Efficacy of topical risedronate and risedronate - Eudragit E complex in a model of cutaneous leishmaniasis induced by Leishmania (Leishmania) amazonensis.

An efficacious topical treatment for cutaneous leishmaniasis (CL) is highly desirable but still an ongoing challenge. Systemic risedronate (Ris) has been reported to have anti-leishmanial properties and Eudragit EPO (EuE) has shown in vitro activity against L. (L.) amazonensis. The aim of this work was to investigate the in vivo efficacy of topical Ris and EuE-Ris complexes on CL. Surface charge and Ris release kinetics from the different dispersions were analyzed. BALB/c mice were infected intradermally with promastigotes of L. (L.) amazonensis. Ulcers were treated with Ris or EuE-Ris hydrogels. All the lesions that received topical Ris or EuE-Ris showed an improvement with respect to control: reduction of ulcer average size, cicatrization, flattened edges and no signs of necrosis. In addition, a marked parasitic inhibition of 69.5 and 73.7% was observed in the groups treated with Ris and EuE-Ris, respectively, with the IgG2a levels indicating a tendency towards cure. The results are promising and the system should now be enhanced to achieve total parasite elimination.

Avaliação do efeito sinérgico entre risedronato sistêmico e genisteína local sobre o reparo peri-implantar em ratas com deficiência de estrógeno e síndrome metabólica / Evaluation of the synergistic effect between systemic Risedronate and local Genistein on peri-implant repair in strogen deficient rats and metabolic syndrome

O objetivo deste estudo foi investigar a ação sinérgica do risedronato de sódio sistêmico e da genisteína administrada localmente, através da funcionalização de implantes, de ratas submetidas a ovariectomia e com hábitos de mimetizam a síndrome metabólica. A parte in vitro deste estudo foi executado em 2 etapas. Na primeira etapa, foi realizada a funcionalização da superfície de discos/implantes com genistína na concentração de 100 µM pela técnica layer by layer (lbl). Na segunda etapa foram feitos testes biológicos em culturas de células, para avaliar as propriedades da superfície funcionalizada, quanto às respostas osteogênicas. Para a cultura de células foram utilizadas células mesenquimais diferenciadas em osteoblastos, isoladas de fêmures de ratos. Após a validação pelos testes executados nas superfícies funcionalizadas, foi realizado estudo in vivo (3ª etapa). Para tanto, no dia 0, as ratas Wistar adultas jovens, fêmeas (n=64) foram divididas em 4 grupos: 1- SHAM (n= 16), animais foram submetidos à ovariectomia (OVX) fictícia e dieta balanceada. 2- SHAM Síndrome Metabólica (SM) (n=16), animais foram submetidos à ovariectomia fictícia e dieta de cafeteria. 3- OVX SM (n=16), animais foram submetidos à ovariectomia bilateral e dieta de cafeteria. 4- OVX SM Risedronato (RIS) (n=16), animais foram submetidos à ovariectomia bilateral, dieta de cafeteria e tratadas com risedronato de sódio. Em cada grupo há 2 subgrupos: A- implantes convencionais e B- implantes funcionalizados com genisteína. No dia 30, foi iniciado o tratamento medicamentoso com risedronato de sódio, na concentração de 0,35mg/kg, ou apenas solução salina, via gavagem, 1 vez por semana. Passados 60 dias da medicação (dia 90), todos os animais foram submetidos à cirurgia para exodontia dos 1os molares superiores bilateralmente e, imediatamente, no alvéolo da raiz mesial, foi instalado os implantes com superfície convencional ou funcionalizada. Os animais foram eutanasiados aos 28 dias (dia 118) após a instalação dos implantes para mensuração do torque de falha na interface osso implante em N/cm. Os dados foram submetidos ao teste de homocedasticidade (Shapiro Wilk). Houve a confirmação de distribuição normal dos dados amostrais e na sequência, foi realizado o teste paramétrico ANOVA One Way or Two Way, seguido do pós teste de Tukey, com o nível de significância de 5% (p< 0,05). Concluiu-se que, a concentração de 100 µM da genisteína manteve a viabilidade celular e resultados favoráveis quanto a genotoxicidade. A dieta de cafeteria e a ovariectomia bilateral mimetizam a síndrome metabólica e a predisposição para osteoporose por deficiência de esteroides gonadais. E, a ação sinérgica entre fármaco sistêmico (risedronato de sódio) e genisteína local foi promissora para a melhora no processo de reparo periimplantar, principalmente no grupo SHAM e OVX SM RIS(AU)

