RESUMEN
A simple, highly sensitive, and robust CE method applied to the determination of alendronate (ALN) was developed from matrices for tissue engineering, characterized by being highly complex systems. The novel method was based on the ALN derivatization with o-phthalaldehyde and 2-mercaptoethanol for direct ultraviolet detection at 254 nm. The BGE consisted of 20 mM sodium borate buffer at pH 10, and the electrophoretic parameters were optimized.The method was validated in terms of specificity, linearity, LOD, LOQ, precision, accuracy, and robustness. The LOD and LOQ obtained were 0.8 and 2.7 µg/mL, respectively. In addition, the method offers higher sensitivity and specificity compared to other CE and HPLC methods using UV-detectors, as well as low cost and simplicity that allowed the rapid and simple quantitation of ALN from bone regeneration matrices.
Asunto(s)
Alendronato/análisis , Portadores de Fármacos/química , Electroforesis Capilar/métodos , Espectrofotometría Ultravioleta/métodos , Alendronato/farmacocinética , Materiales Biocompatibles , Límite de Detección , Modelos Lineales , Reproducibilidad de los ResultadosRESUMEN
Osteomyelitis is a progressive destruction of bones caused by microorganisms. Inadequate or absent treatment increases the risk of bone growth inhibition, fractures, and sepsis. Among the diagnostic techniques, functional images are the most sensitive in detecting osteomyelitis in its early stages. However, these techniques do not have adequate specificity. By contrast, radiolabeled antibiotics could improve selectivity, since they are specifically recognized by the bacteria. The incorporation of these radiopharmaceuticals in drug-delivery systems with high affinity for bones could improve the overall uptake. In this work, long-circulating and alendronate-coated liposomes containing (99m)technetium-radiolabeled ceftizoxime were prepared and their ability to identify infectious foci (osteomyelitis) in animal models was evaluated. The effect of the presence of PEGylated lipids and surface-attached alendronate was evaluated. The bone-targeted long-circulating liposomal (99m)technetium-ceftizoxime showed higher uptake in regions of septic inflammation than did the non-long-circulating and/or alendronate-non-coated liposomes, showing that both the presence of PEGylated lipids and alendronate coating are important to optimize the bone targeting. Scintigraphic images of septic or aseptic inflammation-bearing Wistar rats, as well as healthy rats, were acquired at different time intervals after the intravenous administration of these liposomes. The target-to-non-target ratio proved to be significantly higher in the osteomyelitis-bearing animals for all investigated time intervals. Biodistribution studies were also performed after the intravenous administration of the formulation in osteomyelitis-bearing animals. A significant amount of liposomes were taken up by the organs of the mononuclear phagocyte system (liver and spleen). Intense renal excretion was also observed during the entire experiment period. Moreover, the liposome uptake by the infectious focus was significantly high. These results show that long-circulating and alendronate-coated liposomes containing (99m)technetium-radiolabeled ceftizoxime have a tropism for infectious foci.
Asunto(s)
Alendronato , Ceftizoxima/análogos & derivados , Liposomas , Compuestos de Organotecnecio , Osteomielitis , Alendronato/química , Alendronato/farmacocinética , Animales , Ceftizoxima/química , Ceftizoxima/farmacocinética , Liposomas/química , Liposomas/farmacocinética , Compuestos de Organotecnecio/química , Compuestos de Organotecnecio/farmacocinética , Osteomielitis/diagnóstico , Osteomielitis/metabolismo , Osteomielitis/patología , Ratas , Ratas WistarRESUMEN
This work reports the preparation of tablets by direct compression of sodium alendronate-loaded microparticles, using pullulan as filler. The tableting properties of pullulan were compared with those of microcrystalline cellulose and lactose. Pullulan tablets showed low variations in average weight, thickness and drug content. Moreover, these tablets exhibited a higher hardness compared to the other excipients. In vitro release studies showed that only pullulan was capable to maintain gastroresistance and release properties of microparticles, due to its ability to protect particles against damage caused by compression force. Thus, pullulan was considered an advantageous excipient to prepare tableted microparticles.
