The use of cyclodextrins nanoparticles for oral delivery

This review aims to highlight many of the difficulties encountered in trying to achieve the task of delivering proteins and peptides through oral administration. The necessity of controlled protein and peptide release, protection and stability in the gastrointestinal tract, and ability to target specific areas are only a handful of the many problems associated with trying to engineer a useful solution. Current research gives strong indication that both cyclodextrins and nanoparticles could be highly useful in the search for a suitable method for such successful oral delivery of proteins and peptides. This review focuses on the use of cyclodextrins in pharmaceuticals, aiming to discuss the use of cyclodextrins in conjunction with nanoparticles for oral delivery of proteins. Both classical applications and more advanced "nanomedical" approaches are discussed. In order to achieve a complete overview this review will include background information about cyclodextrins, nanomedicine and their role in oral delivery systems. The use of absorption enhancers like cyclodextrins, bile salts and surfactants was used to facilitate bio-availability into the system. The state-of-the-art technology and challenges in this area are discussed, with typical examples.

Annual high-dose oral vitamin D and falls and fractures in older women : a randomized controlled trial

Context Improving vitamin D status may be an important modifiable risk factor to reduce falls and fractures; however, adherence to daily supplementation is typically poor.

Objective To determine whether a single annual dose of 500 000 IU of cholecalciferol administered orally to older women in autumn or winter would improve adherence and reduce the risk of falls and fracture.

Design, Setting, and Participants A double-blind, placebo-controlled trial of 2256 community-dwelling women, aged 70 years or older, considered to be at high risk of fracture were recruited from June 2003 to June 2005 and were randomly assigned to receive cholecalciferol or placebo each autumn to winter for 3 to 5 years. The study concluded in 2008.

Intervention 500 000 IU of cholecalciferol or placebo.

Main Outcome Measures Falls and fractures were ascertained using monthly calendars; details were confirmed by telephone interview. Fractures were radiologically confirmed. In a substudy, 137 randomly selected participants underwent serial blood sampling for 25-hydroxycholecalciferol and parathyroid hormone levels.

Results Women in the cholecalciferol (vitamin D) group had 171 fractures vs 135 in the placebo group; 837 women in the vitamin D group fell 2892 times (rate, 83.4 per 100 person-years) while 769 women in the placebo group fell 2512 times (rate, 72.7 per 100 person-years; incidence rate ratio [RR], 1.15; 95% confidence interval [CI], 1.02-1.30; P = .03). The incidence RR for fracture in the vitamin D group was 1.26 (95% CI, 1.00-1.59; P = .047) vs the placebo group (rates per 100 person-years, 4.9 vitamin D vs 3.9 placebo). A temporal pattern was observed in a post hoc analysis of falls. The incidence RR of falling in the vitamin D group vs the placebo group was 1.31 in the first 3 months after dosing and 1.13 during the following 9 months (test for homogeneity; P = .02). In the substudy, the median baseline serum 25-hydroxycholecalciferol was 49 nmol/L. Less than 3% of the substudy participants had 25-hydroxycholecalciferol levels lower than 25 nmol/L. In the vitamin D group, 25-hydroxycholecalciferol levels increased at 1 month after dosing to approximately 120 nmol/L, were approximately 90 nmol/L at 3 months, and remained higher than the placebo group 12 months after dosing.

Conclusion Among older community-dwelling women, annual oral administration of high-dose cholecalciferol resulted in an increased risk of falls and fractures.

Capecitabine and oral cyclophosphamide : a novel oral treatment combination for advanced cancer

Background: This dose escalation study assessed feasibility of a totally oral chemotherapy regimen using cyclophosphamide and capecitabine. The rationale for this combination was based on the observation that preclinical models of cyclophosphamide up-regulated tumor thymidine phosphorylase and increased the activation of capecitabine. Methods: Eligible patients with advanced cancer were treated with oral cyclophosphamide and capecitabine on a 28-day cycle. If no dose limiting toxicities (DLT) were encountered during the first two treatment cycles, the next patient group was assigned to the next highest dose level until the maximum tolerable dose (MTD) was determined. Results: Twenty-seven patients entered treatment. The majority of non-DLT were grades 1 and 2. DLT experienced in the first 8-week observation period were grade 3 diarrhea (one patient, level III) and grade 3 emesis (two patients, level V). MTD was observed at level 5, 1331 mg/m2/day capecitabine days 1–28 with 125 mg/m2/day cyclophosphamide days 1–14 of the 28-day cycle. The recommended phase II dose is therefore 1331 mg/m2/day capecitabine with 100 mg/m2/day cyclophosphamide. The best response evaluation showed four partial responses (breast, colon, ovary and pancreas). Conclusion: Cyclophosphamide and capecitabine can be combined at their full oral single agent dose with promising tolerability and activity.

