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The aim of the present study was to show that the physiological variability of fasted gastric pH and tablet gastric retention time contributes to the overall variability of simulated ...plasma profiles of diclofenac. Those two parameters were implemented into dissolution study and plasma profiles were simulated under assumptions that in vitro dissolution well represents that occurring in vivo, and that absorption profiles are identical to dissolution profiles, as diclofenac is a highly permeable drug. Dissolution experiments were performed using USP 2 apparatus and two consecutive dissolution media, namely, an acidic medium of various pH (ranging from 1–3), where tablets were kept for a certain time (10–200min), and phosphate buffer (pH 6.8). It was shown that the acid pH value and acid retention time of tablets affect in vitro drug release, and consequently also influence the simulated plasma profiles. Lower acid pH resulted in lower plasma peaks at each studied acid retention time. Longer acid retention time caused lower plasma concentrations at lower acid pH values, whereas at pH 3 higher plasma concentrations were noted. Additionally, it was demonstrated that the variability of both parameters represents an important contribution to the overall variability of plasma profiles.
Background
After surgical procedures, patients are at high risk of developing venous thromboembolism, clinically manifested as deep vein thrombosis (DVT) or pulmonary embolism (PE).
Objective
To ...evaluate the influence of polypharmacotherapy, comorbidity, drug treatments, packed red blood cells application, adequacy of thromboprophylaxis, and patient characteristics on the occurrence of DVT or PE in postsurgical patients.
Setting
The surgical department at Murska Sobota General Hospital, Slovenia.
Methods
In this retrospective case control study, the records of 286 surgical patients were analysed: DVT or PE group (n = 144) and control group (n = 142). The number of prescribed drugs and drug–drug interactions were reviewed, together with prescription of low-molecular-weight heparins. The odds ratios (OR) of risk factors for DVT or PE were calculated using a multivariable logistic regression model.
Main outcome measure
Risk factors assessment for the occurrence of DVT or PE in surgical patients.
Results
Polypharmacotherapy (OR 2.02, 95% CI 1.03–3.96,
p
= 0.040) and packed red blood cells application (OR 3.44, 95% CI 1.46–8.10,
p
= 0.005) were associated with an increased risk of PE or DVT after surgery. Inadequate thromboprophylaxis with low-molecular-weight heparins significantly increased the likelihood of DVT or PE (OR 2.50, 95% CI 1.41–4.43,
p
= 0.002). There were no differences between the groups concerning the treatment with nonsteroidal anti-inflammatory drugs, benzodiazepines or antipsychotics.
Conclusions
Patients with polypharmacotherapy and patients receiving red blood cells should be monitored more closely after surgery as they are more likely to develop DVT or PE.
The objective of the present study was to check for the possibility to successfully predict individual in vivo dissolution/absorption profiles resulting from fasted administration of a diclofenac ...extended release pellet formulation. For this purpose dissolution profiles were generated with different dissolution setups using a set of media reflecting pH-conditions in the different segments of the gastrointestinal tract. Since gastric emptying of pellets seemed to be a critical factor for in vivo drug release, a set of different gastric residence times was screened in in vitro studies. Subsequently, in vitro release profiles were first directly compared with the individual in vivo absorption profiles and in a second step a mathematical model, which had been developed in a previous study, was applied to calculate predicted individual in vivo release profiles based on in vitro release profiles and individual gastric emptying. The comparison of predicted individual in vivo release profiles and individual in vivo absorption profiles showed a high degree of similarity, thus confirming the suitability of a set of different gastric residence times used in in vitro drug release testing. Additionally, obtained results indicated that a substantial part of variability of diclofenac absorption profiles can be explained by the variability of pellet gastric emptying kinetics.
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To develop a consensus-based set of generic competencies in antimicrobial prescribing and stewardship for European prescribers through a structured consensus procedure.
The RAND-modified Delphi ...procedure comprised two online questionnaire rounds, a face-to-face meeting between rounds, and a final review. Our departure point was a set of competencies agreed previously by consensus among a UK multi-disciplinary panel, and which had been subsequently revised through consultation with ESCMID Study Group representatives. The 46 draft competency points were reviewed by an expert panel consisting of specialists in infectious diseases and clinical microbiology, and pharmacists. Each proposed competency was assessed using a nine-point Likert scale, for relevance as a minimum standard for all independent prescribers in all European countries.
A total of 65 expert panel members participated, from 24 European countries (one to six experts per country). There was very high satisfaction (98%) with the final competencies set, which included 35 competency points, in three sections: core concepts in microbiology, pathogenesis and diagnosing infections (11 points); antimicrobial prescribing (20 points); and antimicrobial stewardship (4 points).
The consensus achieved enabled the production of generic antimicrobial prescribing and stewardship competencies for all European independent prescribers, and of possible global utility. These can be used for training and can be further adapted to the needs of specific professional groups.
