Clinical observation of modified Shenqi Decoction in the treatment for patients with early-to-middle stage nontraumatic osteonecrosis of femoral head / 中成药

AIM To investigate the clinical therapeutic effects of modified Shenqi Decoction in treating earlyto-middle stage nontraumatic osteonecrosis of femoral head (NONFH) due to kindey deficiency and blood stasis syndrome,and its impacts on serum TNF-α,CRP,NO,SOD as well.METHODS Totally,104 cases of eligible patients were randomly divided into traditional Chinese medicine (TCM) group,chemical medicine group and TCM combined with chemical medicine group,38 cases in each group,for a three-month course of treatment.The TCM group was dosed with modified Shenqi Decoction,the chemical medicine group with sodium alendronate,and the TCM combined with chemical medicine group with both modified Shenqi Decoction and sodium alendronate.The Harris SF-36,SF-36,FPS-R and TCM symptoms assessment were applied to estimating the efficacy of three groups before and after the treatment.So were the check of the serum TNF-α,CRP,NO,SOD levels,and rates of efficiency after treatments and six-month follow-ups,and incidence of adverse reactions during the treatment among all the three groups.RESULTS The efficiency rates were found to be in the following sequence:the chemical medicine group (76.5％) ＜ the TCM group (83.8％) ＜ the TCM combined with chemical medicine group (97.2％) (P ＜ 0.05).The TCM combined with chemical medicine group had its post-treatment scores of Harris SF-36,FPS-R,FPS-R,TCM symptom and the serum TNF-α,CRP,NO,SOD levels significantly improved as compared with other two groups (P ＜ 0.05).And the revealed incidence of adverse reactions was ranked as the TCM group (2.7％) ＜ the TCM combined with chemical group (30.6％) ＜ the chemical medicine group (70.6％) (P ＜ 0.05).CONCLUSION Modified Shenqi Decoction is superior to sodium alendronate in the treatment of NONFH due to kidney deficiency and blood stasis syndrome for its better performance in both the efficacy and the incidence of adverse reactions,and its synergistic effect with use of sodium alendronate may associate with its capability in offsetting the adverse reactions of sodium alendronate.

Formulation of gastroresistant tablets containing sodium alendronate-loaded blend microparticles / Formulação de comprimidos gastro-resistentes que contêm na mistura micropartículas carregadas de alendronato de sódio

Sodium alendronate is an antiresorptive drug used for the treatment of postmenopausal osteoporosis. However, its oral administration is associated with low bioavailability and gastroesophageal irritation. This work aimed at developing tablets containing sodium alendronate-loaded microparticles by direct compression to achieve a safe and effective form. The parameters evaluated were average weight, hardness, thickness and drug content. In vitro release tests were carried out using simulated gastric and intestinal fluids, and the profiles were analyzed through the Korsmeyer-Peppas mono- or biexponential dependent approaches. Tablets presented adequate average weight, thickness, good mechanical properties and drug content close to 100%. Moreover, the formulation released less than 11% of sodium alendronate in gastric fluid, exhibiting a good gastroresistance. At pH 6.8, almost 100% of the drug was released in 12h, showing a prolonged profile. The mathematical modeling indicated that the experimental data was better fitted to the biexponential equation. Furthermore, a good correlation coefficient was obtained for the Korsmeyer-Peppas model and the release exponent suggested that the drug dissolution was driven by anomalous transport. In conclusion, the microparticulated tablets can be considered a promising alternative for oral delivery of sodium alendronate...

O alendronato de sódio é um fármaco da classe dos bisfosfonatos, comumente utilizado no tratamento da osteoporose pós-menopausa. Entretanto, sua administração oral está associada à baixa biodisponibilidade e irritação gastroesofágica. Este trabalho objetivou o desenvolvimento de comprimidos contendo micropartículas de alendronato de sódio por compressão direta, a fim de obter uma forma segura e eficaz. Os parâmetros avaliados foram peso médio, dureza, espessura e teor de fármaco. Estudos de liberação in vitro foram realizados utilizando fluído gástrico e intestinal simulado e o perfil de liberação foi analisado pelos modelos matemáticos de Korsmeyer-Peppas, mono- e biexponencial. Os comprimidos apresentaram peso médio adequado, espessura, dureza e teor próximo a 100%. Além disso, a formulação liberou menos de 11% do fármaco em fluído gástrico, mostrando uma boa gastrorresistência. Em pH 6,8, em torno de 100% do fármaco foram liberados em 12 h, apresentando liberação prolongada. A modelagem matemática indica que os resultados seguem a equação biexponencial. Pela análise do expoente de liberação obtido no modelo de Korsmeyer-Peppas sugere-se que a dissolução do fármaco ocorre por transporte anômalo. Concluindo, a preparação dos comprimidos microparticulados pode ser considerada uma alternativa promissora para a liberação oral do alendronato de sódio...