Oral baclofen in children with cerebral palsy : a double-blind cross-over pilot study

Aim: To assess the effectiveness of oral baclofen in reducing spasticity and improving function in children with cerebral palsy. Methods: A double-blind, randomised cross-over pilot study of oral baclofen versus placebo. Assessment tools included the Goal Attainment Scale, Pediatric Evaluation of Disability Inventory, Modified Tardieu Scale and parent questionnaire. Results: Fifteen children with mean age 7.4 years (SD = 2.7 years) and spastic or spastic/dystonic quadriplegia (Gross Motor Function Classification System Level IV or V) were enrolled. Children scored significantly better on the Goal Attainment Scale with baclofen compared with placebo (F(1,13) = 4.5, P = 0.05). There was no significant difference between baclofen and placebo for the Pediatric Evaluation of Disability Inventory or Modified Tardieu Scale. Parent questionnaire results are described. Conclusion: This pilot study demonstrates that oral baclofen has an effect beyond placebo in improving goal-oriented tasks, such as transfers, in children with spastic quadriplegic cerebral palsy.

Estudo de fase I e farmacocinética com etoposide oral em crianças e adolescentes com tumores sólidos refratários

Introdução. Embora muitas crianças com câncer possam ser curadas, um número significativo têm resposta insatisfatória por ineficácia da terapêutica tornando necessário identificar agentes anticâncer mais efetivos contra tumores refratários ou recaídos. Estudos com Etoposide revelaram uma clara relação entre o tempo de exposição e os seus efeitos citotóxicos, mostrando resultados superiores com o uso de doses fracionadas quando comparado ao uso de uma dose única. Estudos de farmacocinética sugerem que as concentrações plasmáticas ativas de Etoposide se situa entre 1 e 5 μg/ml e que níveis acima de 5 μg/ml determinam uma mielotoxicidade importante. O Etoposide apresenta um bom espectro antitumoral mesmo em pacientes que já foram tratados por via parenteral e uma adequada biodisponibilidade pela via oral, podendo ser administrado com segurança em regime ambulatorial. Portanto, torna-se atraente a busca de esquemas de administração deste agente, os quais produzem níveis de concentração plasmática seguras pelo maior tempo possível. Objetivos. Os objetivos deste estudo de fase I é avaliar o perfil de toxicidade, a toxicidade dose-limitante, a dose máxima tolerada, a farmacocinética plasmática e a dose segura do Etoposide oral recomendada para estudos de fase II em pacientes pediátricos portadores de tumor sólido refratário. Materiais e Métodos. Todos os pacientes eram portadores de tumor sólido não responsivo aos tratamentos estabelecidos. A dose inicial do Etoposide foi de 20mg/m2/dose, a cada 8 horas durante 14 dias seguido de um intervalo de 7 dias antes de iniciar o próximo ciclo. A farmacocinética plasmática do Etoposide foi estudada durante o primeiro dia de tratamento e os níveis de Etoposide determinados pelo método de HPLC. Resultados. Dezessete pacientes foram incluídos no estudo, sendo que em 13 foram realizados o estudo de farmacocinética. O número total de cursos de quimioterapia foi de 64. Nove pacientes foram incluídos no Nível de dose I, sendo que leucopenia grau 2-3 foi observada em 5. A dose foi então escalonada para 25 mg/m2 (Nível de dose II) e fornecida a 8 pacientes subsequentes o que determinou leucopenia grau 3-4 em 4 deles. Este Nível de dose foi então considerado como DMT (Dose Máxima Tolerada). A TDL foi neutropenia. As concentrações plasmáticas máximas de Etoposide nos pacientes incluídos no Nível de dose I e II foram de 2,97 e 8,59 μg/ml, respectivamente, e os níveis da droga >1 μg/ml foi mantido durante cerca de 6,3 horas após a administração da droga em ambos os níveis de dose. Resposta parcial foi observada em 1 paciente e 4 apresentaram doença estável. Conclusões. A administração prolongada de Etoposide oral nas doses de 20 mg/m2 a cada 8 horas durante 14 dias consecutivos, seguidos de 7 dias de repouso, foi bem tolerada e determinou uma toxicidade manejável em crianças e adolescentes portadores de doenças malignas refratárias. A dose de 20 mg/m2 aparentemente preencheu os requisitos farmacocinéticos que objetivam melhorar o índice terapêutico do Etoposide, ou seja, a obtenção de níveis plasmáticos citotóxicos sustentados e abaixo do limite de toxicidade clínica da droga.