Neste trabalho relata-se a preparação de comprimidos pela compressão direta de micropartículas contendo alendronato de sódio, utilizando o pullulan como diluente. As propriedades dos comprimidos de pullulan foram comparadas com as de comprimidos de celulose microcristalina e de lactose. Os comprimidos de pullulan mostraram baixa variação no peso médio, espessura e teor. Por outro lado, estes apresentaram altos valores de dureza comparados aos preparados com os outros excipientes. Através dos estudos de liberação in vitro pode-se observar que apenas o pullulan foi capaz de manter a gastrorresistência e as propriedades de liberação das micropartículas, o que se deve à sua capacidade de proteger as partículas do dano causado pela força de compressão. Dessa forma, o pullulan foi considerado um excipiente vantajoso para a preparação de comprimidos microparticulados.
Asunto(s)
Polisacáridos/clasificación , Comprimidos/farmacocinética , Alendronato/farmacocinética , Excipientes/clasificación , Trituración de Residuos SólidosRESUMEN
The bioequivalence and upper digestive tract transit time of a drinkable solution of 70 mg/100 mL alendronate was compared to reference tablets. A randomized, single- dose, two-way crossover study of the rate of urinary recovery of alendronate during 36 h (AE((0-36 h))) by HPLC, in 104 healthy young male volunteers, showed that AE((0-36 h)) and the maximum excretion rate (R (max)) were within the accepted range of bioequivalence 81.8-105.7 and 81.7-106.2, respectively. To characterize the oesophageal passage time of the two alendronate formulations, we performed a randomized, controlled study, in 24 healthy men and women (mean 52 years old), who took the formulations standing or lying down, by an X-ray video deglutition system. When taken in the standing position, both formulations had equal mean transit times from mouth to stomach and tablet disintegration but data dispersion was significantly smaller with the liquid form. When taken in lying position, drinkable alendronate had shorter and less variable median transit times compared to the tablets. These results show that the drinkable alendronate formulation is bioequivalent to the tablets and may be advantageous in patients in whom the transit or disintegration of the tablets is impaired.
Asunto(s)
Alendronato/farmacocinética , Deglución , Tracto Gastrointestinal Superior/metabolismo , Administración Oral , Adulto , Alendronato/administración & dosificación , Disponibilidad Biológica , Química Farmacéutica , Estudios Cruzados , Femenino , Humanos , Masculino , Persona de Mediana Edad , Equivalencia TerapéuticaRESUMEN
Bisphosphonates (BPs) inhibit osteocyte and osteoblast apoptosis via opening of connexin (Cx) 43 hemichannels and activating the extracellular signal regulated kinases ERKs. Previously, we hypothesized that intracellular survival signaling is initiated by interaction of BPs with Cx43. However, using whole cell binding assays with [(3)H]-alendronate, herein we demonstrated the presence of saturable, specific and high affinity binding sites in the Cx43-expressing ROS 17/2.8 osteoblastic cells, authentic osteoblasts and MLO-Y4 cells expressing Cx43 or not, as well as in HeLa cells lacking Cx43 expression and ROS 17/2.8 cells pretreated with agents that disassemble Cx channels. In addition, both BPs and the PTP inhibitor Na(3)VO(4) increased proliferation of cells expressing Cx43 or not. Furthermore, although BPs are internalized and inhibit intracellular enzymes in osteoclasts, whether the drugs penetrate non-resorptive bone cells is not known. To clarify this, we evaluated the osteoblastic uptake of AF-ALN, a fluorescently labeled analog of alendronate. AF-ALN was rapidly internalized in cells expressing Cx43 or not indicating that this process is not mediated via Cx43 hemichannels. Altogether, these findings suggest that although required for triggering intracellular survival signaling by BPs, Cx43 is dispensable for cellular BP binding, its uptake, as well as the proliferative effects of these agents.