The aim of this study was to investigate the synergistic action of systemic risedronate sodium and locally administered genistein, through implant functionalization, of rats submitted to ovariectomy and with habits mimicking the metabolic syndrome. The in vitro part of this study was performed in 2 steps. In the first step, the surface functionalization of discs/implants was performed with genistein at a concentration of 100 µM by the layer by layer (lbl) technique. In the second step biological tests were performed in cell cultures to evaluate the properties of the functionalized surface for osteogenic responses. For the cell culture, mesenchymal cells differentiated into osteoblasts, isolated from rat femurs, were used. After validation by tests performed on the functionalized surfaces, the in vivo study (third test) was performed. For this purpose, on day 0, young adult female Wistar rats (n=64) were divided into 4 groups: 1- SHAM (n=16), animals were submitted to sham ovariectomy (OVX) and balanced diet. 2- SHAM Metabolic Syndrome (MS) (n=16), animals were submitted to sham ovariectomy and cafeteria diet. 3- OVX SM (n=16), animals underwent bilateral ovariectomy and cafeteria diet. 4- OVX SM Risedronate (RIS) (n=16), animals underwent bilateral ovariectomy, cafeteria diet and treated with risedronate sodium. In each group there are 2 subgroups: A- conventional implants and B- implants functionalized with genistein. On day 30, drug treatment was started with risedronate sodium, at a concentration of 0.35 mg/kg, or just saline solution, via gavage, once a week. After 60 days of medication (day 90), all animals underwent surgery to extract the 1st upper molars bilaterally, and implants with conventional or functionalized surfaces were immediately installed in the mesial root alveolus. The animals were euthanized at 28 days (day 118) after implant installation to measure the failure torque at the implant-bone interface in N/cm. The data were submitted to the homoscedasticity test (Shapiro Wilk). The normal distribution of the sample data was confirmed and then the parametric One Way or Two Way ANOVA test was performed, followed by Tukey's post-test, with a significance level of 5% (p< 0.05). It was concluded that, the concentration of 100 µM of genistein maintained cell viability and favorable results regarding genotoxicity. The cafeteria diet and bilateral ovariectomy mimic the metabolic syndrome and predisposition to osteoporosis by gonadal steroid deficiency. And, the synergistic action between systemic drug (risedronate sodium) and local genistein was promising for the improvement in the periimplant repair process, especially in the SHAM and OVX SM RIS groups(AU)

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.

Bone Mass Outcomes in Patients With Osteoporosis Treated With Risedronate After Alendronate Failure: a 12-Month Follow-Up Study.

Oral bisphosphonates are the drugs most frequently used for the treatment of osteoporosis. Clinicians usually switch between these drugs in clinical practice based on differences in efficacy. We aim to investigate the reasons associated with switching between oral bisphosphonates and to evaluate bone mass response and the incidence of fractures 12 mo after the exchange in a cohort of patients with osteoporosis seen at a tertiary hospital. Patients with osteoporosis who switched between oral bisphosphonates between January 2007 and December 2014 were included. Bone mass measured by dual-energy X-ray absorptiometry and the incidence of fracture were evaluated. A total of 112 patients (73.1 yr old on average, 95.5% women, 98% postmenopausal) were included. All patients were taking alendronate at the time of the switch to risedronate. In 91 patients (81.3%), the following reasons for the exchange of medication were identified: bone loss (59.8%), adverse events (11.6%), and recent fragility fracture (10.7%). One year after the switch, bone densitometry revealed bone loss in 51 patients (45.5%), bone mass maintenance in 34 (30.4%), and bone mass gain in 27 (24.1%). No new vertebral fracture was detected and no nonvertebral fracture was reported in 12 mo of follow-up. Bone mass outcomes (gain, loss, or maintenance) were not associated with the reason for switching between oral bisphosphonates. Similarly, none of the parameters evaluated could predict good densitometric response (gain or maintenance) in this scenario. Our findings suggest that the use of risedronate should not be recommended in the scenario of treatment failure or adverse events following the use of alendronate.

Reduced food interaction and enhanced gastrointestinal tolerability of a new system based on risedronate complexed with Eudragit E100: Mechanistic approaches from in vitro and in vivo studies.

Novel complexes consisting of Eudragit E100-risedronate are presented. The oral bioavailability of risedronate in rats was determined through its percentage excreted in urine after administration of complexed or free risedronate in fed and fasted conditions. The evaluation of the risedronate gastro-duodenal irritation potential was carried out by macroscopic and histological analyses in an experimental rat model. The degree of counterionic condensation between Eudragit E100 and risedronate was assessed by dialysis with, mechanistic information about the interaction with calcium and the release of risedronate from the complexes being obtained using physiological solution and simulated gastric fluid without pepsin. Non-significant differences were observed in the urinary excretion of risedronate when the complex or free risedronate was administered to fasted rats. However, the urinary excretion of risedronate in the complex group was 4-times higher than in the free risedronate group when animals were concomitantly administered with food. This behavior was related to the high degree of counterionic condensation in the complex (86.5%), which led to a reduction in the calcium induced rate and magnitude of risedronate precipitation and resulted in a decrease in the gastroduodenal damage from the complex, as evidenced by a lower frequency of gastric mucosae hemorrhage. A sustained release of risedronate from the complex was observed toward water, simulated gastric fluid or physiological solution, through an ionic-exchange mechanism. In conclusion, complexation with Eudragit E100 could be a useful strategy to overcome the unfavorable properties of risedronate.