Improvement of the oral praziquantel anthelmintic effect by cyclodextrin complexation

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Interação competitiva do zinco e ferro após administração oral e venosa de zinco em crianças eutróficas

The aim of this study was to assess the acute and chronic effects of zinc in serum iron profile of children aged 6-9 years in relation to nutritional status and dietary intake. The study participants were 11 children regardless of sex, aged 6-9 years. They were selected from three public schools of the city of Natal, Brazil. Body mass index was used to assess nutritional status. In order to determine the patterns of childhood growth and ideal weight we used the standards of the World Health Organization. The dietary intake assessment was based on information from a three-day prospective food survey. The variables were energy intake, protein, lipids, carbohydrates, fiber, calcium, iron and zinc. All children underwent an intravenous administration of zinc (IVAZn) before and after oral administration of zinc (OAZn) (5 mg Zn / day) for three months. We measured serum iron, hematocrit, hemoglobin and total protein, before and after the use of oral zinc. The analysis of hematocrit, hemoglobin and total protein was performed using standard methods of clinical laboratory. Zinc levels and serum iron were measured by atomic absorption spectrophotometry. The project was evaluated and approved by the Ethics in Research Committee of Federal University of Rio Grande do Norte. Results: All children had normal weight. The consumption of energy, fat, fiber, calcium and iron were below recommended levels. However, the levels of protein and carbohydrates were high. Protein and zinc increased significantly after OAZn. Carbohydrate and protein were elevated in the blood. After OAZn, both protein and zinc increased, being statistically significant. Conclusion: The potential inhibitory effect of physiological or pharmacological doses of zinc on the profile of serum iron was observed in children with healthy weight and aged between 6 and 9 years. This negative effect of zinc did not affect the levels of hematocrit or hemoglobin, and therefore did not cause anemia. This was a multidisciplinary study, involving researchers from medicine, nutrition and pharmacy. This met the requirements of multidisciplinarity of the Post Graduate Program in Health Sciences of Federal University of Rio Grande do Norte.

Anthelmintic efficacy of oral trichlorfon solution against ivermectin resistant nematode strains in cattle

Infected calves from two different rural estates in Brazil were studied to assess the anthelmintic efficacy of oral trichlorfon against naturally occurring ivermectin resistant parasitic nematode strains. In experiment 1, infected animals were from a region where ivermectin resistant populations of Haemoncus placei, Cooperia punctata,Cooperia spatulata and Trichuris discolor have recently been identified. Six calves with natural gastrointestinal nematode infections were treated with 48.5 mg/kg aqueous trichlorfon administered orally and six calves acted as a non-treated control group. In experiment 11 24 naturally infected calves were selected to enter one of four treatment groups, six animals each received: 48.5 mg/kg oral trichlorfon; 200 mu g/kg subcutaneous 1% ivermectin; 630 mu g/kg subcutaneous 3.15% ivermectin; or no treatment (control group). Gastrointestinal helminths were counted and identified post-mortem at 7 days (trichlorfon and 1% ivermectin treated and untreated animals) or 14 days (3.15% ivermectin treated and untreated animals) after administration of the test agents. Experiment I identified a high level efficacy for oral trichlorfon against four helminth species that have previously been shown to be ivermectin resistant in this geographical region: percentage efficacy was 99.82% against adult H. placei, 99.18% against C. punctata, 99.33% against C. spatulata, 81.06% against T. axei, 98.46% against Oesophagostomum radiatum and 100% against T. discolor. Trichlorfon also showed activity against the ivermectin (1% and 3.15%) resistant helminth species identified in experiment 11, attaining efficacy levels of 99.17% against H. placei, 98.46% against C punctata and 100.00% against T. discolor. These findings indicate that oral trichlorfon is an effective treatment option in the management of cattle infected with ivermectin resistant helminths. (C) 2009 Elsevier B.V. All rights reserved.

