An in vivo pharmacokinetic study of metformin microparticles as an oral sustained release formulation in rabbits.

BACKGROUND: Metformin hydrochloride is a biguanide derivative that has been widely used to treat type 2 diabetes in humans. In veterinary medicine, metformin has shown increasing potential for diabetes treatment in different species, such as equids, dogs, cats and rabbits. It is highly hydrophilic, with incomplete gastrointestinal absorption and very large variability in absolute bioavailability between species, ranging from 4% in equids to 60% in humans. Metformin also shows a short half-life of approximately 2 h in dogs, cats, horses and humans. The objectives of this study were to evaluate a poly (lactic acid) (PLA) metformin microparticle formulation to test in rabbits and conduct a pharmacokinetics study of intravenous (SIV) and oral solution (SPO) metformin administration and oral PLA microparticle (SPLA) administration to rabbits to evaluate the improvement in the metformin pharmacokinetics profile. RESULTS: Metformin-loaded PLA microparticles were characterized by a spherical shape and high encapsulation efficiency. The results from Fourier transform infrared (FTIR) spectroscopy suggested the presence of interactions between metformin and PLA. X-Ray diffraction (XRD) analysis corroborated the results from the differential scanning calorimetry (DSC) studies, showing that metformin is present in an amorphous state within the microparticles. Physicochemical characterization suggested that PLA and metformin hydrochloride interacted within the microparticles via hydrogen bonding interactions. The pharmacokinetic study in rabbits showed sustained-release characteristics from the prepared microparticles with a delay in the time needed to reach the maximum concentration (Tmax), decreased Cmax and bioavailability, and increased mean residence time (MRT) and half-life compared to the pure drug solution. CONCLUSIONS: Metformin-loaded PLA microparticles showed optimal and beneficial properties in terms of their physicochemical characteristics, making them suitable for use in an in vivo pharmacokinetic study. The pharmacokinetic parameters of the metformin microparticles from the in vivo study showed a shorter Tmax, longer MRT and half-life, decreased Cmax and the prolonged/sustained release expected for metformin. However, the unexpected decrease in bioavailability of metformin from the microparticles with respect to the oral solution should be evaluated for microparticle and dose design in future works, especially before being tested in other animal species in veterinary medicine.

Pharmacokinetics of Metformin in Combination With Sitagliptin in Adult Horses After Enteral Administration.

Insulin dysregulation (ID) is a common metabolic disorder in horses. Recently, incretin hormone release has been suggested to be involved in ID in horses. In human medicine, metformin and sitagliptin are commonly used in combination for metabolic syndrome. This combination could be useful in treating ID in horses. However, no pharmacokinetics data have been reported in this species. The objective of the present study was to establish the plasma concentration-time profile and to derive pharmacokinetics data for a combination of metformin and sitagliptin in horses after enteral administration. Six healthy adult Purebred Spanish horses were used. A metformin (15 mg/kg) plus sitagliptin (1.5 mg/kg) preparation was administered by intragastric route (IG) as an enteral solution. Blood samples were collected from 0 to 48 hours after IG drug administration. Plasma concentrations of metformin and sitagliptin were measured using high performance liquid chromatography methods. The t½λz for metformin was 2.9 hours and for sitagliptin 21 hours. The Cmax was 442 ± 84 mg/L within 0.9 hours for metformin and 94 ± 14 mg/L within 1.3 hours for sitagliptin. No adverse effects were observed, and the combination of metformin and sitagliptin was well tolerated. Therefore, these results suggest that metformin plus sitagliptin might be a combination to consider in horses with ID. Additional studies are needed to establish the effectiveness and tolerance in equids affected by endocrine disorders.