An assay comprising two simple, selective and isocratic HPLC methods with UV detection was developed and validated for measuring warfarin enantiomers and all five warfarin monohydroxylated ...metabolites in patient blood plasma. Following liquid/liquid extraction from 1 ml of blood plasma a baseline separation of analytes was achieved on chiral (alpha(1) acid glycoprotein - AGP) and achiral (C(18)) column. Both methods were consistent (R.S.D.<6.9% for warfarin enantiomers and<8.9% for monohydroxylated metabolites) and linear (r>0.998). The limits of detection were 25 ng/ml for warfarin enantiomers, 25 ng/ml for 4'-, 10-, 6- and 7-hydroxywarfarin, 35 ng/ml for 8-hydroxywarfarin and 50 ng/ml for racemic warfarin. In a clinical study in 204 patients, it was confirmed that the assay is appropriate for evaluation of influences of genetic polymorphisms, demographic factors and concomitant drug treatment on warfarin metabolism.
Nitrendipine is an effective and safe calcium-channel blocker for the treatment of mild to moderate hypertension. The aim of this study is to show that an artificial neural network (ANN) model of the ...relationship between nitrendipine plasma levels and pharmacodynamic effects can be built and used for pressure-drop prediction after oral administration of the drug in spite of the poor correlation between plasma concentrations and the effect. To achieve the goal, the following steps were taken: evaluation of the quality of the database for training the ANN, definition of the optimal input set for the ANN, and prediction of the diastolic pressure drop using the ANN. The possible consequences of successful ANN modelling are an optimisation of the drug administration regimen, to achieve the best possible effect, as well as optimal drug formulation for drugs with complicated pharmacokinetic/pharmacodynamic relationships.
The aim of this work was to define the time of microsphere solidification during the solvent evaporation process. Microspheres were prepared by the solvent evaporation method, using acetone liquid ...paraffin solvent system, ketoprofen as a model drug and Eudragit RS as a matrix polymer. Two sets of experiments were performed-in the first one the initial temperature of the emulsion system was 5°C and in the second one 25°C. In each set, two batches of microspheres were compared at constant emulsion stirring rate 250 and 1000 rpm and intermediate batches where the emulsion stirring rate was lowered from 1000 to 250 rpm at pre-defined times after the beginning of the inner phase solvent evaporation. By comparison of the properties of these microspheres, an insight was obtained into the mechanism of microspheres formation. The criterion for determination of microsphere solidification time was the resemblance between the microsphere properties of the batches prepared by stirring rate change and the batch prepared by constant stirring at 1000 rpm. A stirring rate change after the solidification has no influence on microsphere properties, that means that they are the same as of the batch prepared by constant stirring at 1000 rpm. The results of the sieve analysis and particle size distribution of microspheres show that the time of microspheres solidification is in the interval between 15-20 min if the initial temperature is 5°C and between 10-20 min if the initial temperature is 25°C. From the release profiles of ketoprofen, one can infer that the times of solidification for both initial temperatures are a bit lower. The microscopic pictures, which enable one to follow the processes in the system, confirmed the result obtained by the sieve analysis. In spite of its inability to distinguish between single particles and agglomerates, the sieve analysis enabled one to determine the actual time of solidification, while the drug release determination was not sensitive enough to trace small differences in surface area due to particles aggregation.
The influence of interactions between polycarbophil and calcium on a model drug permeation into the pig urinary bladder wall was investigated. Pipemidic acid was used as a model drug. One percent w/v ...polycarbophil dispersion significantly increases the permeation of pipemidic acid into the urinary bladder wall. The enhanced absorption of pipemidic acid caused by polycarbophil is significantly less pronounced in polycarbophil dispersions containing calcium. The enhancement of pipemidic acid permeation into the urinary bladder wall could be due to the opening of tight junctions, which causes higher paracellular permeability. In the case of polycarbophil dispersion with calcium some carboxylic groups of polymer are already occupied with calcium, present in the dispersions. As a consequence extracellular calcium binds to polycarbophil in lower extent if compared with polycarbophil dispersion without calcium and transport is increased to a lesser degree. We concluded that the mechanism of drug absorption enhancement caused by polycarbophil could be similar for urinary bladder as described in the literature for intestinal mucosa.
Microspheres containing the mucoadhesive polymer chitosan hydrochloride, with matrix polymer Eudragit RS, pipemidic acid as a model drug and agglomeration preventing agent magnesium stearate were ...prepared by the solvent evaporation method. The amount of magnesium stearate was varied and the following methods were used for microsphere evaluation: sieve analysis, drug content and dissolution determination, scanning electron microscopy, xray diffractometry, DSC and FTIR spectroscopy. The results showed that average particle size decreased with increasing amount of magnesium stearate used for microsphere preparation. This is probably a consequence of stabilization of the emulsion droplets with magnesium stearate. Higher pipemidic acid content in the microspheres was observed in larger particle size fractions and when higher amounts of magnesium stearate were used. It was also found that these two parameters significantly influenced the dissolution rate. The important reason for the differences in drug content in microspheres of different particle sizes is the diffusion of pipemidic acid from the acetone droplets in liquid paraffin during the preparation procedure. The physical state of pipemidic acid changed from crystalline to mostly amorphous with its incorporation in microspheres, as shown by x-ray diffractometry and differential
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