The effects of oral glutamine on cisplatin-induced nephrotoxicity in rats

The antioxidant activity of the amino acid glutamine was investigated to obtain protection against peroxidative damage in rat kidney and nephrotoxicity induced by the treatment with a single dose of the antitumoral cisplatin (5 mg kg(-1) body weight). The animals were divided into four treatment and control groups of six rats each (n = 6). Cisplatin was injected i.p. and glutamine (300 mg kg(-1) body weight) was given by gavage 24 h before the cisplatin injection. After 24 h and 7 days of cisplatin administration, the rats were sacrificed. A single dose of cisplatin resulted in significant reduction in body weight and creatinine clearance, and higher urinary volumes were observed in all groups treated with this antitumor drug (P < 0.05). Renal tissue from cisplatin-treated rats showed an increase in malondialdehyde production and increase in glutathione contents 24 h and 7 days after cisplatin administration. Pretreatment of rats with glutamine substantially inhibited the increase in the levels of renal glutathione induced by cisplatin 24 h after the i.p. injection. The malondialdehyde, in the renal tissues was significantly reduced 7 days after cisplatin treatment. However, the reduction in the peroxidative damage did not reach the value of the control group. The protective effects obtained by glutamine pretreatment in peroxidative alterations were not observed in the other parameters studied. These results suggest that glutamine partially protect against cisplatin-induced lipid peroxidation damage, but it was not enough to inhibit cisplatin-induced nephrotoxicity in rats. (C) 2003 Elsevier B.V. Ltd. All rights reserved.

Rheological, mechanical and mucoadhesive properties of thermoresponsive, bioadhesive binary mixtures composed of poloxamer 407 and carbopol 974P designed as platforms for implantable drug delivery systems for use in the oral cavity

This study described the formulation and characterisation of the viscoelastic, mechanical and mucoadhesive properties of thermoresponsive, binary polymeric systems composed of poloxamer (P407) and poly(acrylic acid, C974P) that were designed for use as a drug delivery platform within the oral cavity. Monopolymeric and binary polymeric formulations were prepared containing 10, 15 and 20% (w/w) poloxamer (407) and 0.10-0.25% (w/w) poly(acrylic acid, 934P). The flow theological and viscoelastic properties of the formulations were determined using controlled stress and oscillatory rheometry, respectively, the latter as a function of temperature. The mechanical and mucoadhesive properties (namely the force required to break the bond between the formulation and a pre-hydrated mucin disc) were determined using compression and tensile analysis, respectively. Binary systems composed of 10% (w/w) P407 and C934P were elastoviscous, were easily deformed under stress and did not exhibit mucoadhesion. Formulations containing 15 or 20% (w/w) Pluronic P407 and C934P exhibited a sol-gel temperature T(sol/gel), were viscoelastic and offered high elasticity and resistance to deformation at 37 degrees C. Conversely these formulations were elastoviscous and easily deformed at temperatures below the sol-gel transition temperature. The sol-gel transition temperatures of systems containing 15% (w/w) P407 were unaffected by the presence of C934P; however, increasing the concentration of C934P decreased the T(sol/gel) in formulations containing 20%(w/w) P407. Rheological synergy between P407 and C934P at 37 degrees C was observed and was accredited to secondary interactions between these polymers, in addition to hydrophobic interactions between P407 micelles. Importantly, formulations composed of 20% (w/w) P407 and C934P exhibited pronounced mucoadhesive properties. The ease of administration (below the T(sol/gel)) in conjunction with the viscoelastic (notably high elasticity) and mucoadhesive properties (at body temperature) render the formulations composed of 20% (w/w) P407 and C934P as potentially useful platforms for mucoadhesive, controlled topical drug delivery within the oral cavity. (c) 2009 Published by Elsevier B.V.