Practical aspects of the use of intrathecal chemotherapy / Aspectos prácticos de la utilización de quimioterapia intratecal

Introduction: Intrathecal chemotherapy is frequently used in clinical practice for treatment and prevention of neoplastic meningitis. Despite its widespread use, there is little information about practical aspects such as the volume of drug to be administered or its preparation and administration. Objective: To conduct a literature review about practical aspects of the use of intrathecal chemotherapy. Materials: Search in PubMed/ Medline using the terms ‘chemotherapy AND intrathecal’, analysis of secondary and tertiary information sources. Results: The most widely used drugs in intrathecal therapy are methotrexate and cytarabine, at variable doses. One of the aspects with higher variability among different studies is their potential combination with a glucocorticoid, the specific corticoid selected and its dose. The efficacy and toxicity of the different combinations have not been compared. Regarding preparation, it is worth highlighting the recommendation to adjust pH and osmolarity to the physiological range, with the aim of improving tolerability. The volume of administration can influence distribution, and recommendated range is between 5 and 12 mL. Overall, it is recommended to extract a similar volume of cerebrospinal fluid before administration. The position of the patient during and after administration can have an impact on distribution and toxicity; lateral decubitus or sitting position is recommended in the first case, and prone and/ or supine position in the second one. Most publications don’t explain how the treatment has been prepared or administered, and the lack of standardization could affect results. Conclusions: There is a great variability in practice when using intrathecal chemotherapy, despite being an effective therapy, accepted by all international groups. This uncertainty is not limited to the drugs and doses administered, but it also includes the manner of preparation and the administration technique. The heterogeneity in clinical practice can influence the efficacy and toxicity of this therapy (AU)

Introducción: La quimioterapia intratecal es utilizada frecuentemente, en la práctica clínica, para el tratamiento y prevención de la meningitis neoplásica. A pesar de su uso extendido, existe poca información acerca de aspectos prácticos tales como el volumen de fármaco a administrar o la forma de preparación y administración. Objetivo: Realizar una revisión de la literatura acerca de aspectos prácticos de la utilización de la quimioterapia intratecal. Material: Búsqueda en PubMed/Medline utilizando los términos ‘chemotherapy AND intrathecal’, análisis de fuentes de información secundarias y terciarias. Resultados: Los fármacos más utilizados en terapia intratecal son metotrexato y citarabina, con dosis variables. La asociación o no con un glucocorticoide, el corticoide concreto seleccionado y su dosis es uno de los aspectos con mayor variabilidad entre distintos estudios. No se han comparado la eficacia y toxicidad de las distintas combinaciones. En la preparación destaca la recomendación de ajustar pH y osmolaridad al rango fisiológico, con el objetivo de mejorar la tolerancia. El volumen de administración puede influir en la distribución, oscilando las recomendaciones entre 5-12 mL. En general, se aconseja extraer previamente un volumen de líquido cefalorraquídeo similar. La posición del paciente durante y tras la administración puede influir en la distribución y la toxicidad; se recomienda el decúbito lateral o la sedestación, en el primer caso, y el decúbito prono y/o supino, en el segundo. La mayoría de las publicaciones no indican cómo se ha preparado o administrado el tratamiento, y la falta de estandarización podría afectar a los resultados. Conclusiones: Existe gran variabilidad en la práctica a la hora de utilizar la quimioterapia intratecal, a pesar de ser una terapia efectiva asumida por todos los grupos internacionales. La incertidumbre no se limita a los fármacos y dosis administradas, sino que se extiende a la forma de preparación de las mezclas y la técnica de administración. La heterogeneidad en la práctica clínica puede influir en la efectividad y toxicidad de esta terapia (AU)

Practical aspects of the use of intrathecal chemotherapy.

INTRODUCTION: Intrathecal chemotherapy is frequently used in clinical practice for treatment and prevention of neoplastic meningitis. Despite its widespread use, there is little information about practical aspects such as the volume of drug to be administered or its preparation and administration. OBJECTIVE: To conduct a literature review about practical aspects of the use of intrathecal chemotherapy. MATERIALS: Search in PubMed/ Medline using the terms "chemotherapy AND intrathecal", analysis of secondary and tertiary information sources. RESULTS: The most widely used drugs in intrathecal therapy are methotrexate and cytarabine, at variable doses. One of the aspects with higher variability among different studies is their potential combination with a glucocorticoid, the specific corticoid selected and its dose. The efficacy and toxicity of the different combinations have not been compared. Regarding preparation, it is worth highlighting the recommendation to adjust pH and osmolarity to the physiological range, with the aim of improving tolerability. The volume of administration can influence distribution, and recommendated range is between 5 and 12 mL. Overall, it is recommended to extract a similar volume of cerebrospinal fluid before administration. The position of the patient during and after administration can have an impact on distribution and toxicity; lateral decubitus or sitting position is recommended in the first case, and prone and/ or supine position in the second one. Most publications don't explain how the treatment has been prepared or administered, and the lack of standardization could affect results. CONCLUSIONS: There is a great variability in practice when using intrathecal chemotherapy, despite being an effective therapy, accepted by all international groups. This uncertainty is not li mited to the drugs and doses administered, but it also includes the manner of preparation and the administration technique. The heterogeneity in clinical practice can influence the efficacy and toxicity of this therapy.

