Effect of pH, mucin and bovine serum on rifampicin permeability through Caco-2 cells.

Rifampicin, a poorly soluble drug, has great importance in therapeutics as it is the main drug used to treat tuberculosis. The characterization of its permeability and the factors that influence it represent an important tool for predicting its bioavailability. Caco-2 cell monolayers were used as models of the intestinal mucosa to assess the uptake and transport of rifampicin and the effects of various experimental conditions were investigated, in order to establish the influence of these variables on rifampicin permeability. Different pHs (5.8, 6.8 and 7.4) in the apical medium, the presence or absence of mucin (3.0% w/v) in the donor site and the presence or absence of bovine serum albumin (4.0% v/v) in the receptor chamber were the evaluated conditions. The quantification of rifampicin in the apical or basolateral chambers was performed by a validated HPLC-UV method. The change in the donor chamber pH showed that permeability values were greater at pH 6.8, although this increase does not result in an alteration of the qualitative classification of rifampicin, which has high permeability. Mucin and bovine serum showed no effects on the permeability of rifampicin at the concentration tested. Overall, the current study suggests that pH, artificial mucin and bovine serum proteins have no influence on rifampicin permeability.

[Pharmacokinetic considerations in critically ill patients]. / Consideraciones farmacocinéticas en el paciente crítico.

Critically ill patients in Intensive Care Units (ICUs) are exposed to multiple procedures and usually require complex treatment regimens. Many of them suffer from comorbidities and different complications such as organ failure, drug-drug interactions, and unusual therapeutic interventions that can produce significant pathophysiologic changes. For that reason, pharmacokinetics for several substances is different to what is described for healthy patients, complicating drug selection and drug dosage to achieve appropriate effects. Low doses may determine a reduction of drug effectiveness and overdoses leading to toxicity. The aim of this paper is to review the pharmacokinetic considerations that must be considered when treating acute ICU patients.

Comparative studies on polyelectrolyte complexes and mixtures of chitosan-alginate and chitosan-carrageenan as prolonged diltiazem clorhydrate release systems.

The aim of this work was to evaluate the possibility of using mixtures and/or polyelectrolyte complexes from both chitosan-alginate and chitosan-carrageenan as prolonged drug release systems. Different dissolution profiles were obtained by changing the polymer matrix system (chitosan-alginate or chitosan-carrageenan) and the method used to include these polymers into the formulation (physical mixture or polyelectrolyte complex). Drug dissolution profiles from the matrices have been discussed by considering the swelling behavior of the polymers used. The swelling behavior of the chitosan-carrageenan and chitosan-alginate systems was analyzed by using the Hopfenberg model which permits to separate the diffusional contribution, kf, from the relaxational contribution, kr, involved in solvent penetration/sorption in glassy polymers. The chitosan-alginate system is better than the chitosan-carrageenan system as prolonged drug release matrix because the drug release is controlled at low percentage of the polymers in the formulation, the mean dissolution time is high, and different dissolution profiles could be obtained by changing the mode of inclusion of the polymers. Good agreement between td and kf/kr values for the system chitosan-alginate was found, which means that the swelling behavior of the polymers controlled the drug release from the matrix. In the case of the system chitosan-carrageenan, the high capacity of carrageenan promotes the entry of water into the tablet and therefore the main mechanism of drug release would be the disintegration instead of the swelling of the matrix.

Population pharmacokinetics and dose simulation of vancomycin in critically ill patients during high-volume haemofiltration.

This study aimed to describe the population pharmacokinetics of vancomycin in critically ill patients with refractory septic shock undergoing continuous venovenous high-volume haemofiltration (HVHF) and to define appropriate dosing for these patients. This was a prospective pharmacokinetic study in the ICU of a university hospital. Eight blood samples were taken over one vancomycin dosing interval. Samples were analysed by a validated liquid chromatography-tandem mass spectrometry assay. Non-linear mixed-effects modelling was used to describe the population pharmacokinetics. Dosing simulations were used to define therapeutic vancomycin doses for different HVHF settings. Nine patients were included (five male). The mean weight and SOFA score were 70 kg and 11, respectively. Mean HVHF settings were: blood flow rate, 240 mL/min; and haemofiltration exchange rate, 100 mL/kg/h. A linear two-compartment model with zero-order input adequately described the data. Mean parameter estimates were: clearance, 2.9 L/h; volume of distribution of central compartment (V(1)), 11.8L; volume of distribution of peripheral compartment (V(2)), 18.0 L; and intercompartmental clearance, 9.3 L/h. HVHF intensity was strongly associated with vancomycin clearance (P < 0.05) and was a covariate in the final model. Simulations indicate that after a loading dose, vancomycin doses required for different HVHF intensities would be 750 mg every 12h (q12h) for 69 mL/kg/h, 1000 mg q12h for 100 mL/kg/h and 1500 mg q12h for 123 mL/kg/h. Continuous infusion would also be a valuable administration strategy. In conclusion, variable and much higher than standard vancomycin doses are required to achieve therapeutic concentrations during different HVHF settings.

An HPLC method for determination of azadirachtin residues in bovine muscle.

A high-performance liquid chromatography (HPLC) method for the determination of azadirachtin (A and B) residues in bovine muscle has been developed. Azadirachtin is a neutral triterpene and chemotherapeutic agent effective in controlling some pest flies in horses, stables, horns and fruit. The actual HPLC method uses an isocratic elution and UV detection. Liquid-liquid extraction and solid-phase purification was used for the clean-up of the biological matrix. The chromatographic determination of these components is achieved using a C18 analytical column with water-acetonitrile mixture (27.5:72.5, v/v) as mobile phase, 1 mL/min as flow rate, 45 °C column temperature and UV detector at 215 nm. The azadirachtin peaks are well resolved and free of interference from matrix components. The extraction and analytical method developed in this work allows the quantitation of azadirachtin with precision and accuracy, establishing a lower limit of quantitation of azadirachtin, extracted from the biological matrix.

Consideraciones farmacocinéticas en el paciente crítico / Pharmacokinetic considerations in critically ill patients

Background: Critically ill patients in Intensive Care Units (ICUs) are exposed to multiple procedures and usually require complex treatment regimens. Many of them suffer from comorbidities and different complications such as organ failure, drug-drug interactions, and unusual therapeutic interventions that can produce significant pathophysiologic changes. For that reason, pharmacokinetics for several substances is different to what is described for healthy patients, complicating drug selection and drug dosage to achieve appropriate effects. Low doses may determine a reduction of drug effectiveness and overdoses leading to toxicity. The aim of this paper is to review the pharmacokinetic considerations that must be considered when treating acute ICU patients.