Asunto(s)
Alendronato/farmacocinética , Apoptosis/efectos de los fármacos , Conservadores de la Densidad Ósea/farmacocinética , Proliferación Celular/efectos de los fármacos , Conexina 43/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Osteocitos/metabolismo , Alendronato/farmacología , Animales , Conservadores de la Densidad Ósea/farmacología , Conexina 43/genética , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Células HeLa , Humanos , Canales Iónicos/metabolismo , Ratones , Osteocitos/citología , Vanadatos/farmacologíaRESUMEN
Spray-dried powders for lung delivery of sodium alendronate (SA) were prepared from hydroalcoholic solutions. Formulations display geometric particle size below to 12 µm and spherical shape associated to a hollow structure. The addition of leucine and ammonium bicarbonate leads to porous particles with rough surfaces. The tapped density ranges from 0.016 to 0.062 g/cm(3), decreasing with the increase of the leucine concentration. For all formulations, the calculated aerodynamic diameters are lower than 5 µm. The in vitro aerodynamic evaluation shows that all powders present a high emitted fraction of 100%, a fine particle fraction ranging from 34.4% to 62.0% and an alveolar fraction ranging from to 23.7% to 42.6%. An optimized sample was evaluated regarding sodium alendronate acute pulmonary toxicity and lung bioavailability. The bronchoalveolar lavage study shows that the intratracheal administration of sodium alendronate dry powder and sodium alendronate aqueous solution do not induce significant increases of lung toxicity indicators as compared with the positive control. Moreover, the intratracheal administration of sodium alendronate dry powder results in a 6.23 ± 0.83% bioavailability, a 3.5-fold increase as compared to oral bioavailability. Finally, these results suggest that sodium alendronate pulmonary delivery could be a new and promising administration route.
Asunto(s)
Alendronato/administración & dosificación , Alendronato/farmacocinética , Pulmón/metabolismo , Administración por Inhalación , Aerosoles/química , Alendronato/toxicidad , Alendronato/orina , Animales , Bicarbonatos/química , Disponibilidad Biológica , Líquido del Lavado Bronquioalveolar/química , Química Farmacéutica/métodos , Perros , Etanol/química , Instilación de Medicamentos , Insuflación , L-Lactato Deshidrogenasa/metabolismo , Leucina/química , Pulmón/efectos de los fármacos , Masculino , Microscopía Electrónica de Rastreo , Tamaño de la Partícula , Excipientes Farmacéuticos/química , Polvos , Proteínas/análisis , Ratas , Ratas Wistar , Gravedad Específica , Propiedades de SuperficieRESUMEN
Sodium alendronate, an antiresorptive drug, primarily used in the treatment of osteoporosis was encapsulated in blended microparticles composed of Eudragit S100 and Methocel K15M. The micropowder obtained by spray-drying technique was characterized in terms of its morphology, particle size, encapsulation efficiency and in vitro drug release. In vivo studies were carried out in order to evaluate the pharmacodynamic effect and the ulcerogenic activity of sodium alendronate-loaded microparticles after oral administration in rats. Drug encapsulation efficiency was close to 80% and particle mean diameter of 13.8 microm. SEM analysis showed spherical collapsed shape particles with smooth surface. At pH 1.2, in vitro experiments showed that <10% of the drug was released from the microparticles. At pH 6.8, the microparticles were able to prolong the sodium alendronate release for 12h. In vivo experiments carried out in ovariectomized rats showed bone mineral density significantly higher for the sodium alendronate-loaded microparticles than for the negative control groups. Furthermore, the microencapsulation of the drug showed a significant reduction in the ulcerative lesion index. In conclusion, the blended microparticles are excellent oral carriers for sodium alendronate since they were able to maintain the drug antiresorptive effect and to reduce the gastrointestinal drug toxicity.
Asunto(s)
Alendronato/administración & dosificación , Conservadores de la Densidad Ósea/administración & dosificación , Resorción Ósea/prevención & control , Portadores de Fármacos/química , Microesferas , Alendronato/química , Alendronato/farmacocinética , Animales , Disponibilidad Biológica , Densidad Ósea , Conservadores de la Densidad Ósea/química , Conservadores de la Densidad Ósea/farmacocinética , Huesos/química , Huesos/metabolismo , Portadores de Fármacos/síntesis química , Ovariectomía , Tamaño de la Partícula , Polímeros , Ratas , Ratas Wistar , Úlcera Gástrica/inducido químicamente , Propiedades de SuperficieRESUMEN
Sodium alendronate is an effective treatment for osteoporosis, but its oral administration is associated with adverse gastrointestinal effects. The aim of this work was to evaluate gastroresistant sodium alendronate-loaded microparticles prepared by spray-drying using Eudragit S100 or a blend of Eudragit S100/Methocel E4M. Both formulations presented high encapsulation efficiencies, mean diameters below 17 microm, and similar collapsed shape. Dissolution experiments showed good gastro-resistance for the microparticles at pH 1.2. At pH 6.8, the blended microparticles retarded the drug release. In vivo studies showed that the formulations were able to protect the rat stomachs against ulcer formation by sodium alendronate. In conclusion, the microparticles seems to be promising oral carriers for sodium alendronate.
