridge derivatization coupled with solid-phase extraction for the ultra-sensitive determination of minodronic acid in human plasma by LC-MS/MS method.

Minodronic acid (MA) is a third-generation bisphosphonate (BP). Its high potency allows lower doses to be administered in clinical settings compared with other BPs, which results in extremely low systemic exposure. Therefore, it is essential to develop an ultra-sensitive bioassay for pharmacokinetics studies of MA. In this work, we used on-cartridge derivatization of MA with trimethylsilyldiazomethane to extract MA from plasma samples and improve its LC-MS/MS behavior. The reaction produced a known derivative, tetramethylated MA, and a novel derivative, pentamethylated MA (PMMA). PMMA exhibited a better signal-to-noise ratio, and was monitored for the quantification of MA. However, the derivatization yield of d4-PMMA was much lower and more variable than that of PMMA, which decreased the effectiveness of its correction function as an internal standard. Therefore, a two-cycle derivatization approach was introduced to increase its yield and improve the reproducibility. The calibration curves of MA showed good linearity over the range of 10.0-1000 pg/mL. A lower limit of quantification of 10.0 pg/mL was achieved with acceptable precision (<10.5%) and accuracy (5.0%). The intra- and inter-batch precision of quality control samples was <9.5%, and the accuracy ranged from -2.8% to 0.6%. The stability results showed that MA was stable in human plasma for 6h at room temperature (25°C), for 115 days at -20°C, during three freeze/thaw cycles (from -20°C to 25°C), and in post-preparative samples for 24h at 4°C. The method was successfully used to characterize the pharmacokinetic profile of MA following an oral dose of 1.0mg MA hydrate to healthy volunteers (n=12). The proposed derivatization procedure was also extended to measure other BPs (risedronic acid and zoledronic acid) in human plasma at low pg/mL.