Repeated exposure of adolescent rats to oral methylphenidate does not induce behavioral sensitization or cross-sensitization to nicotine

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Evaluation of the adverse effects of oral firocoxib in healthy dogs

This study evaluated the adverse effects of oral firocoxib in dogs. Six dogs (20.2 +/- 6.3 kg) were studied. Values for complete blood count (CBC), serum urea, creatinine, alanine transaminase, alanine phosphatase, -glutamyl transferase, occult blood in feces, platelet aggregation, and buccal mucosal bleeding time were measured before and 7, 14, 21, and 29 days after SID treatment with firocoxib 5.3 +/- 0.34 mg/kg (FG) or lactose 1 mg/kg (LG) for 2 8 days, in a randomized crossover study. Gastrointestinal (GI) tract endoscopy was performed before treatment began and at 29 days. Lesions were scored from grade 0 to 6. Data were analyzed using ANOVA and paired t-tests (P < 0.05). None of the dogs presented adverse clinical effects. There were no significant changes in CBC, biochemical profiles within groups, or differences between groups. Pretreatment mean SD bleeding time (LG, 70.7 +/- 32.1 sec; FG, 75.8 +/- 38.1 sec) and platelet aggregation (LG, 86.4 +/- 10.2%; FG, 85.6 +/- 9.2%) were not significantly different from readings at 29 days (LG, 95.2 +/- 25 sec; FG, 91.7 +/- 24 sec and LG, 73.2 +/- 15.1%; FG, 84 +/- 10.3%) nor the groups were different. None of the dogs had positive fecal occult blood tests, and endoscopic lesion scores were grade 0 both before treatment and at 29 days. Administration of firocoxib did not cause any adverse effects on GI, or hematological or serum biochemical variables and appears to have been well tolerated by dogs.

Genomic instability in non-neoplastic oral mucosa cells can predict risk during 4-nitroquinoline 1-oxide-induced rat tongue carcinogenesis

4-Nitroquinotine 1-oxide (4NQO)-induced rat tongue carcinogenesis is a useful model for studying oral squamous cell carcinoma. The aim of this study was to investigate the level of DNA damage induced by 4NQO in oral mucosa cells by the single cell get (comet) assay. Mate Wistar rats were distributed into three groups of 10 animals each and treated with 50 ppm 4NQO solution by drinking water for 4, 12 or 20 weeks. Ten animals were used as negative control. Statistically significant increase of DNA damage was observed in non-neoplastic oral cells at four weeks of 4NQO administration when compared with control (P < 0.05). The level of DNA damage was directly associated with the severity of histological changes. The results suggest that histologically normal tissue is able to harbor genetically unstable cells contributing to the initiation of oral carcinogenesis. Genomic instability appears to be associated with the risk and progression of oral cancer. (C) 2004 Elsevier Ltd. All rights reserved.

Postoperative analgesic effects of intravenous, intramuscular, subcutaneous or oral transmucosal buprenorphine administered to cats undergoing ovariohysterectomy

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Enrofloxacin assay validation and pharmacokinetics following a single oral dose in chickens

The pharmacokinetics of enrofloxacin (ENRO), a fluoroquinolone antimicrobial agent, was studied in male broiler chickens (Cobb) after single oral administration of 10 mg of ENRO/kg b.w. A high-performance liquid chromatography-photodiode array detector (DAD) (HPLC-DAD) method was developed and validated and used for quantitation of ENRO and its major metabolite ciprofloxacin in plasma. The HPLC analyses were carried out using a cationic-octadecyl mixed column and 0.05 mol/L phosphate buffer (pH 2.5)/acetonitrile as mobile phase. The sample preparation of plasma consisted of the precipitation of proteins followed by solid phase extraction on cationic-octadecyl mixed cartridges. The method was validated considering linear range, linearity, selectivity, sensitivity, limit of detection (LOD), limit of quantitation (LOQ), intra- and inter-day precisions and accuracy. The LOD and LOQ for both fluoroquinolones were 60 and 200 ng/mL for plasma. The plasma concentration vs. time graph was characteristic of a two-compartment open model. The maximal plasma concentration of 1.5 +/- 0.2 mg/mL was achieved at 9 +/- 2 h. The elimination half-life and the mean residence time of ENRO were 1.5 +/- 0.2 and 15.64 h, respectively. The area under the concentration-time curve was calculated as 35 +/- 4 mg(.)h/mL.