Asunto(s)
Alendronato/efectos adversos , Mucosa Gástrica/efectos de los fármacos , Mucosa Intestinal/efectos de los fármacos , Alendronato/síntesis química , Alendronato/farmacocinética , Animales , Composición de Medicamentos , Femenino , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patología , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Ratas , Ratas WistarRESUMEN
The aim of this study was to evaluate the influence of erbium:yttrium-aluminum-garnet (Er:YAG) laser compared with traditional treatment on dentin permeability to calcitonin and sodium alendronate. Forty bovine roots were sectioned and divided into eight groups. Groups 1 and 2 (G1/G2) were immersed in saline solution; G1T/G2T were immersed in ethylene diamine tetra-acetic acid plus sodium lauryl ether sulfate (EDTA-T) and sodium hypochlorite (NaOCl); G1I/G2I were irradiated with Er:YAG laser (2.94 microm, 6 Hz, 40.4 J/cm(2)); G1TI/G2TI were immersed in EDTA-T, NaOCl and subjected to Er:YAG irradiation. After 4 h the radioactivity of the saline solution was measured. Statistical analysis revealed a significant difference (P < 0.05) when the groups treated with EDTA-T and NaOCl followed by Er:YAG laser irradiation were compared with the groups treated with EDTA-T only and with the groups that received no treatment. Er:YAG laser associated with traditional procedures significantly increased the diffusion of calcitonin and sodium alendronate through dentin. All groups showed calcitonin and sodium alendronate diffusion.
Asunto(s)
Alendronato/uso terapéutico , Conservadores de la Densidad Ósea/uso terapéutico , Calcitonina/uso terapéutico , Láseres de Estado Sólido/uso terapéutico , Traumatismos de los Dientes/tratamiento farmacológico , Traumatismos de los Dientes/cirugía , Alendronato/farmacocinética , Animales , Conservadores de la Densidad Ósea/farmacocinética , Calcitonina/farmacocinética , Bovinos , Dentina/metabolismo , Técnicas In Vitro , Permeabilidad , Traumatismos de los Dientes/metabolismoRESUMEN
OBJECTIVE: The aim of this study was to test the bioequivalence of two alendronate tablets (CAS 121268-17-5; Marvil 10 and Marvil 70 as test formulations, in short "test"; reference formulation, in short "reference") in vitro and in vivo in healthy adult male subjects and to describe a mode for researching the bisphosphonate oral formulation pharmaceutical quality. METHODS: Two dissolution tests with 10-mg and 70-mg alendronate tablets, a preliminary clinical test with 10-mg tablets (n = 10) and a bioequivalence study with 70-mg tablets (n = 23) were performed. Clinical studies were single-dose, open, cross-over, randomized, including a four-week wash-out period. Alendronate was assessed by HPLC in urine after 6 (UE6) and 24 (UE24) h post-intake. In all the experiments the reference was the one that had proved efficacy and safety in international regulatory clinical trials. RESULTS: The dissolution test showed a comparable release profile between reference and test, of both, the 10-mg and 70-mg tablet, the difference (f1) and similarity (f2) factors being within the acceptance values. The clinical trials showed great variability in urinary recovery, from one third the average figure up to 2-3 fold. The amount recovered with the 70-mg tablet was 11-15 fold higher than with the 10-mg tablets, suggesting higher (test/reference) was found to be 72-122% for UE24, and when analyzed in individuals with apparent steady bone metabolism during the wash-out period (n = 19), it was 86-137%. Both margins are considered acceptable in view of the particular kinetic and dynamic features of bisphosphonates, their very high inter- and intra-individual variability, extremely low absorption, time-changeable bone compartment, high margin of safety and long-term achievable therapeutic benefits. CONCLUSION: Test is bioequivalent to reference.