Pullulan: an advantageous natural polysaccharide excipient to formulate tablets of alendronate-loaded microparticles

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.

Efeito do extrato de Ginkgo biloba L., Ginkgoaceae, na osteoporose induzida em ratas Wistar / Effect of the aqueous extract of Ginkgo biloba L., Ginkgoaceae, in induced osteoporosis in Wistar rats

Este trabalho investigou os efeitos do tratamento por vinte dias com extrato de Ginkgo biloba (EGb) na osteoporose induzida por glicocorticóides. Foram utilizadas 36 ratas divididas em seis grupos (n=6): Controle, osteoporose, controle positivo, EGb1 (14 mg EGb/mg/kg/dia), EGb2 (28 mg EGb/kg/dia) e EGb3 (56 mg EGb/kg/dia). Os tratamentos foram realizados por vinte dias, após a indução da osteoporose. Após a eutanásia foram removidos o fêmur e a mandíbula de todos os animais. A mandíbula esquerda foi radiografada digitalmente para avaliação da cortical e do suporte ósseo periodontal (SOP). A análise histomorfométrica foi realizada no fêmur e mandíbula direitos. O grupo controle foi comparado ao grupo osteoporose (Teste t de Student) e os demais grupos foram submetidos a ANOVA, seguido do teste post-hoc de Dunnett. Houve redução significava do SOP mesial, percentual ósseo alveolar (POA) mandibular, percentual ósseo trabecular (POT) do fêmur no grupo osteoporose. Houve aumento do SOP mesial no grupo controle positivo, EGb2 e EGb3. O POA da mandíbula e o POT do fêmur aumentaram nos grupos EGb2 e EGb3. O EGb nas doses de 28 mg/kg e 56 mg/kg recuperou de forma significativa o SOP mesial, o POA da mandíbula e o POT do fêmur.

The objective of this study was to investigate the effect of a 20 day treatment with extract of Ginkgo biloba (EGb) in glucocorticoid-induced-osteoporosis. 36 rats were divided into six groups (n=6): control, osteoporosis, positive control, EGb1 (14 mg EGb/kg/day), EGb2 (28 mg EGb/kg/day) and EGb3 (56 mg EGb/kg/day). Treatments were conducted for twenty days, after osteoporosis was induced. Following euthanasia the femur and mandible of all animals were removed. The left mandible was radiographed to evaluate the cortical and the periodontal bone support (PBS). The histomorphometric analysis was performed on the right mandible and the right femur. The control group was compared with the osteoporosis group (Student's t-test). The other groups were analyzed through ANOVA test followed by Dunnett post-hoc test. There was a significantly reduction in the mesial PBS, in the percentage of the alveolar bone (PAB) of the mandible and percentage of the trabecular bone (PTB) of the femur in the osteoporosis group. There was an increase in the mesial PBS in the positive control group, EGb2 and EGb3. The PAB of the mandible and the PTB of the femur increased in the EGb2 and EGb3 groups. The EGb in the 28 mg/kg and 56 mg/kg doses were effective to increase the mesial PBS, the PAB of the mandible and the PTB of the femur.

Estudio multicéntrico para evaluar la efectividad y seguridad de una presentación de alendronato de sodio en cápsulas de gelatina blanda (Neobon 70 ®), en el tratamiento de osteoporosis posmenopáusica / Multicentre study to evaluate the effectiveness and security of sodium alendronate in a soft gelatin capsules in the treatment of postmenopausal osteoporosis