Long-term risks of bisphosphonate therapy / Riscos do tratamento a longo prazo com bisfosfonatos

The objective this study was to summarize long-term risks associated with bisphosphonate therapy. Search of relevant medical publications for data from clinical trials, trial extensions, observational studies and post-marketing reports. Trial extensions and modifications did not reveal significant long-term safety issues. Observational data suggest at least as many benefits as risks. Post-marketing reports of musculoskeletal pain, osteonecrosis of the jaw and atypical femur fractures have been widely circulated in the lay press. Most focus on long-terms risks has been on osteonecrosis of the jaw and atypical femur fractures which occur in patients who have not received bisphosphonate therapy but may be more frequent (though still uncommon) in patients who have been on treatment for 5 years or longer. Lower-risk patients may be able to stop treatment after 3-5 years for a “drug holiday,” which mitigates these long-term risks; for higher risk patients, therapy through 6-10 years appears to be advisable and offers more benefits than risks.

O objetivo deste estudo foi resumir os riscos associados ao tratamento a longo prazo com bisfosfonatos. Foram pesquisadas as publicações médicas relevantes incluindo ensaios clínicos, extensões de ensaios clínicos, estudos observacionais e relatórios pós-comercialização (vigilância farmacológica). As extensões e modificações de ensaios clínicos não indicaram nenhuma situação de alarme quanto à segurança dos bisfosfonatos a longo prazo. Dados observacionais sugerem pelo menos tantos benefícios quanto riscos. Entretanto, relatos pós-comercialização de dor musculoesquelética, osteonecrose da mandíbula e fraturas de fêmur atípicas foram amplamente divulgados na imprensa leiga. O foco nos riscos a longo prazo do tratamento com bisfosfonatos tem sido pincipalmente a osteonecrose da mandíbula e as fraturas atípicas de fêmur. Essas últimas, embora mais frequentes (ainda que pouco comuns) em pacientes que receberam tratamento com bisfosfonatos por 5 anos ou mais, podem ocorrer em indivíduos não tratados com esses medicamentos. Pacientes com baixo risco de fratura podem potencialmente parar o tratamento depois de 3 a 5 anos (“drug holiday”). Esse procedimento reduz os riscos desses medicamentos a longo prazo. Não obstante, nos pacientes de maior risco a terapia por 6 a 10 anos parece ser aconselhável e oferece mais benefícios do que riscos.

Novel Pullulan-Eudragit® S100 blend microparticles for oral delivery of risedronate: formulation, in vitro evaluation and tableting of blend microparticles.

Polymer blends have been considered a promising strategy to tailor drug release. In order to achieve gastroresistance and controlled release, Pullulan, a polysaccharide, and Eudragit® S100, an enteric polymer were selected to prepare microparticles for oral delivery of risedronate, an antiresorptive drug associated with GI tract injuries. Blend microparticles were prepared by spray-drying technique at 3 Pullulan and Eudragit® S100 ratios (MP2:1, MP1:1 and MP1:2) and were characterized in terms of yield, particle size, encapsulation efficiency, morphology, moisture content, flowability and in vitro drug release profiles. Microparticles presented yields between 31 and 42%, encapsulation efficiencies close to 100%, moisture contents lower than 11%, particle size ranging from 2.9 to 4.8 µm and narrow distribution. In the gastric medium, MP1:2 showed the best gastroresistance profile. In the intestinal fluid, all samples were able to prolong drug release. MP1:2 was compressed into tablets with or without polyvinylpyrrolidone. Both tableted microparticles could be obtained with acceptable average weights, drug content close to 100%, sufficient hardness and low friability. In vitro studies showed that tablets maintained the gastroresistance observed for microparticles and were also able to prolong risedronate release. In conclusion, Pullulan/Eudragit® S100 microparticles are promising alternatives for the oral delivery of risedronate in the future.