Asunto(s)
Alendronato/química , Alendronato/farmacocinética , Alendronato/efectos adversos , Animales , Química Farmacéutica , Cromatografía Líquida de Alta Presión , Estudios Cruzados , Método Doble Ciego , Masculino , Control de Calidad , Ratas , Solubilidad , Comprimidos , Equivalencia TerapéuticaRESUMEN
Mechanical loads are one of the main factors that affect bone remodelling process. This phenomenon is widely applied to the study of prosthetic replacement, for example hip prosthesis. Elderly people are the most common patient to receive a hip replacement surgery. Alendronate is a drug that is being used to increase bone mineral content in patients with poor bone quality. This work uses a mechanical model based on damage mechanics, which considers bone's porosity as the damage variable, a mechanical stimulus associated thermodynamically to this variable, a damage criterion and an evolution damage law. Our approach simulates the degree of mineralization changes as well as the decrease of BMU activation frequency due to Alendronate doses. The biological changes generated by the drug directly affect the damage's evolution law. As a first approach the two biological parameters to be modeled are the surface of remodelling as well as the degree of mineralization (ash fraction) of the bone. Results show a good correlation with experimental data from alendronate's treatments for short term simulations (1-2 years).
Asunto(s)
Alendronato/uso terapéutico , Artroplastia de Reemplazo de Cadera , Remodelación Ósea , Simulación por Computador , Análisis de Elementos Finitos , Osteoporosis/tratamiento farmacológico , Alendronato/farmacocinética , Fenómenos Biomecánicos , Densidad Ósea , Remodelación Ósea/efectos de los fármacos , Remodelación Ósea/fisiología , Humanos , Modelos Biológicos , Modelos TeóricosRESUMEN
In nuclear medicine radiation absorbed doses are important in the patient's risk/benefit evaluation and are estimated by means of biological and complex mathematical models. The biological model includes radiopharmacokinetic data obtained through blood and urine samples taken at given intervals. A useful mathematical model is the MIRD model and with the value for the time of residence tau the MIRDOSE3 computer program uses several anatomic models and calculates radiation absorbed dose for 25 organs. At the Radiopharmacy Unit of the Nuclear Medicine Department at INCMNSZ two new bone seeking radiopharmaceuticals, 99mTc-ABP and 188Re-ABP, have been designed, characterized and animal-tested. Radiopharmaceutical parameters and sequential scanning were obtained for diagnostic 99mTc-ABP in 10 normal subjects and the aim was to use % 24 hour urine elimination and % bone uptake to calculate radiation absorbed dose and extrapolate the values to 188Re-ABP as the basis for a therapeutic treatment. 99mTc-ABP was eliminated in women's urine 63.2 +/- 7.3%/activity and 70 +/- 11%/activity in men. In women 36.8 +/- 7.3% of the radiopharmaceutical remains on the bone surface and in men 30 +/- 11%. ROIs were drawn on the images and the time-integrated renal cpm/pixel/ROI gave a residence time tau = 0.52 h. Cumulative bone activity A calculated with A = 1.443 (T1/2) A0 was 2358 +/- 469 MBq h for women and 1923 +/- 707 MBq h for men. Residence time tau was 3.19 +/- 0.63 h in women and 2.6 +/- 0.95 h in men. Radiation absorbed dose for the whole body was 0.0020 +/- 0.0004 mGy/MBq for women and 0.0013 +/- 0.0005 mGy/MBq for men. For women's bone marrow it was 0.0063 +/- 0.0013 mGy/MBq and for men 0.0041 +/- 0.0015 mGy/MBq. 188Re-ABP behaves as 99mTc-ABP therefore, the effective dose given by 188Re, a beta emitter, would be for women 0.0936 mSv/MBq and for men 0.0608 mSv/MBq. These characteristics and the radionuclidic characteristics of 188Re indicate that 188Re-ABP might be a good bone metastases pain palliation radiopharmaceutical.