Introducción: La quimioterapia intratecal es utilizada frecuentemente, en la practica clinica, para el tratamiento y prevencion de la meningitis neoplasica. A pesar de su uso extendido, existe poca informacion acerca de aspectos practicos tales como el volumen de farmaco a administrar o la forma de preparacion y administracion. Objetivo: Realizar una revision de la literatura acerca de aspectos practicos de la utilizacion de la quimioterapia intratecal. MATERIAL: Busqueda en PubMed/Medline utilizando los terminos "chemotherapy AND intrathecal", analisis de fuentes de informacion secundarias y terciarias. Resultados: Los farmacos mas utilizados en terapia intratecal son metotrexato y citarabina, con dosis variables. La asociacion o no con un glucocorticoide, el corticoide concreto seleccionado y su dosis es uno de los aspectos con mayor variabilidad entre distintos estudios. No se han comparado la eficacia y toxicidad de las distintas combinaciones. En la preparacion destaca la recomendacion de ajustar pH y osmolaridad al rango fisiologico, con el objetivo de mejorar la tolerancia. El volumen de administracion puede influir en la distribucion, oscilando las recomendaciones entre 5-12 mL. En general, se aconseja extraer previamente un volumen de liquido cefalorraquideo similar. La posicion del paciente durante y tras la administracion puede influir en la distribucion y la toxicidad; se recomienda el decubito lateral o la sedestacion, en el primer caso, y el decubito prono y/o supino, en el segundo. La mayoria de las publicaciones no indican como se ha preparado o administrado el tratamiento, y la falta de estandarizacion podria afectar a los resultados. Conclusiones: Existe gran variabilidad en la practica a la hora de utilizar la quimioterapia intratecal, a pesar de ser una terapia efectiva asumida por todos los grupos internacionales. La incertidumbre no se limita a los farmacos y dosis administradas, sino que se extiende a la forma de preparacion de las mezclas y la tecnica de administracion. La heterogeneidad en la practica clinica puede influir en la efectividad y toxicidad de esta terapia.

Pharmacokinetics (PK), pharmacodynamics (PD), and PK-PD integration of ceftiofur after a single intravenous, subcutaneous and subcutaneous-LA administration in lactating goats.

BACKGROUND: Bacterial pneumonia in goats is usually caused by Mannheimia haemolytica and Pasteurella multocida. Another important infection disease in lactating goats is intramammary infection producing mastitis, usually associated with coagulase-negative Staphylococcus spp. However, treatment of bacterial pneumonia in goats not affected by mastitis problems should be restricted to antimicrobials with scant penetration to milk in order to avoid long withdrawal times. Ceftiofur is a third-generation cephalosporin antimicrobial with activity against various gram-positive and gram-negative, aerobic and anaerobic bacteria encountered by domestic animals. The objectives of the present study were to establish the serum concentration-time profile for ceftiofur in lactating goats after intravenous, subcutaneous and a SC-long-acting ceftiofur formulation; to determine ceftiofur penetration into milk; to determine in vitro and ex vivo activity of ceftiofur establishing MIC, MBC, MPC and time-kill profiles against field strains of M. haemolytica and finally to calculate the main surrogate markers of efficacy. RESULTS: The pharmacokinetics studies revealed an optimal PK properties for the SC-LA formulation tested. Ceftiofur was well absorbed following SC and SC-LA administration, with absolute bioavailabilities (F) of 85.16 and 84.43 %, respectively. After ceftiofur analysis from milk samples, no concentrations were found at any sampling time. The MIC, MBC and MPC data of ceftiofur against five M. haemolytica strains isolated from goats affected by pneumonia were tested showing excelent sensitivity of ceftiofur against this pathogen. For PK-PD analysis, ratios were calculated suggesting a high level of bacterial kill against the five strains of M. haemolytica tested. CONCLUSIONS: The systemic ceftiofur exposure achieved in lactating goats following IV, SC and especially with the SC-LA administration is consistent with the predicted PK-PD ratios needed for a positive therapeutic outcome for M. haemolytica. Subcutaneous administration of the long-acting formulation showed safety and tolerance for all the animals used. Ceftiofur concentrations exceeded the MIC and MBC for up to 72 h and MPC for up 32 h in serum. Thus, this drug could be effective in treating infectious diseases of goats caused by M. haemolytica at a dose of 6 mg/kg with the SC-LA formulation.