Estudo de biodisponibilidade relativa/bioequivalência de duas formulações de risedronato de sódio em voluntários sadios de ambos os sexos / Study of relative bioavailability/bioequivalence of two formulations of risendronate sodium in healthy volunteers of both sexes

O estudo foi realizado para comparar a biodisponibilidade de duas formulações de risedronato de sódio 35 mg comprimido revestido (risedronato de sódio do Aché Laboratórios Farmacêuticos S/A, formulação teste, e Actonel® da Sanofi-Aventis Farmacêutica Ltda., formulação referência, Brasil) em 80 voluntários de ambos os sexos. O estudo foi aberto, aleatorizado, 2-sequências, 2-períodos, cruzado, dose única com dois tratamentos, nos quais um grupo de voluntários recebeu a formulação teste e outro a formulação referência. As amostras de sangue foram obtidas ao longo de um intervalo de 96 horas. As concentrações de risedronato de sódio foram determinadas através de espectrometria de massa (UPLC-MS-MS), utilizando ácido risedrônico-D4 (risedronato deuterado) como padrão interno. A partir dos dados obtidos se calcularam os seguintes parâmetros farmacocinéticos: ASC0-t, ASC0-¥ e Cmax. A média geométrica de Risedronato de Sódio/Actonel® 35 mg foi de 101,90 % para ASC0-t, 97,95 % para ASC0-¥ e 100,70 % para Cmax. Os intervalos de confiança de 90% foram de 86,43%-120,14%, 83,04%-115,54% e 85,50%-118,61%, respectivamente. Uma vez que os intervalos de confiança de 90% para Cmax e ASC0-t estiveram dentro da faixa de 80%-125% proposta pelo FDA e pela ANVISA (Agência Nacional de Vigilância Sanitária do Brasil), conclui-se que o comprimido de risedronato de sódio de 35 mg foi bioequivalente ao comprimido de Actonel® de 35 mg e, dessa forma, o produto teste pode ser considerado intercambiável na prática médica.

Farmacoterapia de raloxifeno y de risedronato en el proceso de reparación ósea en ratones machos con osteopenia / Pharmacotherapy of raloxifene and risedronate in the process of bone repair in male mice with osteopenia

El objetivo del estudio era el de analizar radiográficamente los efectos del risedronato de sodio (OSG Norwich Pharmaceticals, U. S. UN.) y del raloxifeno clorhidrato (Eli Lirio & Compañía Ltda, ING. ) En la reparación ósea en ratones osteopénicos. Se utilizó cincuenta ratones divididos en cinco grupos de 10 animales: (I) SHAM, (II) Castrado, (III) Castrados y tratados con risedronato 1mg/kg/dia, (IV) Castrados y tratados con raloxifeno 1mg/kg/día y (V) Castrados y tratados con raloxifeno 3mg/kg/día. Después de treinta días de la castración se les produjo heridas en el hueso de 3 mm de en las de tibias derechas. Entre 7 y 28 días de tratamiento los ratones fueron sacrificados y las tibias evaluadas considerando la densidad óptica radiográfica de la región de la reparación del defecto óseo por medio del sistema digital RVG Trophy y Programa de Imagen Tool® 2,03. Los resultados fueron sometidos al ANOVA y al Test de Tukey (p?0,05). Los datos mostraron que a los 7 días de observación los grupos I y II fueron estadísticamente semejantes en relación al grado de densidad radiográfica, así como los demás grupos entre sí. A los 28 días el grupo V presentó los valores de densidad radiográfica superior y estadísticamente significativos con respecto a los grupos II, III y IV y semejante al grupo I. Los grupos III y IV fueron semejantes entre sí y estadísticamente superior al grupo II. Se concluyó que el raloxifeno en dosis de 3mg/kg/dia presentó mejor desempeño en el proceso de reparación ósea, siendo semejante al grupo SHAM a los 28 días. El efecto del raloxifeno se mostró dosis dependiente, a los 28 días, en las posologias testadas

The aim of this study was to analyse radiographically the effects of sodium risedronate (OSG Norwich Pharmaceticals, EUA) and raloxifene hydrochloride (Eli Lilly & Company Ltd; ING.) in bone repair of male rats with osteopenia. 50 animals were divided in 5 groups of 10: (I) SHAM, (II) Castrated rats, (III) Castrated rats treated with 1mg/kg/day risedronate, (IV) Castrated rats treated with 1mg/kg/day raloxifene and (V) Castrated rats treated with 3mg/kg/day raloxifene. 30 days after castration, a 3 mm bone defect was made in the right tibia of the animals. After 7 and 28 days of treatment, the animals were sacrificed and the tibias were removed for analysis of radiographic optical density by the digital system RVG Trophy and the Image Programme Tool 2.03®. All data collected were analysed by ANOVA and the Tukey´s Test (p?0.05). The results showed that at 7 days of bone repair, groups I and II had similar and statistically significant values of optical density while the other groups had similar values among themselves. At 28 days of bone repair, group V showed greater and statistically significant values of optical density compared to groups II, III and IV, but similar values to group I. Groups III and IV had similar values between themselves but greater and statistically significant values than group II. It could be concluded that 3 mg/kg/day raloxifene had a better performance in bone repair when compared to the other groups, similar results to group I and a dose-dependent relation at 28 days