Asunto(s)
Alendronato , Compuestos de Organotecnecio , Dosis de Radiación , Radiofármacos , Adulto , Alendronato/farmacocinética , Alendronato/orina , Algoritmos , Huesos/diagnóstico por imagen , Femenino , Humanos , Riñón/diagnóstico por imagen , Masculino , Compuestos de Organotecnecio/farmacocinética , Compuestos de Organotecnecio/orina , Radiometría/métodos , Cintigrafía , Radiofármacos/farmacocinética , Radiofármacos/orina , Distribución TisularRESUMEN
Etidronate and medronate have been labelled with technetium-99m (99mTc-HEDP, 99mTc-MDP) for bone scanning and, with rhenium-188 (188Re-HEDP) to palliate the pain resulting from bone metastases. The objective of this study was to label alendronate, ABP, a new bisphosphonate, with SnF2-reduced-188Re. The reagents for the 5 mg ABP kit were SnF2, KReO4 and gentisic acid at acid pH. The chemical, spectroscopic and microscopic characteristics, quality control, rat bone uptake of [188Re]Re-ABP and similarities with 99mTc-ABP are presented. We conclude that this is a promising new radiopharmaceutical for bone metastases pain palliation.
Asunto(s)
Alendronato/análogos & derivados , Neoplasias Óseas/radioterapia , Neoplasias Óseas/secundario , Radioisótopos/uso terapéutico , Radiofármacos/síntesis química , Radiofármacos/uso terapéutico , Renio/uso terapéutico , Alendronato/síntesis química , Alendronato/farmacocinética , Alendronato/uso terapéutico , Animales , Humanos , Indicadores y Reactivos , Cuidados Paliativos , Radioisótopos/farmacocinética , Radiofármacos/farmacocinética , Ratas , Ratas Wistar , Renio/farmacocinética , Distribución TisularRESUMEN
La osteoporosis es un problema de salud pública de alta incidencia en la población femenina. Afortunadamente en la actualidad se dispone en el mercado de medicamentos que corrigen este defecto previniendo así sus consecuencias por todos ya conocidas, obviamente junto con dieta y ejercicio. Uno de estos medicamentos es el alendronato sódico que ha demostrado gran eficacia en el tratamiento de esta entidad; en la literatura científica se han descrito efectos adversos gastrointestinales importantes los cuales se pueden prevenir con medidas como tomar el alendronato en ayunas acompañado de un vaso con agua completo, no recostarse inmediatamente se ingiera el medicamento y no tomarlo con café o leche. Para evaluar si estas medidas eran seguidas por poblaciones que no hicieran parte de un estudio clínico en donde se controlaran una serie de variables, se realizó el estudio ®Kaiser¼ a través de un cuestionario que se obtuvo de una base de datos en California (EUA) en 981 mujeres que habían tomado alendronato. En el presente artículo se revisan los resultados obtenidos en esta población sobre la adherencia al tratamiento
Asunto(s)
Humanos , Alendronato/administración & dosificación , Alendronato/uso terapéutico , Alendronato/farmacología , Alendronato/farmacocinéticaRESUMEN
OBJECTIVE: To compare the quality of bone scans obtained with 99mTc-ABP, a new radiopharmaceutical, and 99mTc-MDP. MATERIAL AND METHODS: A comparative study within subjects was done in nine healthy volunteers, 5 female and 4 male, aged 23 to 39 years. The dose for both radiopharmaceuticals was 740 MBq; radiopharmacokinetic parameters were determined and a whole body bone scan was taken with a MultiSpect 2 gamma camera two hours post administration with a wash-out period of 72 hours between preparations. The images were independently evaluated by three nuclear medicine physicians by drawing of regions of interest (ROIs) on vertebrae, ribs, femur, sternum, joints and skull. Ratios bone/soft tissue were obtained drawing ROIs on several bones. The kappa test and the Wilcoxon rank test were used for statistical comparisons. RESULTS: The agreement on the quality of the images with Tc-ABP and Tc-MDP was fair (kappa 0.4). The femur/soft tissue ratio had a normal distribution and the Wilcoxon test showed no statistical difference between preparations. CONCLUSIONS: Even though bone uptake was higher and faster with Tc-ABP, the quality of the scans obtained with either radiopharmaceutical was similar. We recommend the use of Tc-ABP as a routine bone scan agent because of its less radiation exposure to the patient.