Stability of four standardized preparations of methotrexate, cytarabine, and hydrocortisone for intrathecal use.

INTRODUCTION: Intrathecal administration of methotrexate, cytarabine, and hydrocortisone is commonly used to treat and prevent central nervous system involvement in leukemias and lymphomas. The use of intrathecal solutions with pH and osmolarity values close to physiologic range of CSF (pH 7.31-7.37, osmolarity 281-306 mOsm/kg) and standardization of the methotrexate, cytarabine, and hydrocortisone doses in children and adults based on age is highly recommended. Stability studies of standardized intrathecal mixtures under these conditions have not yet been published. OBJECTIVE: The purpose of this study was to evaluate the physical and chemical stabilities of four standardized mixtures of methotrexate, cytarabine, and hydrocortisone stored at 2-8℃ and 25℃ up to 7 days after preparation. METHODS: Four different standardized intrathecal mixtures were prepared and stored at 2-8℃ and 25℃ and protected from light. Triplicate samples were taken at different times and precipitation, appearance, color, pH, and osmolarity were analyzed. Methotrexate, cytarabine, and hydrocortisone concentrations were measured using a modified high-performance liquid chromatography method. RESULTS: No variation greater than 10% of the initial concentration of methotrexate, cytarabine, and hydrocortisone was observed in any of the four standardized mixtures for the 7 days of study when stored at 2-8℃ and 25℃ and protected from light. The osmolarity of the four preparations was within the physiologic range of CSF for 7 days at both 2-8℃ and 25℃. The pH values close to the physiologic range of CSF were stable for 48 h at 25℃ and for 120 h at 2-8℃. CONCLUSIONS: Triple intrathecal standardized preparations of methotrexate, cytarabine, and hydrocortisone sodium phosphate are physically and chemically stable at 25℃ for 48 h and at 2-8℃ for 5 days.

Pharmacokinetics of an ampicillin-sulbactam combination after intravenous and intramuscular administration to neonatal calves.

The pharmacokinetics of a 2:1 ampicillin-sulbactam combination after intravenous (i.v.) and intramuscular (i.m.) injection at a single dose rate of 20 mg/kg bodyweight (13.33 mg/kg of sodium ampicillin and 6.67 mg/kg of sodium sulbactam) were studied in 10-day-old neonatal calves (n = 10). The plasma concentration-time data of both antibiotics were best fitted to an open two-compartment model after i.v. administration. After i.m. administration, an open two-compartment model demonstrated first order absorption. The apparent volumes of distribution of ampicillin and sulbactam, calculated by the area method, were 0.20+/-0.01 and 0.18+/-0.01 L/kg, respectively, and the total body clearances were 0.51+/-0.03 and 0.21+/-0.01 L/kg h. The elimination half-lives of ampicillin after i.v. and i.m. administration were 0.99+/-0.03 and 1.01+/-0.02 h, respectively, whereas for sulbactam the half-lives were 2.24+/-0.02 and 3.44+/-0.94 h. The bioavailability after i.m. injection was high and similar for both drugs (70.31+/-0.2% for ampicillin and 68.62+/-4.44% for sulbactam). The mean peak plasma concentrations of ampicillin and sulbactam were reached at similar times (0.47+/-0.02 and 0.72+/-0.01 h, respectively) and peak concentrations were also similar but not proportional to the dose administered (17.88+/-0.91 mg/L of ampicillin and 12.92+/-0.79 mg/L of sulbactam). Both drugs had similar pharmacokinetic behaviour after i.m. administration. Since the plasma concentrations of sulbactam were consistently higher during the elimination phase of their disposition, consideration could be given to formulating the ampicillin-sulbactam combination in a ratio higher than 2:1.