Objetivos: el objetivo del estudio fue evaluar la respuesta al tratamiento y seguridad del alendronato de sodio en una presentación de cápsulas blandas de gelatina (Neobon 70 ®), en mujeres posmenopáusicas con osteoporosis u osteopenia. Métodos: estudio clínico multicéntrico abierto a un año de tratamiento en mujeres postmenopáusicas. Las pacientes fueron asignadas a recibir 70 mg cada semana de alendronato sódico en presentación de cápsulas de gelatina blanda. Los desenlaces primarios fueron la densidad mineral ósea medida por DEXA y el valor plasmático del C-Telopéptido. La condición ósea fue evaluada por densitometría al inicio del estudio, al mes 6 y a los 12 meses de tratamiento. La resorción ósea fue evaluada por los niveles de C-Telopéptido basal, a los 3, 6 y 12 meses de tratamiento. Como desenlace secundario se evaluó la presentación de eventos adversos secundarios. Resultados: el estudio incluyó 146 mujeres reclutadas en diez centros de consulta externa de reumatología en cuatro ciudades de Colombia, que tuvieran diagnóstico de osteoporosis u osteopenia. La media de edad fue de 67±8 años (rango entre 45,7 y 92,8 años), y el promedio de tiempo transcurrido desde el inicio de la menopausia fue de 16±7,8 años. Treinta pacientes (20,54%) tenían una historia de fracturas previas. Al mes 12 de tratamiento se observó una reducción clínica y estadísticamente significativa en el nivel del C-Telopéptido (basal 0,53, tercer mes 0,22, sexto mes 0,17 y al año 0,17, p < 0,00001). Adicionalmente, se observó una mejoría estadísticamente significativa con el tratamiento en los valores del T-score a nivel de vértebras lumbares L2-L4 (basal -2,57, al sexto mes -2,27 y -2,29 al año), en el cuello de fémur (basal -2,37, al sexto mes -1,98 y al año -1,99), en el trocánter (basal -1,95, al sexto mes -1,55, y al año -1,41) y en la cadera (basal -1,73, al sexto mes -1,6 y -1,57 al año). También se observó mejoría en los parámetros de densidad mineral ósea, con un incremento de 2,3% a nivel vertebral lumbar y 2,59% en cadera. No hubo cambios en la densidad mineral ósea a nivel de cuello de fémur y trocánter. Estos cambios son similares a los observados con otras presentaciones de alendronatos y bifosfonatos. Como eventos adversos relacionados, solo se observó en el 8,2% la presencia de síntomas dispépticos, vértigo en el 3,4%, cefalea en el 2,7% y estreñimiento en el 1,4%. Conclusiones: estos resultados muestran que la presentación de alendronato sódico en cápsulas de gelatina blanda produce una gran mejoría en los parámetros evaluados por la densitometría y en el C-Telopéptido en mujeres posmenopáusicas con osteoporosis u osteopenia, y es una presentación farmacológica segura en mujeres jóvenes y de mayor edad.

Objectives: the purpose of this study was to evaluate the response to treatment and safety of Sodium Alendronate in a soft gelatin capsules presentation (Neobon 70 ®), in a postmenopausal women with osteoporosis or osteopenia. Methods: open multicenter clinical trial during one year was conducted in postmenopausal women. The patients were assigned to receive 70 mg of Sodic Alendronate in a soft gelatin capsule presentation, once time per week. The primaries endpoints were the bone density mineral measured by DEXA and the C-telopeptide serum level. The bone condition was evaluated by basal bone densitometry, 6 and 12 months. The bone resortion was evaluated by basal C-telopeptide serum levels, to 3, 6 and 12 months. The secondary endpoint was the presentation of secondary adverse events. Results: the study included 146 patients recruited in 10 rheumatologic clinical centers in Colombia, with diagnosis of osteopenia or osteporosis. Mean aged was 67±8 years (range 45.7 to 92.8 years) and the mean duration of menopausal time was 16±7.8 years. Thirty patients (20.54%) had a history of previous fracture bone. At month 12, a statistically significant reduction from base line in mean of C-telopeptide serum level was observed (basal 0.53, 3 month 0.22, 6 month 0.17 and 12 month 0.17, p < 0.00001). In addition, there was a clinical and statistically significant improvement in the T-score with the treatment in lumbar vertebrae L2-L4 (basal -2.57, 6 month -2.27 and 12 month -2.29), femur (basal -2.37, 6 month -1.98 and 12 month -1.99), trochanter (basal -1.95, 6 month -1.55 and 12 month -1.41), and in hip (basal -1.73, 6 month -1.6 and 12 month -1.57). Also it was observed an improvement in the parameters of bone density of 2.3% at lumbar vertebral level and of 2.59% in hip. No significant changes were observed in a left neck femur and trochanter. These increases are similar to observed with other presentations of alendronates and biphosphonates. Among this population, only the 8.2% had dyspeptic symptoms, 3.4% vertigo, 2.7% cephalea and 1.4% constipation. Conclusion: these findings showed that the presentation of sodium Alendronate in soft gelatin capsules produced a greater improvement in bone markers and densitometry scores in postmenopausal women with osteoporosis and osteopenia and is a safety pharmacological presentation in young and older patients.